Effects of anatomy and diet on gastrointestinal pH in rodents.

PubMed

Kohl, Kevin D; Stengel, Ashley; Samuni-Blank, Michal; Dearing, M Denise

2013-04-01

The pH of the gastrointestinal tract can have profound influences on digestive processes. Rodents exhibit wide variation in both stomach morphology and dietary strategies, both of which may influence gut pH. Various rodent species have evolved bilocular (or semi-segmented) stomachs that may allow for more microbial growth compared to unilocular (single-chambered) stomachs. Additionally, herbivory has evolved multiple times in rodents. The high dietary fiber typical of an herbivorous diet is known to induce secretion of bicarbonate in the gut. We predicted that stomach segmentation might facilitate the separation of contents in the proximal chamber from that of the gastric stomach, facilitating a chemical environment suitable to microbial growth. To investigate the effect of stomach anatomy and diet on gut pH, several species of rodent with varying stomach morphology were fed either a high or low-fiber diet for 7 days, and pH of the proximal stomach, gastric stomach, small intestine, and cecum were measured. We discovered that rodents with bilocular stomach anatomy maintained a larger pH gradient between the proximal and gastric stomach compartments, and were able to achieve a lower absolute gastric pH compared to those with unilocular stomachs. Dietary fiber increased the pH of the small intestine, but not in any other gut regions. The stomach pH data supports the century old hypothesis that bilocular stomach anatomy creates an environment in the proximal stomach that is suitable for microbial growth. Additionally, the alkaline small intestinal pH on a high fiber diet may enhance digestion. Copyright © 2013 Wiley Periodicals, Inc.

Animal models for prenatal gene therapy: rodent models for prenatal gene therapy.

PubMed

Roybal, Jessica L; Endo, Masayuki; Buckley, Suzanne M K; Herbert, Bronwen R; Waddington, Simon N; Flake, Alan W

2012-01-01

Fetal gene transfer has been studied in various animal models, including rabbits, guinea pigs, cats, dogs, and nonhuman primate; however, the most common model is the rodent, particularly the mouse. There are numerous advantages to mouse models, including a short gestation time of around 20 days, large litter size usually of more than six pups, ease of colony maintenance due to the small physical size, and the relatively low expense of doing so. Moreover, the mouse genome is well defined, there are many transgenic models particularly of human monogenetic disorders, and mouse-specific biological reagents are readily available. One criticism has been that it is difficult to perform procedures on the fetal mouse with suitable accuracy. Over the past decade, accumulation of technical expertise and development of technology such as high-frequency ultrasound have permitted accurate vector delivery to organs and tissues. Here, we describe our experiences of gene transfer to the fetal mouse with and without ultrasound guidance from mid to late gestation. Depending upon the vector type, the route of delivery and the age of the fetus, specific or widespread gene transfer can be achieved, making fetal mice excellent models for exploratory biodistribution studies.

Animal Models of Diabetic Retinopathy: Summary and Comparison

PubMed Central

Lo, Amy C. Y.

2013-01-01

Diabetic retinopathy (DR) is a microvascular complication associated with chronic exposure to hyperglycemia and is a major cause of blindness worldwide. Although clinical assessment and retinal autopsy of diabetic patients provide information on the features and progression of DR, its underlying pathophysiological mechanism cannot be deduced. In order to have a better understanding of the development of DR at the molecular and cellular levels, a variety of animal models have been developed. They include pharmacological induction of hyperglycemia and spontaneous diabetic rodents as well as models of angiogenesis without diabetes (to compensate for the absence of proliferative DR symptoms). In this review, we summarize the existing protocols to induce diabetes using STZ. We also describe and compare the pathological presentations, in both morphological and functional aspects, of the currently available DR animal models. The advantages and disadvantages of using different animals, ranging from zebrafish, rodents to other higher-order mammals, are also discussed. Until now, there is no single model that displays all the clinical features of DR as seen in human. Yet, with the understanding of the pathological findings in these animal models, researchers can select the most suitable models for mechanistic studies or drug screening. PMID:24286086

A new method to model electroconvulsive therapy in rats with increased construct validity and enhanced translational value.

PubMed

Theilmann, Wiebke; Löscher, Wolfgang; Socala, Katarzyna; Frieling, Helge; Bleich, Stefan; Brandt, Claudia

2014-06-01

Electroconvulsive therapy is the most effective therapy for major depressive disorder (MDD). The remission rate is above 50% in previously pharmacoresistant patients but the mechanisms of action are not fully understood. Electroconvulsive stimulation (ECS) in rodents mimics antidepressant electroconvulsive therapy (ECT) in humans and is widely used to investigate the underlying mechanisms of ECT. For the translational value of findings in animal models it is essential to establish models with the highest construct, face and predictive validity possible. The commonly used model for ECT in rodents does not meet the demand for high construct validity. For ECT, cortical surface electrodes are used to induce therapeutic seizures whereas ECS in rodents is exclusively performed by auricular or corneal electrodes. However, the stimulation site has a major impact on the type and spread of the induced seizure activity and its antidepressant effect. We propose a method in which ECS is performed by screw electrodes placed above the motor cortex of rats to closely simulate the clinical situation and thereby increase the construct validity of the model. Cortical ECS in rats induced reliably seizures comparable to human ECT. Cortical ECS was more effective than auricular ECS to reduce immobility in the forced swim test. Importantly, auricular stimulation had a negative influence on the general health condition of the rats with signs of fear during the stimulation sessions. These results suggest that auricular ECS in rats is not a suitable ECT model. Cortical ECS in rats promises to be a valid method to mimic ECT. Copyright © 2014 Elsevier Ltd. All rights reserved.

Diurnal rhythms in peripheral blood immune cell numbers of domestic pigs.

PubMed

Engert, Larissa C; Weiler, Ulrike; Pfaffinger, Birgit; Stefanski, Volker; Schmucker, Sonja S

2018-02-01

Diurnal rhythms within the immune system are considered important for immune competence. Until now, they were mostly studied in humans and rodents. However, as the domestic pig is regarded as suitable animal model and due to its importance in agriculture, this study aimed to characterize diurnal rhythmicity in porcine circulating leukocyte numbers. Eighteen pigs were studied over periods of up to 50 h. Cosinor analyses revealed diurnal rhythms in cell numbers of most investigated immune cell populations in blood. Whereas T cell, dendritic cell, and eosinophil counts peaked during nighttime, NK cell and neutrophil counts peaked during daytime. Relative amplitudes of cell numbers in blood differed in T helper cell subtypes with distinctive differentiation states. Mixed model analyses revealed that plasma cortisol concentration was negatively associated with cell numbers of most leukocyte types, except for NK cells and neutrophils. The observed rhythms mainly resemble those found in humans and rodents. Copyright © 2017 Elsevier Ltd. All rights reserved.

How many species of mammals are there in Brazil? New records of rare rodents (Rodentia: Cricetidae: Sigmodontinae) from Amazonia raise the current known diversity

PubMed Central

2017-01-01

Background Since 1996, when Vivo questioned how many species of mammals occur in Brazil, there has been a huge effort to assess this biodiversity. In this contribution, we present new records for rare species of the sigmodontine rodent genera Rhagomys and Neusticomys previously unknown to Brazilian Amazon. We provided detailed information on the morphologic variation to allow the proper identification of these species. We also furnished updated information on their collection, aiming to establish hypothesis of their geographic distribution, based on SDM’s, aiming to hypothesize potential occurrence areas for these species. Methods Rodent specimens were sampled in separate inventories in two sites of Rondônia State (Hydroelectric Dam Jirau and Parque Nacional de Pacaás Novos) and one site in Pará State (Pacajá), Brazil, and were compared to specimens from museum collections to apply appropriate names. The SDM were conducted using two algorithms for rare species, MaxEnt and randomForest (RF), and were based on seven localities for Rhagomys, and 10 for Neusticomys. Results All specimens were collected with pitfall traps. One specimen of genus Rhagomys was trapped in the Hydroelectric Dam Jirau. We identified this specimen as R. longilingua, and the SDM species indicates suitable areas for its occurrence at high elevations near on the Andes and lowlands of Amazon Basin to the South of the Rio Amazonas. Two specimens of Neusticomys were recorded, and we identified the specimen from Pacaás Novos as N. peruviensis, with SDM suggesting main areas of occurrence on Western Amazon. We applied the name N. ferreirai to the specimen from Pacajá, with SDM recovering suitable areas in Eastern Amazon. Discussion We reinforced the importance of pitfall traps on the study of Neotropical rodents. We described morphologic variation within and among all species that do not invalidate their specific status, but in the near future a re-evaluation will be mandatory. The new records extended the species distribution considerably. SDM was successful to predict their distributions, as the two algorithms presented important differences in range size recovered by the models that can be explained by differences in the thresholds used for the construction of the models. Most suitable areas coincide with the areas facing most of the deforestation in Amazon. We added two rare species of sigmodontine rodents to the list of Brazilian Mammals, which now comprises 722 species (or 775 valid nominal taxa). Although more information is available than in 1996, it is essential that mammal experts maintain inventory and revisionary programs to update and revise this information. This is even more important, as changes in Brazilian environmental legislation are being discussed, suggesting reduced need for environmental impact reports prior to beginning commercial enterprises, resulting in the loss of information about native biodiversity in the affected areas. PMID:29259840

How many species of mammals are there in Brazil? New records of rare rodents (Rodentia: Cricetidae: Sigmodontinae) from Amazonia raise the current known diversity.

PubMed

Percequillo, Alexandre R; Dalapicolla, Jeronymo; Abreu-Júnior, Edson F; Roth, Paulo Ricardo O; Ferraz, Katia M P M B; Chiquito, Elisandra A

2017-01-01

Since 1996, when Vivo questioned how many species of mammals occur in Brazil, there has been a huge effort to assess this biodiversity. In this contribution, we present new records for rare species of the sigmodontine rodent genera Rhagomys and Neusticomys previously unknown to Brazilian Amazon. We provided detailed information on the morphologic variation to allow the proper identification of these species. We also furnished updated information on their collection, aiming to establish hypothesis of their geographic distribution, based on SDM's, aiming to hypothesize potential occurrence areas for these species. Rodent specimens were sampled in separate inventories in two sites of Rondônia State (Hydroelectric Dam Jirau and Parque Nacional de Pacaás Novos) and one site in Pará State (Pacajá), Brazil, and were compared to specimens from museum collections to apply appropriate names. The SDM were conducted using two algorithms for rare species, MaxEnt and randomForest (RF), and were based on seven localities for Rhagomys , and 10 for Neusticomys . All specimens were collected with pitfall traps. One specimen of genus Rhagomys was trapped in the Hydroelectric Dam Jirau. We identified this specimen as R. longilingua , and the SDM species indicates suitable areas for its occurrence at high elevations near on the Andes and lowlands of Amazon Basin to the South of the Rio Amazonas. Two specimens of Neusticomys were recorded, and we identified the specimen from Pacaás Novos as N. peruviensis , with SDM suggesting main areas of occurrence on Western Amazon. We applied the name N. ferreirai to the specimen from Pacajá, with SDM recovering suitable areas in Eastern Amazon. We reinforced the importance of pitfall traps on the study of Neotropical rodents. We described morphologic variation within and among all species that do not invalidate their specific status, but in the near future a re-evaluation will be mandatory. The new records extended the species distribution considerably. SDM was successful to predict their distributions, as the two algorithms presented important differences in range size recovered by the models that can be explained by differences in the thresholds used for the construction of the models. Most suitable areas coincide with the areas facing most of the deforestation in Amazon. We added two rare species of sigmodontine rodents to the list of Brazilian Mammals, which now comprises 722 species (or 775 valid nominal taxa). Although more information is available than in 1996, it is essential that mammal experts maintain inventory and revisionary programs to update and revise this information. This is even more important, as changes in Brazilian environmental legislation are being discussed, suggesting reduced need for environmental impact reports prior to beginning commercial enterprises, resulting in the loss of information about native biodiversity in the affected areas.

Long-term population patterns of rodents and associated damage in German forestry.

PubMed

Imholt, Christian; Reil, Daniela; Plašil, Pavel; Rödiger, Kerstin; Jacob, Jens

2017-02-01

Several rodent species can damage forest trees, especially at young tree age in afforestation. Population outbreaks of field voles (Microtus agrestis L.) and bank voles (Myodes glareolus Schreber) in particular can cause losses. Analyses of long-term time series indicate good synchrony of population abundance in rodent species associated with damage in forestry. This synchrony could be related to the effect of beech (Fagus spec.) mast in the previous year on population growth rates of both species. In shorter time series from Eastern Germany, damage in forestry was mostly associated with autumn abundances of rodents. Environmental factors such as beech mast and snow cover did not explain additional variation in rodent damage to trees. Beech mast is a good indicator of long-term rodent abundance in Northern German afforestation areas. However, rodent damage to forestry in Central Germany did not seem to depend on environmental parameters other than rodent abundance at large scale. As a result, there is still uncertainty about the link between environmental predictors and rodent damage to forestry, and further experimental work is required to identify suitable environmental drivers and their interplay with other potential factors such as the local predator community. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Regulatory acceptability of the minipig in the development of pharmaceuticals, chemicals and other products.

PubMed

van der Laan, Jan Willem; Brightwell, John; McAnulty, Peter; Ratky, Joszef; Stark, Claudia

2010-01-01

As part of the RETHINK European FP6 Project an overview of the acceptability and usefulness of minipigs has been carried out in the regulatory arenas of human and veterinary pharmaceuticals, food additives, cosmetics, biocides and agrochemicals, chemicals and medical devices. The safety of new pharmaceuticals for human use should be tested in non-rodents, but the regulatory world is not too prescriptive regarding the choice of species. The choice is most often dogs through long tradition. When dogs are not appropriate, in many cases non-human primates are chosen as an alternative. From information in the public domain as well as literature from the EMA and FDA, it is clear that minipigs have already been identified as suitable to take the role of non-rodent species in toxicity testing of pharmaceutical products. In the field of foodstuffs, the pig is used more extensively because of the apparent similarity in the omnivorous food pattern and digestive tract between humans and pigs. The extensive use of pigs in this field provides historical data. In the field of medical devices the ISO Guidelines indicate that the pig is regarded as a suitable animal model because of its haematological and cardiovascular similarities to man. The pig is also mentioned as suitable for testing local effects after implantation. Political and societal support for using nonhuman primates is decreasing, and it is an appropriate time to consider the role of the minipig. We have reviewed the costs of testing in minipigs, and these are not significantly higher than the costs for a study in dogs. Economical reasons should therefore not be used to argue against the use of minipigs instead of dogs or monkeys. For most purposes, minipigs may be considered an acceptable choice as non-rodent species, provided adequate justification for this choice is made. Copyright © 2010 Elsevier Inc. All rights reserved.

Visual pigment coexpression in all cones of two rodents, the Siberian hamster, and the pouched mouse.

PubMed

Lukáts, Akos; Dkhissi-Benyahya, Ouria; Szepessy, Zsuzsanna; Röhlich, Pál; Vígh, Béla; Bennett, Nigel C; Cooper, Howard M; Szél, Agoston

2002-07-01

To decide whether the identical topography of short- and middle-wavelength cone photoreceptors in two species of rodents reflects the presence of both opsins in all cone cells. Double-label immunocytochemistry using antibodies directed against short-wavelength (S)-and middle- to long-wavelength (M/L)-sensitive opsin were used to determine the presence of visual pigments in cones of two species of rodents, the Siberian hamster (Phodopus sungorus) and the pouched mouse (Saccostomus campestris) from South Africa. Topographical distribution was determined from retinal whole-mounts, and the colocalization of visual pigments was examined using confocal laser scanning microscopy. Opsin colocalization was also confirmed in consecutive semithin tangential sections. The immunocytochemical results demonstrate that in both the Siberian hamster and the pouched mouse all retinal cones contain two visual pigments. No dorsoventral gradient in the differential expression of the two opsins is observed. The retina of the Siberian hamster and the pouched mouse is the first example to show a uniform coexpression of M and S cone opsins in all cones, without any topographical gradient in opsin expression. This finding makes these two species good models for the study of molecular control mechanisms in opsin coexpression in rodents, and renders them suitable as sources of dual cones for future investigations on the role and neural connections of this cone type.

Plant Secondary Metabolites as Rodent Repellents: a Systematic Review.

PubMed

Hansen, Sabine C; Stolter, Caroline; Imholt, Christian; Jacob, Jens

2016-09-01

The vast number of plant secondary metabolites (PSMs) produced by higher plants has generated many efforts to exploit their potential for pest control. We performed a systematic literature search to retrieve relevant publications, and we evaluated these according to PSM groups to derive information about the potential for developing plant-derived rodent repellents. We screened a total of 54 publications where different compounds or plants were tested regarding rodent behavior/metabolism. In the search for widely applicable products, we recommend multi-species systematic screening of PSMs, especially from the essential oil and terpenoid group, as laboratory experiments have uniformly shown the strongest effects across species. Other groups of compounds might be more suitable for the management of species-specific or sex-specific issues, as the effects of some compounds on particular rodent target species or sex might not be present in non-target species or in both sexes. Although plant metabolites have potential as a tool for ecologically-based rodent management, this review demonstrates inconsistent success across laboratory, enclosure, and field studies, which ultimately has lead to a small number of currently registered PSM-based rodent repellents.

Pleistocene climatic oscillations in Neotropical open areas: Refuge isolation in the rodent Oxymycterus nasutus endemic to grasslands

PubMed Central

Peçanha, Willian T.; Althoff, Sergio L.; Galiano, Daniel; Quintela, Fernando M.; Maestri, Renan; Freitas, Thales R. O.

2017-01-01

Pleistocene climatic oscillations favoured the expansion of grassland ecosystems and open vegetation landscapes throughout the Neotropics, and influenced the evolutionary history of species adapted to such environments. In this study, we sampled populations of the rodent Oxymycterus nasutus endemic to open areas in the Pampas and Atlantic Forest biomes to assess the tempo and mode of population divergence using an integrative approach, including coalescence theory, ecological niche models, and morphometry. Our results indicated that these O. nasutus populations exhibited high levels of genetic structure. Six major mtDNA clades were found, structuring these biomes into distinct groups. Estimates of their divergence times was indicated to be 0.571 myr. The high degree of genetic structure is reflected in the analyses of geometric morphometric; skull differences between lineages in the two ecoregions were detected. During the last glacial maximum, there was a strong increase in suitable abiotic conditions for O. nasutus. Distinct molecular markers revealed a population expansion over time, with a possible demographic retraction during the post-glacial period. Considering that all clades coalesce with the last interglacial maximum, our results indicated that reduction in suitable conditions during this period may have resulted in a possible vicariance associated with refuge isolation. PMID:29176839

Gait Analysis Methods for Rodent Models of Osteoarthritis

PubMed Central

Jacobs, Brittany Y.; Kloefkorn, Heidi E.; Allen, Kyle D.

2014-01-01

Patients with osteoarthritis (OA) primarily seek treatment due to pain and disability, yet the primary endpoints for rodent OA models tend to be histological measures of joint destruction. The discrepancy between clinical and preclinical evaluations is problematic, given that radiographic evidence of OA in humans does not always correlate to the severity of patient-reported symptoms. Recent advances in behavioral analyses have provided new methods to evaluate disease sequelae in rodents. Of particular relevance to rodent OA models are methods to assess rodent gait. While obvious differences exist between quadrupedal and bipedal gait sequences, the gait abnormalities seen in humans and in rodent OA models reflect similar compensatory behaviors that protect an injured limb from loading. The purpose of this review is to describe these compensations and current methods used to assess rodent gait characteristics, while detailing important considerations for the selection of gait analysis methods in rodent OA models. PMID:25160712

First detection of Echinococcus multilocularis in rodent intermediate hosts in Turkey.

PubMed

Avcioglu, Hamza; Guven, Esin; Balkaya, Ibrahim; Kirman, Ridvan; Bia, Mohammed Mebarek; Gulbeyen, Hatice; Kurt, Ali; Yaya, Sali; Demirtas, Sadik

2017-11-01

Echinococcus multilocularis is the causative agent of alveolar echinococcosis (AE), a potentially fatal zoonotic disease. Large parts of Turkey are considered as endemic for E. multilocularis. The aim of this study was to determine the occurrence of metacestode of E. multilocularis in wild rodents in Erzurum, an endemic region for human AE in Turkey. During the sampling period, a total of 498 rodents were trapped in twenty counties of Erzurum Province. Suspected lesions were observed on the livers of 48 rodents, and then partial fragment of mitochondrial 12S rRNA gene was PCR-amplified. Five liver samples exhibited E. multilocularis infection. The prevalence of E. multilocularis for Microtus spp. was 1·3%. All of the infected rodents had fertile metacestodes. Infected rodents were morphologically and molecularly analysed and were confirmed to be Microtus irani by the mitochondrial cytochrome b gene sequence analysis. This is the first report of the presence of E. multilocularis in rodent intermediate hosts in Turkey. Our findings of infected M. irani with protoscoleces show that this rodent can act as suitable intermediate host for E. multilocularis' life cycle in Turkey. However, there was a complete lack of data on the infection of carnivores from the country. An extensive survey is recommended to determine the prevalence of E. multilocularis in definitive hosts in this endemic region.

Spacelab Life Sciences 1 results

NASA Technical Reports Server (NTRS)

Seddon, Rhea

1992-01-01

Results are presented from the experiments conducted by the first Shuttle/Spacelab mission dedicated entirely to the life sciences, the Spacelab Life Sciences 1, launched on June 5, 1991. The experiments carried out during the 9-day flight included investigations of changes in the human cardiovascular, pulmonary, renal/endocrine, blood, and vestibular systems that were brought about by microgravity. Results were also obtained from the preflight and postflight complementary experiments performed on rats, which assessed the suitability of rodents as animal models for humans. Most results verified, or expanded on, the accepted theories of adaptation to zero gravity.

Experimental models for aging and their potential for novel drug discovery.

PubMed

Folch, Jaume; Busquets, Oriol; Sánchez-López, Miren EttchetoElena; Pallàs, Mercè; Beas-Zarate, Carlos; Marin, Miguel; Casadesus, Gemma; Olloquequi, Jordi; Auladell, Carme; Camins, Antoni

2017-07-07

The development of antiaging drugs is an interesting area of scientific research. In order to evaluate the beneficial effects of new potential drugs, it is necessary to gather the specific knowledge on the adequate preclinical models that are available. This review focuses on invertebrate and vertebrate preclinical models used to evaluate the efficacy of antiaging compounds, with the objective to extend lifespan and health span. Dietary restriction (DR), a common experimental process to extend lifespan in all organisms, is also discussed. Besides, classical antiaging drugs such as resveratrol, rapamycin and metformin, denominated DR mimetics, are reviewed. The main therapeutic targets of these drugs include sirtuins, IGF-1, and mTOR, all of them being modulated by DR. The National Institute on Aging (NIA) developed the Interventions Testing Program (ITP). At the preclinical level, the ITP uses genetically heterogeneous mice model (HET), which is probably the most suitable rodent model to study potential drugs preventing aging-related diseases. The accelerated-senescence mouse P8 is also an interesting rodent model for the research in the field of aging. Notwithstanding, non-human primates are still necessary prior to clinical trials, since they allow an easier extrapolation to humans due to their anatomical and physiological similarities. In this review, the different models and approaches for antiaging studies were evaluated. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Rodent Models of Invasive Aspergillosis due to Aspergillus fumigatus: Still a Long Path toward Standardization

PubMed Central

Desoubeaux, Guillaume; Cray, Carolyn

2017-01-01

Invasive aspergillosis has been studied in laboratory by the means of plethora of distinct animal models. They were developed to address pathophysiology, therapy, diagnosis, or miscellaneous other concerns associated. However, there are great discrepancies regarding all the experimental variables of animal models, and a thorough focus on them is needed. This systematic review completed a comprehensive bibliographic analysis specifically-based on the technical features of rodent models infected with Aspergillus fumigatus. Out the 800 articles reviewed, it was shown that mice remained the preferred model (85.8% of the referenced reports), above rats (10.8%), and guinea pigs (3.8%). Three quarters of the models involved immunocompromised status, mainly by steroids (44.4%) and/or alkylating drugs (42.9%), but only 27.7% were reported to receive antibiotic prophylaxis to prevent from bacterial infection. Injection of spores (30.0%) and inhalation/deposition into respiratory airways (66.9%) were the most used routes for experimental inoculation. Overall, more than 230 distinct A. fumigatus strains were used in models. Of all the published studies, 18.4% did not mention usage of any diagnostic tool, like histopathology or mycological culture, to control correct implementation of the disease and to measure outcome. In light of these findings, a consensus discussion should be engaged to establish a minimum standardization, although this may not be consistently suitable for addressing all the specific aspects of invasive aspergillosis. PMID:28559881

Modelling cognitive affective biases in major depressive disorder using rodents

PubMed Central

Hales, Claire A; Stuart, Sarah A; Anderson, Michael H; Robinson, Emma S J

2014-01-01

Major depressive disorder (MDD) affects more than 10% of the population, although our understanding of the underlying aetiology of the disease and how antidepressant drugs act to remediate symptoms is limited. Major obstacles include the lack of availability of good animal models that replicate aspects of the phenotype and tests to assay depression-like behaviour in non-human species. To date, research in rodents has been dominated by two types of assays designed to test for depression-like behaviour: behavioural despair tests, such as the forced swim test, and measures of anhedonia, such as the sucrose preference test. These tests have shown relatively good predictive validity in terms of antidepressant efficacy, but have limited translational validity. Recent developments in clinical research have revealed that cognitive affective biases (CABs) are a key feature of MDD. Through the development of neuropsychological tests to provide objective measures of CAB in humans, we have the opportunity to use ‘reverse translation’ to develop and evaluate whether similar methods are suitable for research into MDD using animals. The first example of this approach was reported in 2004 where rodents in a putative negative affective state were shown to exhibit pessimistic choices in a judgement bias task. Subsequent work in both judgement bias tests and a novel affective bias task suggest that these types of assay may provide translational methods for studying MDD using animals. This review considers recent work in this area and the pharmacological and translational validity of these new animal models of CABs. Linked Articles This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20 PMID:24467454

Species-specific vesicular monoamine transporter 2 (VMAT2) expression in mammalian pancreatic beta cells: implications for optimising radioligand-based human beta cell mass (BCM) imaging in animal models

PubMed Central

Hartwig, N. R.; Kalmbach, N.; Klietz, M.; Anlauf, M.; Eiden, L. E.; Weihe, E.

2014-01-01

Aims/hypothesis Imaging of beta cell mass (BCM) is a major challenge in diabetes research. The vesicular monoamine transporter 2 (VMAT2) is abundantly expressed in human beta cells. Radiolabelled analogues of tetrabenazine (TBZ; a low-molecular-weight, cell-permeant VMAT2-selective ligand) have been employed for pancreatic islet imaging in humans. Since reports on TBZ-based VMAT2 imaging in rodent pancreas have been fraught with confusion, we compared VMAT2 gene expression patterns in the mouse, rat, pig and human pancreas, to identify appropriate animal models with which to further validate and optimise TBZ imaging in humans. Methods We used a panel of highly sensitive VMAT2 antibodies developed against equivalently antigenic regions of the transporter from each species in combination with immunostaining for insulin and species-specific in situ hybridisation probes. Individual pancreatic islets were obtained by laser-capture microdissection and subjected to analysis of mRNA expression of VMAT2. Results The VMAT2 protein was not expressed in beta cells in the adult pancreas of common mouse or rat laboratory strains, in contrast to its expression in beta cells (but not other pancreatic endocrine cell types) in the pancreas of pigs and humans. VMAT2- and tyrosine hydroxylase co-positive (catecholaminergic) innervation was less abundant in humans than in rodents. VMAT2-positive mast cells were identified in the pancreas of all species. Conclusions/interpretation Primates and pigs are suitable models for TBZ imaging of beta cells. Rodents, because of a complete lack of VMAT2 expression in the endocrine pancreas, are a ‘null’ model for assessing interference with BCM measurements by VMAT2-positive mast cells and sympathetic innervation in the pancreas. PMID:23404442

Hippocampal P3-like auditory event-related potentials are disrupted in a rat model of cholinergic degeneration in Alzheimer's disease: reversal by donepezil treatment.

PubMed

Laursen, Bettina; Mørk, Arne; Kristiansen, Uffe; Bastlund, Jesper Frank

2014-01-01

P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

Influence of environmental heterogeneity on the distribution and persistence of a subterranean rodent in a highly unstable landscape.

PubMed

Gómez Fernández, María Jimena; Boston, Emma S M; Gaggiotti, Oscar E; Kittlein, Marcelo J; Mirol, Patricia M

2016-12-01

In this study we combine information from landscape characteristics, demographic inference and species distribution modelling to identify environmental factors that shape the genetic distribution of the fossorial rodent Ctenomys. We sequenced the mtDNA control region and amplified 12 microsatellites from 27 populations distributed across the Iberá wetland ecosystem. Hierarchical Bayesian modelling was used to construct phylogenies and estimate divergence times. We developed species distribution models to determine what climatic variables and soil parameters predicted species presence by comparing the current to the historic and predicted future distribution of the species. Finally, we explore the impact of environmental variables on the genetic structure of Ctenomys based on current and past species distributions. The variables that consistently correlated with the predicted distribution of the species and explained the observed genetic differentiation among populations included the distribution of well-drained sandy soils and temperature seasonality. A core region of stable suitable habitat was identified from the Last Interglacial, which is projected to remain stable into the future. This region is also the most genetically diverse and is currently under strong anthropogenic pressure. Results reveal complex demographic dynamics, which have been in constant change in both time and space, and are likely linked to the evolution of the Paraná River. We suggest that any alteration of soil properties (climatic or anthropic) may significantly impact the availability of suitable habitat and consequently the ability of individuals to disperse. The protection of this core stable habitat is of prime importance given the increasing levels of human disturbance across this wetland system and the threat of climate change.

Comparison of the polarization properties in the retinas of different rodents using high resolution polarization sensitive OCT

NASA Astrophysics Data System (ADS)

Fialová, Stanislava; Augustin, Marco; Plasenzotti, Roberto; Rauscher, Sabine; Gröger, Marion; Pircher, Michael; Hitzenberger, Christoph K.; Baumann, Bernhard

2015-07-01

Animal models play an important role for understanding the pathophysiology of glaucoma and age-related macular degeneration. With these models, longitudinal studies can be performed and therefore there is need for non-invasive evaluation of disease progress. For that purpose optical coherence tomography (OCT) can be used. Since tissues with different polarization properties are important in these diseases, polarization sensitive OCT (PS-OCT) could be a valuable tool in preclinical research. In this work a high resolution PS-OCT (HR-PS-OCT) system was used in-vivo for rodent retinal imaging. A super luminescent diode with a bandwidth of 100 nm was used as a light source that yielded an axial resolution of 5.1 μm in air (3.8 μm in tissue). The A-scan rate was 83 kHz, a whole 3D dataset was acquired in a few seconds (1536x1024x200 pixels in 3.5 s) which reduced motion artifacts. Rats (Sprague-Dawley, Long-Evans and Brown Norway) as well as mice (C57BL/6) were imaged. High resolution reflectivity images showed all retinal layers in all animals. From acquired data also phase retardation, fast axis orientation and degree of polarization uniformity (DOPU) images were calculated. On phase retardation images sclera was identified as birefringent and retinal pigment epithelium (RPE) and choroid as depolarizing tissues. Our results demonstrate the suitability of the system for high speed/resolution imaging in follow up studies on rodents.

Effect of spaceflight on the functional, biochemical, and metabolic properties of skeletal muscle

NASA Technical Reports Server (NTRS)

Baldwin, K. M.

1996-01-01

This paper summarizes the effects of spaceflight on the functional, morphological, and biochemical properties of human and rodent skeletal muscle. The findings suggest that following as little as 5-6 in space there are deficits in both human and rodent motor capacity, strength, and endurance properties of skeletal muscle. The reduced strength is associated, in part, with a reduction in muscle mass as reflected in smaller cross-sectional areas of both fast- and slow-twitch fibers. Available evidence in animal models suggests that slow-twitch fibers are more sensitive to the atrophying process. Accompanying the atrophy is a transformation of slow to fast protein phenotype involving myosin heavy chain and sarcoplasmic reticulum protein isoforms. These transformations appear to be regulated, in part, by pretranslational processes. Data on the oxidative capacity of rodent skeletal muscle suggest a bias toward preferential utilization of carbohydrate as the primary substrate. These collective findings suggest that skeletal muscles comprised chiefly of slow fibers are highly dependent on gravity for the normal expression of protein mass and slow phenotype. Future studies need to focus on elucidating the mechanisms associated with the atrophy response, as well as identifying suitable exercise and other countermeasures capable of preserving the structural and functional integrity of skeletal muscle.

Neurobiology of rodent self-grooming and its value for translational neuroscience

PubMed Central

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 evolutionary 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. PMID:26675822

Reliable critical sized defect rodent model for cleft palate research.

PubMed

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.

Evaluation of monkeypox virus infection of prairie dogs (Cynomys ludovicianus) using in vivo bioluminescent imaging

USGS Publications Warehouse

Falendysz, Elizabeth A.; Londoño-Navas, Angela M.; Meteyer, Carol U.; Pussini, Nicola; Lopera, Juan G.; Osorio, Jorge E.; Rocke, Tonie E.

2014-01-01

Monkeypox (MPX) is a re-emerging zoonotic disease that is endemic in Central and West Africa, where it can cause a smallpox-like disease in humans. Despite many epidemiologic and field investigations of MPX, no definitive reservoir species has been identified. Using recombinant viruses expressing the firefly luciferase (luc) gene, we previously demonstrated the suitability of in vivo bioluminescent imaging (BLI) to study the pathogenesis of MPX in animal models. Here, we evaluated BLI as a novel approach for tracking MPX virus infection in black-tailed prairie dogs (Cynomys ludovicianus). Prairie dogs were affected during a multistate outbreak of MPX in the US in 2003 and have since been used as an animal model of this disease. Our BLI results were compared with PCR and virus isolation from tissues collected postmortem. Virus was easily detected and quantified in skin and superficial tissues by BLI before and during clinical phases, as well as in subclinical secondary cases, but was not reliably detected in deep tissues such as the lung. Although there are limitations to viral detection in larger wild rodent species, BLI can enhance the use of prairie dogs as an animal model of MPX and can be used for the study of infection, disease progression, and transmission in potential wild rodent reservoirs.

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

PubMed

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.

Euthanasia using gaseous agents in laboratory rodents.

PubMed

Valentim, A M; Guedes, S R; Pereira, A M; Antunes, L M

2016-08-01

Several questions have been raised in recent years about the euthanasia of laboratory rodents. Euthanasia using inhaled agents is considered to be a suitable aesthetic method for use with a large number of animals simultaneously. Nevertheless, its aversive potential has been criticized in terms of animal welfare. The data available regarding the use of carbon dioxide (CO2), inhaled anaesthetics (such as isoflurane, sevoflurane, halothane and enflurane), as well as carbon monoxide and inert gases are discussed throughout this review. Euthanasia of fetuses and neonates is also addressed. A table listing currently available information to ease access to data regarding euthanasia techniques using gaseous agents in laboratory rodents was compiled. Regarding better animal welfare, there is currently insufficient evidence to advocate banning or replacing CO2 in the euthanasia of rodents; however, there are hints that alternative gases are more humane. The exposure to a volatile anaesthetic gas before loss of consciousness has been proposed by some scientific studies to minimize distress; however, the impact of such a measure is not clear. Areas of inconsistency within the euthanasia literature have been highlighted recently and stem from insufficient knowledge, especially regarding the advantages of the administration of isoflurane or sevoflurane over CO2, or other methods, before loss of consciousness. Alternative methods to minimize distress may include the development of techniques aimed at inducing death in the home cage of animals. Scientific outcomes have to be considered before choosing the most suitable euthanasia method to obtain the best results and accomplish the 3Rs (replacement, reduction and refinement). © The Author(s) 2015.

Validation of serum IGF-I as a biomarker to monitor the bioactivity of exogenous growth hormone agonists and antagonists in rabbits

PubMed Central

Bielohuby, Maximilian; Zarkesh-Esfahani, Sayyed Hamid; Manolopoulou, Jenny; Wirthgen, Elisa; Walpurgis, Katja; Toghiany Khorasgani, Mohaddeseh; Aghili, Zahra Sadat; Wilkinson, Ian Robert; Hoeflich, Andreas; Thevis, Mario; Ross, Richard J.; Bidlingmaier, Martin

2014-01-01

The development of new growth hormone (GH) agonists and growth hormone antagonists (GHAs) requires animal models for pre-clinical testing. Ideally, the effects of treatment are monitored using the same pharmacodynamic marker that is later used in clinical practice. However, intact rodents are of limited value for this purpose because serum IGF-I, the most sensitive pharmacodynamic marker for the action of GH in humans, shows no response to treatment with recombinant human GH and there is little evidence for the effects of GHAs, except when administered at very high doses or when overexpressed. As an alternative, more suitable model, we explored pharmacodynamic markers of GH action in intact rabbits. We performed the first validation of an IGF-I assay for the analysis of rabbit serum and tested precision, sensitivity, linearity and recovery using an automated human IGF-I assay (IDS-iSYS). Furthermore, IGF-I was measured in rabbits of different strains, age groups and sexes, and we monitored IGF-I response to treatment with recombinant human GH or the GHA Pegvisomant. For a subset of samples, we used LC-MS/MS to measure IGF-I, and quantitative western ligand blot to analyze IGF-binding proteins (IGFBPs). Although recovery of recombinant rabbit IGF-I was only 50% in the human IGF-I assay, our results show that the sensitivity, precision (1.7–3.3% coefficient of variation) and linearity (90.4–105.6%) were excellent in rabbit samples. As expected, sex, age and genetic background were major determinants of IGF-I concentration in rabbits. IGF-I and IGFBP-2 levels increased after single and multiple injections of recombinant human GH (IGF-I: 286±22 versus 434±26 ng/ml; P<0.01) and were highly correlated (P<0.0001). Treatment with the GHA lowered IGF-I levels from the fourth injection onwards (P<0.01). In summary, we demonstrated that the IDS-iSYS IGF-I immunoassay can be used in rabbits. Similar to rodents, rabbits display variations in IGF-I depending on sex, age and genetic background. Unlike in rodents, the IGF-I response to treatment with recombinant human GH or a GHA closely mimics the pharmacodynamics seen in humans, suggesting that rabbits are a suitable new model to test human GH agonists and antagonists. PMID:25239917

Oxidative and nutrient stability of a standard rodent spaceflight diet during long-term storage.

PubMed

Sun, Gwo-Shing; Tou, Janet C; Reiss-Bubenheim, Debra A; Hill, Esther L; Liittschwager, Kurt W; Girten, Beverly E; Pena-Yewkukhiw, Eugenia

2012-09-01

The National Aeronautics and Space Administration's standard spaceflight diet for rodents is the nutrient-upgraded rodent food bar (NuRFB). The shelf life of the NuRFB needs to be determined in order to avoid malnutrition of rodents and confounding of research results resulting from nutritional deficiency. The authors compared the oxidative and nutrient stability of NuRFBs stored at either ambient temperature (26 °C) or at refrigeration temperature (4 °C) for use in long-term rodent feeding experiments. After 0, 3, 6, 9 and 12 months (mo) of storage, lipid oxidation, fatty acid composition and amounts of specific vitamins and amino acids in NuRFBs were analyzed. No oxidative rancidity developed in NuRFBs stored at 4 °C for up to 12 mo, but NuRFBs stored at 26 °C for 6 mo developed oxidative rancidity and had reduced amounts of γ-linolenic acid (18:3n-6). Despite loss of vitamin E, vitamin A and thiamin after storage at 26 °C for 12 mo, vitamin levels in NuRFBs remained at or above the levels recommended for optimal rodent health. The amino acid profile of NuRFBs was unaffected by storage at 4 °C or 26 °C for 12 mo. The results suggest that NuRFBs stored at 4 °C for up to 12 mo and NuRFBs stored at 26 °C for up to 6 mo provide suitable nutrition for rodents in long-term experiments.

The Search for New Screening Models of Pharmacoresistant Epilepsy: Is Induction of Acute Seizures in Epileptic Rodents a Suitable Approach?

PubMed

Löscher, Wolfgang

2017-07-01

Epilepsy, a prevalent neurological disease characterized by spontaneous recurrent seizures (SRS), is often refractory to treatment with anti-seizure drugs (ASDs), so that more effective ASDs are urgently needed. For this purpose, it would be important to develop, validate, and implement new animal models of pharmacoresistant epilepsy into drug discovery. Several chronic animal models with difficult-to-treat SRS do exist; however, most of these models are not suited for drug screening, because drug testing on SRS necessitates laborious video-EEG seizure monitoring. More recently, it was proposed that, instead of monitoring SRS, chemical or electrical induction of acute seizures in epileptic rodents may be used as a surrogate for testing the efficacy of novel ASDs against refractory SRS. Indeed, several ASDs were shown to lose their efficacy on acute seizures, when such seizures were induced by pentylenetetrazole (PTZ) in epileptic rather than nonepileptic rats, whereas this was not observed when using the maximal electroshock seizure test. Subsequent studies confirmed the loss of anti-seizure efficacy of valproate against PTZ-induced seizures in epileptic mice, but several other ASDs were more potent against PTZ in epileptic than nonepileptic mice. This was also observed when using the 6-Hz model of partial seizures in epileptic mice, in which the potency of levetiracetam, in particular, was markedly increased compared to nonepileptic animals. Overall, these observations suggest that performing acute seizure tests in epileptic rodents provides valuable information on the pharmacological profile of ASDs, in particular those with mechanisms inherent to disease-induced brain alterations. However, it appears that further work is needed to define optimal approaches for acute seizure induction and generation of epileptic/drug refractory animals that would permit reliable screening of new ASDs with improved potential to provide seizure control in patients with pharmacoresistant epilepsy.

Malaria in pregnancy: the relevance of animal models for vaccine development.

PubMed

Doritchamou, Justin; Teo, Andrew; Fried, Michal; Duffy, Patrick E

2017-10-06

Malaria during pregnancy due to Plasmodium falciparum or P. vivax is a major public health problem in endemic areas, with P. falciparum causing the greatest burden of disease. Increasing resistance of parasites and mosquitoes to existing tools, such as preventive antimalarial treatments and insecticide-treated bed nets respectively, is eroding the partial protection that they offer to pregnant women. Thus, development of effective vaccines against malaria during pregnancy is an urgent priority. Relevant animal models that recapitulate key features of the pathophysiology and immunology of malaria in pregnant women could be used to accelerate vaccine development. This review summarizes available rodent and nonhuman primate models of malaria in pregnancy, and discusses their suitability for studies of biologics intended to prevent or treat malaria in this vulnerable population.

Prenatal Alcohol Exposure in Rodents As a Promising Model for the Study of ADHD Molecular Basis

PubMed Central

Rojas-Mayorquín, Argelia E.; Padilla-Velarde, Edgar; Ortuño-Sahagún, Daniel

2016-01-01

A physiological parallelism, or even a causal effect relationship, can be deducted from the analysis of the main characteristics of the “Alcohol Related Neurodevelopmental Disorders” (ARND), derived from prenatal alcohol exposure (PAE), and the behavioral performance in the Attention-deficit/hyperactivity disorder (ADHD). These two clinically distinct disease entities, exhibits many common features. They affect neurological shared pathways, and also related neurotransmitter systems. We briefly review here these parallelisms, with their common and uncommon characteristics, and with an emphasis in the subjacent molecular mechanisms of the behavioral manifestations, that lead us to propose that PAE in rats can be considered as a suitable model for the study of ADHD. PMID:28018163

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

PubMed Central

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. PMID:28638807

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

PubMed

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.

Rodent models of diabetic nephropathy: their utility and limitations

PubMed Central

Kitada, Munehiro; Ogura, Yoshio; Koya, Daisuke

2016-01-01

Diabetic nephropathy is the most common cause of end-stage renal disease. Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and many type 1 and type 2 diabetic rodent models have been established for the study of diabetes and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26 mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 diabetes. In addition, db/db mice, KK-Ay mice, Zucker diabetic fatty rats, Wistar fatty rats, Otsuka Long-Evans Tokushima Fatty rats and Goto-Kakizaki rats serve as rodent models of type 2 diabetes. An animal model of diabetic nephropathy should exhibit progressive albuminuria and a decrease in renal function, as well as the characteristic histological changes in the glomeruli and the tubulointerstitial lesions that are observed in cases of human diabetic nephropathy. A rodent model that strongly exhibits all these features of human diabetic nephropathy has not yet been developed. However, the currently available rodent models of diabetes can be useful in the study of diabetic nephropathy by increasing our understanding of the features of each diabetic rodent model. Furthermore, the genetic background and strain of each mouse model result in differences in susceptibility to diabetic nephropathy with albuminuria and the development of glomerular and tubulointerstitial lesions. Therefore, the validation of an animal model reproducing human diabetic nephropathy will significantly facilitate our understanding of the underlying genetic mechanisms that contribute to the development of diabetic nephropathy. In this review, we focus on rodent models of diabetes and discuss the utility and limitations of these models for the study of diabetic nephropathy. PMID:27881924

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

PubMed

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.

Titanium wound chambers for wound healing research.

PubMed

Nuutila, Kristo; Singh, Mansher; Kruse, Carla; Philip, Justin; Caterson, Edward J; Eriksson, Elof

2016-11-01

Standardized and reproducible animal models are crucial in medical research. Rodents are commonly used in wound healing studies since, they are easily available, affordable and simple to handle and house. However, the most significant limitation of rodent models is that the wounds heal by contraction while in humans the primary mechanisms of healing are reepithelialization and granulation tissue formation. The robust contraction results in faster wound closure that complicates the reproducibility of rodent studies in clinical trials. We have developed a titanium wound chamber for rodent wound healing research. The chamber is engineered from two pieces of titanium and is placed transcutaneously on the dorsum of a rodent. The chamber inhibits wound contraction and provides a means for controlled monitoring and sampling of the wound environment in vivo with minimal foreign body reaction. This technical report introduces two modalities utilizing the titanium chambers in rats: (1) Wound in a skin island model and, (2) Wound without skin model. Here, we demonstrate in rats how the "wound in a skin island model" slows down wound contraction and how the "wound without skin" model completely prevents the closure. The titanium wound chamber provides a reproducible standardized models for wound healing research in rodents. © 2016 by the Wound Healing Society.

Translating Research from Animal Models: Does It Matter that Our Rodents are So Cold?

EPA Science Inventory

Does it matter that preclinical rodent models are routinely housed below their thermoneutral zone and are thereby cold-stressed? We compile evidence showing that rodents housed below their thermoneutral zone are cold-stressed, hypermetalbolic, hypertensive, sleep-deprived, obesi...

Evaluation of Chemotherapeutic Agents Against Malaria, Drugs, Diet, and Biological Response Modifiers.

DTIC Science & Technology

1991-10-29

The oils, MCT and Miglyol , were found to be suitable placebos for fish oil. A normal chow diet (with adequate vitamin E levels) supplemented with 20...year. Co-enzyme Q10 did not act as an antioxidant like vitamin E during a malarial infection. Two oils, MCT and Miglyol , were found to be suitable...manipulation. In experiment 84 miglyol was added to a standard rodent chow diet with normal levels of vitamin E to see whether it whould interfere with the

Changes in Black-legged Tick Population in New England with Future Climate Change

NASA Astrophysics Data System (ADS)

Krishnan, S.; Huber, M.

2015-12-01

Lyme disease is one of the most frequently reported vector-borne diseases in the United States. In the Northeastern United States, vector transmission is maintained in a horizontal transmission cycle between the vector, the black-legged ticks, and the vertebrate reservoir hosts, which include white-tailed deer, rodents and other medium to large sized mammals. Predicting how vector populations change with future climate change is critical to understanding disease spread in the future, and for developing suitable regional adaptation strategies. For the United States, these predictions have mostly been made using regressions based on field and lab studies, or using spatial suitability studies. However, the relation between tick populations at various life-cycle stages and climate variables are complex, necessitating a mechanistic approach. In this study, we present a framework for driving a mechanistic tick population model with high-resolution regional climate modeling projections. The goal is to estimate changes in black-legged tick populations in New England for the 21st century. The tick population model used is based on the mechanistic approach of Ogden et al., (2005) developed for Canada. Dynamically downscaled climate projections at a 3-kms resolution using the Weather and Research Forecasting Model (WRF) are used to drive the tick population model.

The use of genetically modified mice in cancer risk assessment: challenges and limitations.

PubMed

Eastmond, David A; Vulimiri, Suryanarayana V; French, John E; Sonawane, Babasaheb

2013-09-01

The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53⁺/⁻, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program's conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals.

The use of genetically modified mice in cancer risk assessment: Challenges and limitations*

PubMed Central

Eastmond, David A.; Vulimiri, Suryanarayana V.; French, John E.; Sonawane, Babasaheb

2015-01-01

The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53+/−, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program’s conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals. PMID:23985072

EVALUTION OF COGNITIVE FUNCTION IN WEANLING RATS: A REVIEW OF METHODS SUITABLE FOR CHEMICAL SCREENING.

EPA Science Inventory

The current developmental neurotoxicity (DNT) guidelines for environmental agents require cognitive testing around the age of weaning as well as adulthood. There are challenges associated with testing weanling rodents that are not present with testing older subjects, including r...

Estimation of Wildlife Hazard Levels Using Interspecies Correlation Models and Standard Laboratory Rodent Toxicity Data

EPA Science Inventory

Toxicity data from laboratory rodents are widely available and frequently used in human health assessments as an animal model. We explore the possibility of using single rodent acute toxicity values to predict chemical toxicity to a diversity of wildlife species and to estimate ...

PREDICTIVE SIMULATION MODELING FOR ANTIANDROGEN IMPACTS ON RODENT PROSTATE

EPA Science Inventory

Predictive simulation modeling for antiandrogen impacts on rodent prostate
HA Barton1, RW Setzer1, LK Potter1,2
1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Park, NC and 2Curriculum in Toxicology, UNC, Chapel Hill, NC

Changes in rodent prostate weight and functi...

Spatial Learning and Action Planning in a Prefrontal Cortical Network Model

PubMed Central

Martinet, Louis-Emmanuel; Sheynikhovich, Denis; Benchenane, Karim; Arleo, Angelo

2011-01-01

The interplay between hippocampus and prefrontal cortex (PFC) is fundamental to spatial cognition. Complementing hippocampal place coding, prefrontal representations provide more abstract and hierarchically organized memories suitable for decision making. We model a prefrontal network mediating distributed information processing for spatial learning and action planning. Specific connectivity and synaptic adaptation principles shape the recurrent dynamics of the network arranged in cortical minicolumns. We show how the PFC columnar organization is suitable for learning sparse topological-metrical representations from redundant hippocampal inputs. The recurrent nature of the network supports multilevel spatial processing, allowing structural features of the environment to be encoded. An activation diffusion mechanism spreads the neural activity through the column population leading to trajectory planning. The model provides a functional framework for interpreting the activity of PFC neurons recorded during navigation tasks. We illustrate the link from single unit activity to behavioral responses. The results suggest plausible neural mechanisms subserving the cognitive “insight” capability originally attributed to rodents by Tolman & Honzik. Our time course analysis of neural responses shows how the interaction between hippocampus and PFC can yield the encoding of manifold information pertinent to spatial planning, including prospective coding and distance-to-goal correlates. PMID:21625569

Pluripotent cells in farm animals: state of the art and future perspectives.

PubMed

Nowak-Imialek, Monika; Niemann, Heiner

2012-01-01

Pluripotent cells, such as embryonic stem (ES) cells, embryonic germ cells and embryonic carcinoma cells are a unique type of cell because they remain undifferentiated indefinitely in in vitro culture, show self-renewal and possess the ability to differentiate into derivatives of the three germ layers. These capabilities make them a unique in vitro model for studying development, differentiation and for targeted modification of the genome. True pluripotent ESCs have only been described in the laboratory mouse and rat. However, rodent physiology and anatomy differ substantially from that of humans, detracting from the value of the rodent model for studies of human diseases and the development of cellular therapies in regenerative medicine. Recently, progress in the isolation of pluripotent cells in farm animals has been made and new technologies for reprogramming of somatic cells into a pluripotent state have been developed. Prior to clinical application of therapeutic cells differentiated from pluripotent stem cells in human patients, their survival and the absence of tumourigenic potential must be assessed in suitable preclinical large animal models. The establishment of pluripotent cell lines in farm animals may provide new opportunities for the production of transgenic animals, would facilitate development and validation of large animal models for evaluating ESC-based therapies and would thus contribute to the improvement of human and animal health. This review summarises the recent progress in the derivation of pluripotent and reprogrammed cells from farm animals. We refer to our recent review on this area, to which this article is complementary.

EALUATION OF COGNITIVE FUNCTION IN WEANLING RATS: A REVIEW OF METHODS SUITABLE FOR CHEMICAL SCREENING

EPA Science Inventory

Current developmental neurotoxicity (DNT) tests that are used for environmental agents call for cognitive testing around the age of weaning as well as adulthood. There are challenges associated with testing weanling rodents that are not present with testing older subjects, inclu...

Talking with Children about Furry Classroom Pets.

ERIC Educational Resources Information Center

Texas Child Care, 1994

1994-01-01

Notes that rodents and rabbits share many characteristics that make them suitable classroom pets and gives background information on rabbits, guinea pigs, hamsters, and gerbils. Offers advice on buying a classroom pet, the pet's home, feeding, helping the children handle the pet, and pet health and family planning. (TJQ)

The MAM rodent model of schizophrenia

PubMed Central

Lodge, Daniel J.

2013-01-01

Rodent models of human disease are essential to obtain a better understanding of disease pathology, the mechanism of action underlying conventional treatments, as well as for the generation of novel therapeutic approaches. There are a number of rodent models of schizophrenia based on either genetic manipulations, acute or sub-chronic drug administration, or developmental disturbances. The prenatal methylazoxymethanol acetate (MAM) rodent model is a developmental disruption model gaining increased attention because it displays a number of histological, neurophysiological and behavioral deficits analogous to those observed in schizophrenia patients. This unit describes the procedures required to safely induce the MAM phenotype in rats. In addition, we describe a simple behavioral procedure, amphetamine-induced hyper-locomotion, which can be utilized to verify the MAM phenotype. PMID:23559309

DEVELOPING A PREDICTIVE SIMULATION MODEL FOR ANTIANDROGEN IMPACTS ON RODENT PROSTATE

EPA Science Inventory

Developing a predictive simulation model for antiandrogen impacts on rodent prostate
HA Barton1, RW Setzer1, LK Potter1,2
1US EPA, ORD, NHEERL, ETD, PKB, Research Triangle Park, NC and 2Curriculum in Toxicology, UNC, Chapel Hill, NC

Alterations in rodent prostate wei...

Prevalence of Leishmania species in rodents: A systematic review and meta-analysis in Iran.

PubMed

Foroutan, Masoud; Khademvatan, Shahram; Majidiani, Hamidreza; Khalkhali, Hamidreza; Hedayati-Rad, Faezeh; Khashaveh, Shahla; Mohammadzadeh, Habib

2017-08-01

Leishmaniasis are diverse group of diseases caused by numerous species of genus Leishmania. Herein we have contrived a systematic review and meta-analysis on the prevalence of Leishmania species in rodents of Iran. For this purpose, following the general methodology recommended for systematic reviews and meta-analysis, six English databases (PubMed, Science Direct, Scopus, Ovid, Web of Science and Google Scholar) and four Persian databases (Magiran, SID, Iran Doc and Iran Medex) were explored during January 1995 till June 2015. Papers were selected based on 8 pre-defined inclusion criteria. During the years, a total number of 4485 different rodents were captured; among which 1291 cases were Leishmania positive. The calculated weighted prevalence of Leishmania species in rodents was 23% (95% CI=18-28). Given geographical zones of Iran, the highest and lowest prevalence rate was belonged to North 50% (95% CI=40-61) and West 11% (95% CI=5-17), respectively. Rhombomys opimus (1766), Meriones lybicus (1258) and Tatera indica (488) were the three most abundant captured rodents, while the highest prevalence of Leishmania species was observed in Nesokia indica 48% (95% CI=42-54) and followed by R. opimus 39% (95% CI=30-47). Egger's regression test was performed to detect publication bias, which revealed it may not have a significant influence on overall weighted prevalence estimate (P=0.317). Meta-regression analysis demonstrated that there is no significant relationship between overall prevalence with sample size (P=0.1) and year of publication (P=0.7). The results showed remarkable prevalence of Leishmania species in rodent reservoirs. In future, adopting a suitable strategy for control and combat with rodents is necessary. Copyright © 2017 Elsevier B.V. All rights reserved.

Rodent models of glaucoma and their applicability for drug discovery.

PubMed

Agarwal, Renu; Agarwal, Puneet

2017-03-01

Rodents have widely been used to represent glaucomatous changes both in the presence and absence of elevated intraocular pressure (IOP) as they offer clear advantages over other animal species. IOP elevation is commonly achieved by creating an obstruction in the aqueous outflow pathways, consequently leading to retinal ganglion cell and optic nerve (ON) damage, the hallmark of glaucoma. These changes may also be achieved in the absence of elevated IOP by directly inflicting injury to retina or ON. Areas covered: This paper presents a summary of currently used rodent models of glaucoma. The characteristics of these models from several studies are summarized. The benefits and shortcomings of these models are also discussed. Expert opinion: The choice of animal model that closely represents human disease is key for successful translational of preclinical research to clinical practice. Rodent models of rapid IOP elevation are likely to be least representative, whereas models such as steroid-induced glaucoma models more closely resemble the trabecular meshwork changes seen in glaucomatous human eyes. However, this model needs further characterization. Rodent models based on direct retinal and ON injury are also useful tools to investigate molecular mechanisms involved at the site of final common pathology and neuroprotective strategies.

[Dynamic model of seasonal breeding rodent pest population controlled with short-acting sterilant].

PubMed

Liu, Han-wu; Jin, Zhen; Zhang, Feng-qin; Li, Qiu-ying

2013-04-01

Rodent pests bring great damage to human beings, while rodenticide and sterilant can be used to control the pests. After ingesting sterilant, rodent pests lose their fertility, but in some cases, the sterile individuals may gain their fertility again, produce offspring, and enlarge population size. In this paper, the dynamic models of rodent pest population under lethal control and shortacting contraception control were formulated, and, with the prerequisite of the seasonal breeding of rodent pest population, the models were used to regularly analyze their behaviors and the effects of the contraception rate, lethal rate, control interval, and sterilant valid period on the dynamics of the pest population. The results showed that larger contraception rate and lethal rate and shorter control interval could have better control effect, making the controlled population become smaller and even died out. Short-acting sterilant limited the control effect. At the later period of breeding season, the rodent pest population controlled with short-acting sterilant would have a weak recovery.

Characterization of enamel caries lesions in rat molars using synchrotron X-ray microtomography

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

Free, R. D.; DeRocher, K.; Stock, S. R.

Dental caries is a ubiquitous infectious disease with a nearly 100% lifetime prevalence. Rodent caries models are widely used to investigate the etiology, progression and potential prevention or treatment of the disease. To explore the suitability of these models for deeper investigations of intact surface zones during enamel caries, the structures of early-stage carious lesions in rats were characterized and compared with previous reports on white spot enamel lesions in humans. Synchrotron X-ray microcomputed tomography non-destructively mapped demineralization in carious rat molar specimens across a range of caries severity, identifying 52 lesions across the 30 teeth imaged. Of these lesions,more » 13 were shown to have intact surface zones. Depth profiles of fractional mineral density were qualitatively similar to lesions in human teeth. However, the thickness of the surface zone in the rat model ranges from 10 to 58 µm, and is therefore significantly thinner than in human enamel. These results indicate that a fraction of lesions in rat caries possess an intact surface zone and are qualitatively similar to human lesions at the micrometer scale. This suggests that rat caries models may be a suitable analog through which to investigate the structure of surface zone enamel and its role during dental caries.« less

Seed dispersal and seed fate in Joshua tree (Yucca brevifolia)

USGS Publications Warehouse

Waitman, B.A.; Vander Wall, S.B.; Esque, Todd

2012-01-01

Joshua tree (Yucca brevifolia) is a charismatic symbol of the Mojave Desert. Despite its familiarity, we know little about the reproduction of this species, including mechanisms of seed dispersal. Here we examine mechanisms of seed dispersal and resulting seed fate. We experimentally tracked fruit and seed removal and followed the fates of Joshua tree seeds using radioactive tracers. The majority of Joshua tree fruits monitored were taken directly from the tree canopy by white-tailed antelope squirrels, and seeds and fruits on the soil surface were quickly removed by animals. Rodents given seeds labeled with scandium-46 cached them between 0.1 cm and 4.1 cm deep. Seedling emergence was most common for seeds planted 1 cm deep, whereas seeds placed on the soil surface seldom germinated. Wind dispersal is unlikely because fruits and seeds lack adaptations for wind dispersal; wind speeds required to move Joshua tree seeds and fruits across the soil surface were higher than those typically found in the Mojave Desert. Further, rodents removed most seeds before abiotic burial was possible. We conclude that most Joshua tree seeds are dispersed by scatter hoarding by rodents, and that caches made by rodents are suitable sites for seedling emergence.

Gait Analysis Methods for Rodent Models of Arthritic Disorders: Reviews and Recommendations

PubMed Central

Lakes, Emily H.; Allen, Kyle D.

2016-01-01

Gait analysis is a useful tool to understand behavioral changes in preclinical arthritis models. While observational scoring and spatiotemporal gait parameters are the most widely performed gait analyses in rodents, commercially available systems can now provide quantitative assessments of spatiotemporal patterns. However, inconsistencies remain between testing platforms, and laboratories often select different gait pattern descriptors to report in the literature. Rodent gait can also be described through kinetic and kinematic analyses, but systems to analyze rodent kinetics and kinematics are typically custom made and often require sensitive, custom equipment. While the use of rodent gait analysis rapidly expands, it is important to remember that, while rodent gait analysis is a relatively modern behavioral assay, the study of quadrupedal gait is not new. Nearly all gait parameters are correlated, and a collection of gait parameters is needed to understand a compensatory gait pattern used by the animal. As such, a change in a single gait parameter is unlikely to tell the full biomechanical story; and to effectively use gait analysis, one must consider how multiple different parameters contribute to an altered gait pattern. The goal of this article is to review rodent gait analysis techniques and provide recommendations on how to use these technologies in rodent arthritis models, including discussions on the strengths and limitations of observational scoring, spatiotemporal, kinetic, and kinematic measures. Recognizing rodent gait analysis is an evolving tool, we also provide technical recommendations we hope will improve the utility of these analyses in the future. PMID:26995111

Positron Emission Tomography studies with [11C]PBR28 in the Healthy Rodent Brain: Validating SUV as an Outcome Measure of Neuroinflammation.

PubMed

Tóth, Miklós; Doorduin, Janine; Häggkvist, Jenny; Varrone, Andrea; Amini, Nahid; Halldin, Christer; Gulyás, Balázs

2015-01-01

Molecular imaging of the 18 kD Translocator protein (TSPO) with positron emission tomography (PET) is of great value for studying neuroinflammation in rodents longitudinally. Quantification of the TSPO in rodents is, however, quite challenging. There is no suitable reference region and the use of plasma-derived input is not an option for longitudinal studies. The aim of this study was therefore to evaluate the use of the standardized uptake value (SUV) as an outcome measure for TSPO imaging in rodent brain PET studies, using [11C]PBR28. In the first part of the study, healthy male Wistar rats (n = 4) were used to determine the correlation between the distribution volume (VT, calculated with Logan graphical analysis) and the SUV. In the second part, healthy male Wistar rats (n = 4) and healthy male C57BL/6J mice (n = 4), were used to determine the test-retest variability of the SUV, with a 7-day interval between measurements. Dynamic PET scans of 63 minutes were acquired with a nanoScan PET/MRI and nanoScan PET/CT. An MRI scan was made for anatomical reference with each measurement. The whole brain VT of [11C]PBR28 in rats was 42.9 ± 1.7. A statistically significant correlation (r2 = 0.96; p < 0.01) was found between the VT and the SUV. The test-retest variability in 8 brain region ranged from 8 to 20% in rats and from 7 to 23% in mice. The interclass correlation coefficient (ICC) was acceptable to excellent for rats, but poor to acceptable for mice. The SUV of [11C]PBR28 showed a high correlation with VT as well as good test-retest variability. For future longitudinal small animal PET studies the SUV can thus be used to describe [11C]PBR28 uptake in healthy brain tissue. Based on the present observations, further studies are needed to explore the applicability of this approach in small animal disease models, with special regard to neuroinflammatory models.

Ventral tegmental area/substantia nigra and prefrontal cortex rodent organotypic brain slices as an integrated model to study the cellular changes induced by oxygen/glucose deprivation and reperfusion: effect of neuroprotective agents.

PubMed

Colombo, Laura; Parravicini, Chiara; Lecca, Davide; Dossi, Elena; Heine, Claudia; Cimino, Mauro; Wanke, Enzo; Illes, Peter; Franke, Heike; Abbracchio, Maria P

2014-01-01

Unveiling the roles of distinct cell types in brain response to insults is a partially unsolved challenge and a key issue for new neuroreparative approaches. In vivo models are not able to dissect the contribution of residential microglia and infiltrating blood-borne monocytes/macrophages, which are fundamentally undistinguishable; conversely, cultured cells lack original tissue anatomical and functional complexity, which profoundly alters reactivity. Here, we tested whether rodent organotypic co-cultures from mesencephalic ventral tegmental area/substantia nigra and prefrontal cortex (VTA/SN-PFC) represent a suitable model to study changes induced by oxygen/glucose deprivation and reperfusion (OGD/R). OGD/R induced cytotoxicity to both VTA/SN and PFC slices, with higher VTA/SN susceptibility. Neurons were highly affected, with astrocytes and oligodendrocytes undergoing very mild damage. Marked reactive astrogliosis was also evident. Notably, OGD/R triggered the activation of CD68-expressing microglia and increased expression of Ym1 and Arg1, two markers of "alternatively" activated beneficial microglia. Treatment with two well-known neuroprotective drugs, the anticonvulsant agent valproic acid and the purinergic P2-antagonist PPADS, prevented neuronal damage. Thus, VTA/SN-PFC cultures are an integrated model to investigate OGD/R-induced effects on distinct cells and easily screen neuroprotective agents. The model is particularly adequate to dissect the microglia phenotypic shift in the lack of a functional vascular compartment. Copyright © 2014 Elsevier Ltd. All rights reserved.

Climate Change and Risk of Leishmaniasis in North America: Predictions from Ecological Niche Models of Vector and Reservoir Species

PubMed Central

González, Camila; Wang, Ophelia; Strutz, Stavana E.; González-Salazar, Constantino; Sánchez-Cordero, Víctor; Sarkar, Sahotra

2010-01-01

Background Climate change is increasingly being implicated in species' range shifts throughout the world, including those of important vector and reservoir species for infectious diseases. In North America (México, United States, and Canada), leishmaniasis is a vector-borne disease that is autochthonous in México and Texas and has begun to expand its range northward. Further expansion to the north may be facilitated by climate change as more habitat becomes suitable for vector and reservoir species for leishmaniasis. Methods and Findings The analysis began with the construction of ecological niche models using a maximum entropy algorithm for the distribution of two sand fly vector species (Lutzomyia anthophora and L. diabolica), three confirmed rodent reservoir species (Neotoma albigula, N. floridana, and N. micropus), and one potential rodent reservoir species (N. mexicana) for leishmaniasis in northern México and the United States. As input, these models used species' occurrence records with topographic and climatic parameters as explanatory variables. Models were tested for their ability to predict correctly both a specified fraction of occurrence points set aside for this purpose and occurrence points from an independently derived data set. These models were refined to obtain predicted species' geographical distributions under increasingly strict assumptions about the ability of a species to disperse to suitable habitat and to persist in it, as modulated by its ecological suitability. Models successful at predictions were fitted to the extreme A2 and relatively conservative B2 projected climate scenarios for 2020, 2050, and 2080 using publicly available interpolated climate data from the Third Intergovernmental Panel on Climate Change Assessment Report. Further analyses included estimation of the projected human population that could potentially be exposed to leishmaniasis in 2020, 2050, and 2080 under the A2 and B2 scenarios. All confirmed vector and reservoir species will see an expansion of their potential range towards the north. Thus, leishmaniasis has the potential to expand northwards from México and the southern United States. In the eastern United States its spread is predicted to be limited by the range of L. diabolica; further west, L. anthophora may play the same role. In the east it may even reach the southern boundary of Canada. The risk of spread is greater for the A2 scenario than for the B2 scenario. Even in the latter case, with restrictive (contiguous) models for dispersal of vector and reservoir species, and limiting vector and reservoir species occupancy to only the top 10% of their potential suitable habitat, the expected number of human individuals exposed to leishmaniasis by 2080 will at least double its present value. Conclusions These models predict that climate change will exacerbate the ecological risk of human exposure to leishmaniasis in areas outside its present range in the United States and, possibly, in parts of southern Canada. This prediction suggests the adoption of measures such as surveillance for leishmaniasis north of Texas as disease cases spread northwards. Potential vector and reservoir control strategies—besides direct intervention in disease cases—should also be further investigated. PMID:20098495

Climate change and risk of leishmaniasis in north america: predictions from ecological niche models of vector and reservoir species.

PubMed

González, Camila; Wang, Ophelia; Strutz, Stavana E; González-Salazar, Constantino; Sánchez-Cordero, Víctor; Sarkar, Sahotra

2010-01-19

Climate change is increasingly being implicated in species' range shifts throughout the world, including those of important vector and reservoir species for infectious diseases. In North America (México, United States, and Canada), leishmaniasis is a vector-borne disease that is autochthonous in México and Texas and has begun to expand its range northward. Further expansion to the north may be facilitated by climate change as more habitat becomes suitable for vector and reservoir species for leishmaniasis. The analysis began with the construction of ecological niche models using a maximum entropy algorithm for the distribution of two sand fly vector species (Lutzomyia anthophora and L. diabolica), three confirmed rodent reservoir species (Neotoma albigula, N. floridana, and N. micropus), and one potential rodent reservoir species (N. mexicana) for leishmaniasis in northern México and the United States. As input, these models used species' occurrence records with topographic and climatic parameters as explanatory variables. Models were tested for their ability to predict correctly both a specified fraction of occurrence points set aside for this purpose and occurrence points from an independently derived data set. These models were refined to obtain predicted species' geographical distributions under increasingly strict assumptions about the ability of a species to disperse to suitable habitat and to persist in it, as modulated by its ecological suitability. Models successful at predictions were fitted to the extreme A2 and relatively conservative B2 projected climate scenarios for 2020, 2050, and 2080 using publicly available interpolated climate data from the Third Intergovernmental Panel on Climate Change Assessment Report. Further analyses included estimation of the projected human population that could potentially be exposed to leishmaniasis in 2020, 2050, and 2080 under the A2 and B2 scenarios. All confirmed vector and reservoir species will see an expansion of their potential range towards the north. Thus, leishmaniasis has the potential to expand northwards from México and the southern United States. In the eastern United States its spread is predicted to be limited by the range of L. diabolica; further west, L. anthophora may play the same role. In the east it may even reach the southern boundary of Canada. The risk of spread is greater for the A2 scenario than for the B2 scenario. Even in the latter case, with restrictive (contiguous) models for dispersal of vector and reservoir species, and limiting vector and reservoir species occupancy to only the top 10% of their potential suitable habitat, the expected number of human individuals exposed to leishmaniasis by 2080 will at least double its present value. These models predict that climate change will exacerbate the ecological risk of human exposure to leishmaniasis in areas outside its present range in the United States and, possibly, in parts of southern Canada. This prediction suggests the adoption of measures such as surveillance for leishmaniasis north of Texas as disease cases spread northwards. Potential vector and reservoir control strategies-besides direct intervention in disease cases-should also be further investigated.

78 FR 27417 - Federal Property Suitable as Facilities To Assist the Homeless

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-10

..., Washington, DC 20593-0001; (202) 475- 5609; NASA: Mr. Frank T. Bellinger, Facilities Engineering Division...: Unutilized Comments: Off-site removal; 1,836 sf.; storage; 60 months vacant; lead-based paint; very poor....; storage; 60 months vacant; very poor conditions; lead-based paint; repairs a must; rodents w/Hanta virus...

A systematic review on the anxiolytic effects of aromatherapy on rodents under experimentally induced anxiety models.

PubMed

Tsang, Hector W H; Ho, Timothy Y C

2010-01-01

We reviewed studies from 1999 to 2009 on anxiolytic effects of different essential oils toward rodents in anxiety-related behavioral models. Journal papers that evaluated the anxiolytic effects of essential oils for rodents were extracted from available electronic data bases. The results based on 14 studies showed that different rodent species were recruited including ICR mice and Swiss mice. Most of studies applied the Elevated Plus Maze (EPM) as the animal behavioral model. Lavender oil was the most popular within the 14 studies. Lavender and rose oils were found to be effective in some of the studies. Only one study reported the underlying neurophysiological mechanism in terms of concentrations of emotionally related neuro-transmitters such as dopamine, serotonin, and their derivatives, in various brain regions. Some essential oils are found to be effective to induce anxiolytic effect in rodents under different animal anxiety models. However, more standardized experimental procedures and outcome measures are needed in future studies. Translational research to human subjects is also recommended.

Does age matter? The impact of rodent age on study outcomes.

PubMed

Jackson, Samuel J; Andrews, Nick; Ball, Doug; Bellantuono, Ilaria; Gray, James; Hachoumi, Lamia; Holmes, Alan; Latcham, Judy; Petrie, Anja; Potter, Paul; Rice, Andrew; Ritchie, Alison; Stewart, Michelle; Strepka, Carol; Yeoman, Mark; Chapman, Kathryn

2017-04-01

Rodent models produce data which underpin biomedical research and non-clinical drug trials, but translation from rodents into successful clinical outcomes is often lacking. There is a growing body of evidence showing that improving experimental design is key to improving the predictive nature of rodent studies and reducing the number of animals used in research. Age, one important factor in experimental design, is often poorly reported and can be overlooked. The authors conducted a survey to assess the age used for a range of models, and the reasoning for age choice. From 297 respondents providing 611 responses, researchers reported using rodents most often in the 6-20 week age range regardless of the biology being studied. The age referred to as 'adult' by respondents varied between six and 20 weeks. Practical reasons for the choice of rodent age were frequently given, with increased cost associated with using older animals and maintenance of historical data comparability being two important limiting factors. These results highlight that choice of age is inconsistent across the research community and often not based on the development or cellular ageing of the system being studied. This could potentially result in decreased scientific validity and increased experimental variability. In some cases the use of older animals may be beneficial. Increased scientific rigour in the choice of the age of rodent may increase the translation of rodent models to humans.

Does age matter? The impact of rodent age on study outcomes

PubMed Central

Andrews, Nick; Ball, Doug; Bellantuono, Ilaria; Gray, James; Hachoumi, Lamia; Holmes, Alan; Latcham, Judy; Petrie, Anja; Potter, Paul; Rice, Andrew; Ritchie, Alison; Stewart, Michelle; Strepka, Carol; Yeoman, Mark; Chapman, Kathryn

2016-01-01

Rodent models produce data which underpin biomedical research and non-clinical drug trials, but translation from rodents into successful clinical outcomes is often lacking. There is a growing body of evidence showing that improving experimental design is key to improving the predictive nature of rodent studies and reducing the number of animals used in research. Age, one important factor in experimental design, is often poorly reported and can be overlooked. The authors conducted a survey to assess the age used for a range of models, and the reasoning for age choice. From 297 respondents providing 611 responses, researchers reported using rodents most often in the 6–20 week age range regardless of the biology being studied. The age referred to as ‘adult’ by respondents varied between six and 20 weeks. Practical reasons for the choice of rodent age were frequently given, with increased cost associated with using older animals and maintenance of historical data comparability being two important limiting factors. These results highlight that choice of age is inconsistent across the research community and often not based on the development or cellular ageing of the system being studied. This could potentially result in decreased scientific validity and increased experimental variability. In some cases the use of older animals may be beneficial. Increased scientific rigour in the choice of the age of rodent may increase the translation of rodent models to humans. PMID:27307423

A Comparison of Pathophysiology in Humans and Rodent Models of Subarachnoid Hemorrhage

PubMed Central

Leclerc, Jenna L.; Garcia, Joshua M.; Diller, Matthew A.; Carpenter, Anne-Marie; Kamat, Pradip K.; Hoh, Brian L.; Doré, Sylvain

2018-01-01

Non-traumatic subarachnoid hemorrhage (SAH) affects an estimated 30,000 people each year in the United States, with an overall mortality of ~30%. Most cases of SAH result from a ruptured intracranial aneurysm, require long hospital stays, and result in significant disability and high fatality. Early brain injury (EBI) and delayed cerebral vasospasm (CV) have been implicated as leading causes of morbidity and mortality in these patients, necessitating intense focus on developing preclinical animal models that replicate clinical SAH complete with delayed CV. Despite the variety of animal models currently available, translation of findings from rodent models to clinical trials has proven especially difficult. While the explanation for this lack of translation is unclear, possibilities include the lack of standardized practices and poor replication of human pathophysiology, such as delayed cerebral vasospasm and ischemia, in rodent models of SAH. In this review, we summarize the different approaches to simulating SAH in rodents, in particular elucidating the key pathophysiology of the various methods and models. Ultimately, we suggest the development of standardized model of rodent SAH that better replicates human pathophysiology for moving forward with translational research. PMID:29623028

Application of FDA-Approved Memantine and Newer NitroMemantine Derivatives to Treat Neurological Manifestations in Rodent Models of Tuberous Sclerosis Complex

DTIC Science & Technology

2014-05-01

Memantine and Newer NitroMemantine Derivatives to Treat Neurological Manifestations in Rodent Models of Tuberous Sclerosis Complex PRINCIPAL...Approved Memantine and Newer NitroMemantine Derivatives to Treat 5a. CONTRACT NUMBER W81XWH-13-1-0053 Neurological Manifestations in Rodent Models of...to investigate if administration of the FDA-approved drug, Memantine , an uncompetitive/fast off-rate antagonist of the N- methyl-D-aspartate-type

-(S)-Alpha-phenyl-2-pyridine-ethanamine Dihydrochloride-, a low affinity uncompetitive N-methyl-D-aspartic acid antagonist, is effective in rodent models of global and focal ischemia.

PubMed

Cregan, E F; Peeling, J; Corbett, D; Buchan, A M; Saunders, J; Auer, R N; Gao, M; Mccarthy, D J; Eisman, M S; Campbell, T M; Murray, R J; Stagnitto, M L; Palmer, G C

1997-12-01

[(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low affinity uncompetitive N-methyl-D-aspartic acid receptor antagonist that was tested in animal models of anoxia and ischemia. Pretreatment of rodents with ARL 15896AR extended survival time during exposure to hypoxia. With the rat four-vessel occlusion model of global ischemia (20 min), oral dosing commencing at reflow, resulted in significant protection of the CA1 hippocampal neurons. ARL 15896AR was, however, ineffective in the rat two-vessel occlusion model and in the gerbil models of forebrain ischemia, the latter due to an inability to attain suitable plasma levels. In the spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) (2 hr plus 22 hr reflow), acute dosing with ARL 15896AR (i.p.) beginning from 30 min before or up to 1 hr post-MCAO significantly reduced cortical infarct volume. The ability of ARL 15896AR to influence infarct size, as well as functional correlates was examined in SHR after 90 min of MCAO. T2 weighted magnetic resonance images taken at 2 and 6 days post-MCAO revealed significantly smaller lesion sizes in the group receiving injections with ARL 15896AR beginning 30 min after occlusion. Spontaneously hypertensive rats were subsequently tested (30-42 days post-MCAO) and found to be deficient in skilled use of the forepaws (staircase test). The contralateral forepaw was most severely impaired, however, ARL 15896AR treatment prevented motor impairment in only the ipsilateral forepaw. Histopathological examination of cortical infarct size was unremarkable between treated and control rats. The findings indicate that ARL 15896AR exhibits neuroprotection in global and focal models of ischemia

Development and validation of a point-of-care test for detecting hantavirus antibodies in human and rodent samples.

PubMed

Koishi, Andrea Cristine; Aoki, Mateus Nóbrega; Jorge, Taissa Ricciardi; Suzukawa, Andréia Akemi; Zanluca, Camila; Levis, Silvana; Duarte Dos Santos, Claudia Nunes

2016-07-01

Hantaviruses are etiologic agents of a zoonotic disease transmitted mainly from wild rodents to humans, causing Hemorrhagic Fever with Renal Syndrome in Eurasia and the Hantavirus Cardiopulmonary Syndrome in the Americas (HCPS), reaching a lethality rate of 40% in Brazil. Hantavirus diagnostic and seroprevalence are often based on the presence of IgM and IgG antibodies against the virus. Here we propose a rapid test assay able to identify hantavirus antibodies with sensibility and specificity similar to ELISA assays. We analyzed five groups of samples, including healthy human population and small mammals of endemic areas, suspected cases of HCPS, patients with non-related infections and a serum panel from a different geographical region. The test presented good rates of sensibility (87-100%) and specificity (97-100%) for all groups, being a promising tool suitable for both rodent and human hantavirus epidemiological surveys. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluating social defeat as a model for psychopathology in adult female rodents.

PubMed

Solomon, Matia B

2017-01-02

Social conflict is a predominant stressor in humans and is associated with increased risk for developing psychological illnesses including depression and anxiety. Overwhelmingly, more women suffer from these disorders, which may be due to increased stress sensitivity. Like humans, rodents experience a myriad of physiological and behavioral sequelae due to prolonged stress exposure. Although the motivation for social conflict may differ between humans and rodents, female rodents may provide an opportunity to explore the underlying mechanisms by which stress confers risk for psychopathology in women. Because most female rodents do not express spontaneous aggression, the majority of basic research examines the physiological and behavioral outcomes of social conflict in male rodents. However, there are instances where female rodents exhibit territorial (California mice and Syrian hamsters) and maternal aggression (rats, mice, and hamsters) creating a venue to examine sex differences in physiology and behavior in response to stress. While many studies rely upon nonsocial behavioral assays (e.g., elevated plus maze, forced swim test) to assess the impact of stress on emotionality, here we primarily focus on behavioral outcomes in social-based assays in rodents. This is critically important given that disruptions in social relationships can be a cause and consequence of neuropsychiatric diseases. Next, we briefly discuss how sex differences in the recruitment of neural circuitry and/or neurochemistry in response to stress may underlie sex differences in neuroendocrine and behavioral stress responses. Finally, the translational value of females in rodent stress models and considerations regarding behavioral interpretations of these models are discussed. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Treatment with Uric Acid Reduces Infarct and Improves Neurologic Function in Female Mice After Transient Cerebral Ischemia.

PubMed

Dhanesha, Nirav; Vázquez-Rosa, Edwin; Cintrón-Pérez, Coral J; Thedens, Daniel; Kort, Alexa J; Chuong, Vicky; Rivera-Dompenciel, Adriana M; Chauhan, Anil K; Leira, Enrique C; Pieper, Andrew A

2018-05-01

Exogenous administration of uric acid, a naturally occurring antioxidant that scavenges reactive oxygen species in vasculature, has shown protective efficacy in both rodent models of stroke and human stroke patients in Spain as an adjuvant treatment to mechanical thrombectomy. Before clinical trials can be initiated in the United States, however, confirmation of efficacy in alternative preclinical models is required in accordance with stroke therapy academic industry roundtable-RIGOR criteria. To date, preclinical efficacy has only been established in the acute setting in male rodents. To address this need, we subjected 7- to 9-week old ovariectomized female mice to filament-induced right middle cerebral artery ischemia and reperfusion, an established preclinical model of mechanical thrombectomy. Fidelity of the procedure was monitored by laser Doppler flowmetry. A separate lab randomly assigned animals to vehicle versus uric acid infusion, which was initiated immediately after 45 minutes of reperfusion. Poststroke analysis of infarction size and neurologic function were conducted by investigators blind to treatment group, with a 7-day primary endpoint and a 3-day intermediary analysis at 1and. Infarct size and neurologic function at 7 days poststroke were significantly improved in uric acid-treated animals, relative to vehicle. Efficacy of uric acid in preclinical models of stroke is now expanded to include female mice analyzed at a later time point than has been investigated previously. These results support stroke therapy academic industry roundtable-RIGOR driven determination of the suitability of acute administration of uric acid as an adjuvant to mechanical thrombectomy in clinical trials for patients with stroke. Published by Elsevier Inc.

Relationships between Rodent White Adipose Fat Pads and Human White Adipose Fat Depots

PubMed Central

Chusyd, Daniella E.; Wang, Donghai; Huffman, Derek M.; Nagy, Tim R.

2016-01-01

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 (WAT) 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 WAT. Thus, further research is warranted to more carefully define the strengths and limitations of rodent WAT as a model for humans, with a particular emphasis on comparable fat depots, such as mesenteric fat. PMID:27148535

A comparison of two rodent repellents in broadcast seeding Douglas-fir.

Treesearch

Edward J. Dimock

1957-01-01

Broadcast seeding of cutover lands is a promising, yet still problematical, means of tree regeneration. Substantial progress has been made since 1950, particularly with the introduction of new rodenticides and repellents suitable for direct application to the seed. One of these is tetramine (tetramethylene disulpho tetramine), a highly lethal repellent that has shown...

The trophic responses of two different rodent–vector–plague systems to climate change

PubMed Central

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

2015-01-01

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. PMID:25540277

2015 Summer Series - Ruth Globus - Flying Through the Ages: Rodent Research for Human Health

NASA Image and Video Library

2015-06-16

Rodents are a model organism to study the short and long term effects of space travel. Building on its space shuttle experience, NASA Ames has developed the Rodent Research Habitat for the International Space Station to implement space biology investigations. Dr. Ruth Globus' seminar takes us into the world of rodent research in space and explains how it can support human health.

Perceptual and neural responses to sweet taste in humans and rodents.

PubMed

Lemon, Christian H

2015-08-01

This mini-review discusses some of the parallels between rodent neurophysiological and human psychophysical data concerning temperature effects on sweet taste. "Sweet" is an innately rewarding taste sensation that is associated in part with foods that contain calories in the form of sugars. Humans and other mammals can show unconditioned preference for select sweet stimuli. Such preference is poised to influence diet selection and, in turn, nutritional status, which underscores the importance of delineating the physiological mechanisms for sweet taste with respect to their influence on human health. Advances in our knowledge of the biology of sweet taste in humans have arisen in part through studies on mechanisms of gustatory processing in rodent models. Along this line, recent work has revealed there are operational parallels in neural systems for sweet taste between mice and humans, as indexed by similarities in the effects of temperature on central neurophysiological and psychophysical responses to sucrose in these species. Such association strengthens the postulate that rodents can serve as effective models of particular mechanisms of appetitive taste processing. Data supporting this link are discussed here, as are rodent and human data that shed light on relationships between mechanisms for sweet taste and ingestive disorders, such as alcohol abuse. Rodent models have utility for understanding mechanisms of taste processing that may pertain to human flavor perception. Importantly, there are limitations to generalizing data from rodents, albeit parallels across species do exist.

The role of free radicals in traumatic brain injury.

PubMed

O'Connell, Karen M; Littleton-Kearney, Marguerite T

2013-07-01

Traumatic brain injury (TBI) is a significant cause of death and disability in both the civilian and the military populations. The primary impact causes initial tissue damage, which initiates biochemical cascades, known as secondary injury, that expand the damage. Free radicals are implicated as major contributors to the secondary injury. Our review of recent rodent and human research reveals the prominent role of the free radicals superoxide anion, nitric oxide, and peroxynitrite in secondary brain injury. Much of our current knowledge is based on rodent studies, and the authors identified a gap in the translation of findings from rodent to human TBI. Rodent models are an effective method for elucidating specific mechanisms of free radical-induced injury at the cellular level in a well-controlled environment. However, human TBI does not occur in a vacuum, and variables controlled in the laboratory may affect the injury progression. Additionally, multiple experimental TBI models are accepted in rodent research, and no one model fully reproduces the heterogeneous injury seen in humans. Free radical levels are measured indirectly in human studies based on assumptions from the findings from rodent studies that use direct free radical measurements. Further study in humans should be directed toward large samples to validate the findings in rodent studies. Data obtained from these studies may lead to more targeted treatment to interrupt the secondary injury cascades.

Epigenetic memory: the Lamarckian brain

PubMed Central

Fischer, Andre

2014-01-01

Recent data support the view that epigenetic processes play a role in memory consolidation and help to transmit acquired memories even across generations in a Lamarckian manner. Drugs that target the epigenetic machinery were found to enhance memory function in rodents and ameliorate disease phenotypes in models for brain diseases such as Alzheimer's disease, Chorea Huntington, Depression or Schizophrenia. In this review, I will give an overview on the current knowledge of epigenetic processes in memory function and brain disease with a focus on Morbus Alzheimer as the most common neurodegenerative disease. I will address the question whether an epigenetic therapy could indeed be a suitable therapeutic avenue to treat brain diseases and discuss the necessary steps that should help to take neuroepigenetic research to the next level. PMID:24719207

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

PubMed Central

Wahl, Devin; Coogan, Sean CP; Solon-Biet, Samantha M; de Cabo, Rafael; Haran, James B; Raubenheimer, David; Cogger, Victoria C; Mattson, Mark P; Simpson, Stephen J; Le Couteur, David G

2017-01-01

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. PMID:28932108

Comparative analysis of the oral mucosae from rodents and non-rodents: Application to the nonclinical evaluation of sublingual immunotherapy products

PubMed Central

Thirion-Delalande, Catherine; Gervais, Frédéric; Fisch, Cécile; Cuiné, Jean; Baron-Bodo, Véronique; Moingeon, Philippe

2017-01-01

Background A comparative characterization of the oral mucosa in various animals is needed to identify the best animal model(s) for nonclinical evaluation of sublingual immunotherapy products. With this aim, we studied the histological characteristics and immune cell infiltrates of oral mucosae from common animal species. Methods Three oral regions (i.e. ventral surface of the tongue, mouth floor and cheek) obtained from eight animal species, including rodents (i.e. mice, rats, hamsters, guinea pigs) and non-rodents (i.e. rabbits, dogs, minipigs and monkeys) were characterized by histology and immunohistology in comparison with a human tongue. Results Rodents exhibit a thin keratinized epithelium with low epithelial extensions, whereas non-rodents, most particularly minipigs and monkeys, display a non-keratinized epithelium with larger rete ridges, similarly to humans. Glycogen-rich cells in the superficial epithelial layers are observed in samples from both minipigs, monkeys and humans. Comparable immune subpopulations detected in the 3 oral regions from rodent and non-rodent species include MHC-II+ antigen presenting cells, mostly CD163+ macrophages, located in the lamina propria (LP) and muscle tissue in the vicinity of resident CD3+CD4+ T cells. Limited numbers of mast cells are also detected in the LP and muscle tissue from all species. Conclusion The oral mucosae of minipigs and monkeys are closest to that of humans, and the immune networks are quite similar between all rodents and non-rodents. Taking into account the ethical and logistical difficulties of performing research in the latter species, rodents and especially mice, should preferentially be used for pharmacodynamics/efficacy studies. Our data also support the use of minipigs to perform biodistribution and safety studies of sublingual immunotherapy products. PMID:28886055

The roots of empathy: through the lens of rodent models

PubMed Central

Meyza, K.Z.; Bartal, I. Ben-Ami; Monfils, M.H.; Panksepp, J.B.; Knapska, E.

2016-01-01

Empathy is a phenomenon often considered dependent on higher-order emotional control and an ability to relate to the emotional state of others. It is, by many, attributed only to species having well-developed cortical circuits capable of performing such complex tasks. However, over the years, a wealth of data has been accumulated showing that rodents are capable not only of sharing emotional states of their conspecifics, but also of prosocial behavior driven by such shared experiences. The study of rodent empathic behaviors is only now becoming an independent research field. Relevant animal models allow precise manipulation of neural networks, thereby offering insight into the foundations of empathy in the mammalian brains. Here we review the data on empathic behaviors in rat and mouse models, their neurobiological and neurophysiological correlates, and the factors influencing these behaviors. We discuss how simple rodent models of empathy enhance our understanding of how brain controls empathic behaviors. PMID:27825924

Detection of genotoxic and non-genotoxic carcinogens in Xpc(-/-)p53(+/-) mice.

PubMed

Melis, Joost P M; Speksnijder, Ewoud N; Kuiper, Raoul V; Salvatori, Daniela C F; Schaap, Mirjam M; Maas, Saskia; Robinson, Joke; Verhoef, Aart; van Benthem, Jan; Luijten, Mirjam; van Steeg, Harry

2013-01-15

An accurate assessment of the carcinogenic potential of chemicals and pharmaceutical drugs is essential to protect humans and the environment. Therefore, substances are extensively tested before they are marketed to the public. Currently, the rodent two-year bioassay is still routinely used to assess the carcinogenic potential of substances. However, over time it has become clear that this assay yields false positive results and also has several economic and ethical drawbacks including the use of large numbers of animals, the long duration, and the high cost. The need for a suitable alternative assay is therefore high. Previously, we have proposed the Xpa*p53 mouse model as a very suitable alternative to the two-year bioassay. We now show that the Xpc*p53 mouse model preserves all the beneficial traits of the Xpa*p53 model for sub-chronic carcinogen identification and can identify both genotoxic and non-genotoxic carcinogens. Moreover, Xpc*p53 mice appear to be more responsive than Xpa*p53 mice towards several genotoxic and non-genotoxic carcinogens. Furthermore, Xpc*p53 mice are far less sensitive than Xpa*p53 mice for the toxic activity of DNA damaging agents and as such clearly respond in a similar way as wild type mice do. These advantageous traits of the Xpc*p53 model make it a better alternative for in vivo carcinogen testing than Xpa*p53. This pilot study suggests that Xpc*p53 mice are suited for routine sub-chronic testing of both genotoxic and non-genotoxic carcinogens and as such represent a suitable alternative to possibly replace the murine life time cancer bioassay. Copyright © 2012 Elsevier Inc. All rights reserved.

The valproic acid-induced rodent model of autism.

PubMed

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.

Studies into abnormal aggression in humans and rodents: Methodological and translational aspects.

PubMed

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.

Structured networks support sparse traveling waves in rodent somatosensory cortex.

PubMed

Moldakarimov, Samat; Bazhenov, Maxim; Feldman, Daniel E; Sejnowski, Terrence J

2018-05-15

Neurons responding to different whiskers are spatially intermixed in the superficial layer 2/3 (L2/3) of the rodent barrel cortex, where a single whisker deflection activates a sparse, distributed neuronal population that spans multiple cortical columns. How the superficial layer of the rodent barrel cortex is organized to support such distributed sensory representations is not clear. In a computer model, we tested the hypothesis that sensory representations in L2/3 of the rodent barrel cortex are formed by activity propagation horizontally within L2/3 from a site of initial activation. The model explained the observed properties of L2/3 neurons, including the low average response probability in the majority of responding L2/3 neurons, and the existence of a small subset of reliably responding L2/3 neurons. Sparsely propagating traveling waves similar to those observed in L2/3 of the rodent barrel cortex occurred in the model only when a subnetwork of strongly connected neurons was immersed in a much larger network of weakly connected neurons.

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

PubMed Central

Auger, Jacques; Eustache, Florence; Rouiller-Fabre, Virginie; Canivenc-Lavier, Marie Chantal; Livera, Gabriel

2014-01-01

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. PMID:24369134

Considering our methods: Methodological issues with rodent models of appetite and obesity research.

PubMed

Lutz, Thomas A

2018-08-01

A large number of animal models are currently used in appetite and obesity research. Because the worldwide incidence of obesity continues to climb, it is imperative that animal models sharing characteristics of human obesity and its co-morbidities be used appropriately in the quest for novel preventions or treatments. There is probably no animal model, at least in rodents, that recapitulates all aspects of "common" human obesity and its comorbidities, but rodent models allow insight into specific mechanisms of disease or its consequences. Frequently used obesity models can be partitioned into different categories, the major ones being a) based on mutations or manipulations of one or a few individual genes or b) those in genetically intact animals exposed to obesogenic environments such as, e.g., being maintained on high-fat diets or being raised in small litters. Characteristics of these models include distinct phenotypes of obesity, hyperphagia or changes in energy metabolism, and frequent comorbidities of obesity, like hyperglycemia, insulin resistance or diabetes-like syndromes. This review which is based on a presentation given during the Annual Meeting of the Society for the Study of Ingestive Behavior in July 2017 points out some observations and characteristics of rodent models in obesity and diabetes research. The choice of rodent models discussed here is subjective and based on the author's own experience or on fruitful discussions with colleagues about the pros and cons of specific models. Hence, this review, by no means, is meant to give a complete picture of rodent models used in this type of research, but the review tries to bring up some issues which, in the author's mind, may also be relevant for models not discussed here. For example, by discussing specific mouse and rat models, similarities and differences between mice and rats will be discussed that need to be considered to interpret experimental findings cautiously and in the context of the respective animal model. Knowing which animal model to use means, knowing its limitations. Copyright © 2018 Elsevier Inc. All rights reserved.

Neuromuscular electrical stimulation of the hindlimb muscles for movement therapy in a rodent model.

PubMed

Ichihara, Kazuhiko; Venkatasubramanian, Ganapriya; Abbas, James J; Jung, Ranu

2009-01-30

Neuromuscular electrical stimulation (NMES) can provide functional movements in people after central nervous system injury. The neuroplastic effects of long-term NMES-induced repetitive limb movement are not well understood. A rodent model of neurotrauma in which NMES can be implemented may be effective for such investigations. We present a rodent model for NMES of the flexor and extensor muscles of the hip, knee, and ankle hindlimb muscles. Custom fabricated intramuscular stimulating electrodes for rodents were implanted near identified motor points of targeted muscles in ten adult, female Long Evans rats. The effects of altering NMES pulse stimulation parameters were characterized using strength duration curves, isometric joint torque recruitment curves and joint angle measures. The data indicate that short pulse widths have the advantage of producing graded torque recruitment curves when current is used as the control parameter. A stimulus frequency of 75 Hz or more produces fused contractions. The data demonstrate ability to accurately implant the electrodes and obtain selective, graded, repeatable, strong muscle contractions. Knee and ankle angular excursions comparable to those obtained in normal treadmill walking in the same rodent species can be obtained by stimulating the target muscles. Joint torques (normalized to body weight) obtained were larger than those reported in the literature for small tailed therian mammals and for peak isometric ankle plantarflexion in a different rodent species. This model system could be used for investigations of NMES assisted hindlimb movement therapy.

Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator

PubMed Central

Elcombe, Clifford R.; Peffer, Richard C.; Wolf, Douglas C.; Bailey, Jason; Bars, Remi; Bell, David; Cattley, Russell C.; Ferguson, Stephen S.; Geter, David; Goetz, Amber; Goodman, Jay I.; Hester, Susan; Jacobs, Abigail; Omiecinski, Curtis J.; Schoeny, Rita; Xie, Wen; Lake, Brian G.

2014-01-01

The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk. PMID:24180433

Can we use mice to study schizophrenia?

PubMed

Canetta, Sarah; Kellendonk, Christoph

2018-03-19

The validity of rodent models for the study of psychiatric disorders is controversial. Despite great efforts from academic institutions and pharmaceutical companies, as of today, no major therapeutic intervention has been developed for the treatment of psychiatric disorders based on mechanistic insights from rodent models. Here, we argue that despite these historical shortcomings, rodent studies are nevertheless instrumental for identifying neuronal circuit mechanisms underlying behaviours that are affected in psychiatric disorders. Focusing on schizophrenia, we will give four examples of rodent models that were generated based on genetic and environmental risk factors or pathophysiological evidence as entry points. We will then discuss how circuit analysis in these specific examples can be used for testing hypotheses about neuronal mechanisms underlying symptoms of schizophrenia, which will then guide the development of new therapies.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'. © 2018 The Author(s).

Animal models of toxicology testing: the role of pigs.

PubMed

Helke, Kristi L; Swindle, Marvin Michael

2013-02-01

In regulatory toxicological testing, both a rodent and non-rodent species are required. Historically, dogs and non-human primates (NHP) have been the species of choice of the non-rodent portion of testing. The pig is an appropriate option for these tests based on metabolic pathways utilized in xenobiotic biotransformation. This review focuses on the Phase I and Phase II biotransformation pathways in humans and pigs and highlights the similarities and differences of these models. This is a growing field and references are sparse. Numerous breeds of pigs are discussed along with specific breed differences in these enzymes that are known. While much available data are presented, it is grossly incomplete and sometimes contradictory based on methods used. There is no ideal species to use in toxicology. The use of dogs and NHP in xenobiotic testing continues to be the norm. Pigs present a viable and perhaps more reliable model of non-rodent testing.

CHEMICAL AND RADIATION LEUKEMOGENESIS IN HUMANS AND RODENTS AND THE VALUE OF RODENT MODELS FOR ASSESSING RISKS OF LYMPHOHEMATOPOIETIC CANCERS

EPA Science Inventory

This report is intended to provide an up-to-date overview of the lymphoid and hematopoietic diseases induced in humans and rodents following exposure to chemical agents. It includes a brief introduction to hematopoiesis and leukemia-inducing agents and their effects in mice and r...

Vaccines and Animal Models for Arboviral Encephalitides

DTIC Science & Technology

2003-01-01

equine encephalitis Rodents Aedes, Culex mosquitoes and other species Central and South America, southern Florida IND Western equine encephalitis Birds...former Soviet Union Licensed Louping ill Birds Britain Murray Valley encephalitis Birds Culex mosquitoes Australia, New Guinea None Powassan Rodents ...Birds Culex mosquitoes North and South America None Tick-borne encephalitis Rodents Ixodes, Dermacentor, Haemaphysalis ticks Europe, Russia, former

Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension Models

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

Yamada, Ken; Levell, Julian; Yoon, Taeyong

The observed structure–activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirmingmore » that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.« less

A Review of Applied Aspects of Dealing with Gut Microbiota Impact on Rodent Models.

PubMed

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

2015-01-01

The gut microbiota (GM) affects numerous human diseases, as well as rodent models for these. We will review this impact and summarize ways to handle this challenge in animal research. The GM is complex, with the largest fractions being the gram-positive phylum Firmicutes and the gram-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 characterization of all individual animals and incorporation of their GM composition in data evaluation may therefore be considered in future protocols. Germfree isolator-housed rodents or rodents made virtually germ free by antibiotic cocktails can be used to study diverse microbial influences on disease expression. Through subsequent inoculation with selected strains or cocktails of microbes, new "defined flora" models can yield valuable knowledge on the impact of the GM, and of specific GM members and their interactions, on important disease phenotypes and mechanisms. Rodent husbandry and microbial quality assurance practices will be important to ensure and confirm appropriate and research relevant GM. © The Author 2015. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Localised hyperthermia in rodent models using an MRI-compatible high-intensity focused ultrasound system

PubMed Central

Bing, Chenchen; Nofiele, Joris; Staruch, Robert; Ladouceur-Wodzak, Michelle; Chatzinoff, Yonatan; Ranjan, Ashish; Chopra, Rajiv

2015-01-01

Purpose Localised hyperthermia in rodent studies is challenging due to the small target size. This study describes the development and characterisation of an MRI-compatible high-intensity focused ultrasound (HIFU) system to perform localised mild hyperthermia treatments in rodent models. Material and methods The hyperthermia platform consisted of an MRI-compatible small animal HIFU system, focused transducers with sector-vortex lenses, a custom-made receive coil, and means to maintain systemic temperatures of rodents. The system was integrated into a 3T MR imager. Control software was developed to acquire images, process temperature maps, and adjust output power using a proportional-integral-derivative feedback control algorithm. Hyperthermia exposures were performed in tissue-mimicking phantoms and in a rodent model (n = 9). During heating, an ROI was assigned in the heated region for temperature control and the target temperature was 42 °C; 30 min mild hyperthermia treatment followed by a 10-min cooling procedure was performed on each animal. Results 3D-printed sector-vortex lenses were successful at creating annular focal regions which enables customisation of the heating volume. Localised mild hyperthermia performed in rats produced a mean ROI temperature of 42.1 ± 0.3 °C. The T10 and T90 percentiles were 43.2 ± 0.4 °C and 41.0 ± 0.3 °C, respectively. For a 30-min treatment, the mean time duration between 41–45 °C was 31.1 min within the ROI. Conclusions The MRI-compatible HIFU system was successfully adapted to perform localised mild hyperthermia treatment in rodent models. A target temperature of 42 °C was well-maintained in a rat thigh model for 30 min. PMID:26540488

Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades

PubMed Central

Blanga-Kanfi, Shani; Miranda, Hector; Penn, Osnat; Pupko, Tal; DeBry, Ronald W; Huchon, Dorothée

2009-01-01

Background Rodentia is the most diverse order of placental mammals, with extant rodent species representing about half of all placental diversity. In spite of many morphological and molecular studies, the family-level relationships among rodents and the location of the rodent root are still debated. Although various datasets have already been analyzed to solve rodent phylogeny at the family level, these are difficult to combine because they involve different taxa and genes. Results We present here the largest protein-coding dataset used to study rodent relationships. It comprises six nuclear genes, 41 rodent species, and eight outgroups. Our phylogenetic reconstructions strongly support the division of Rodentia into three clades: (1) a "squirrel-related clade", (2) a "mouse-related clade", and (3) Ctenohystrica. Almost all evolutionary relationships within these clades are also highly supported. The primary remaining uncertainty is the position of the root. The application of various models and techniques aimed to remove non-phylogenetic signal was unable to solve the basal rodent trifurcation. Conclusion Sequencing and analyzing a large sequence dataset enabled us to resolve most of the evolutionary relationships among Rodentia. Our findings suggest that the uncertainty regarding the position of the rodent root reflects the rapid rodent radiation that occurred in the Paleocene rather than the presence of conflicting phylogenetic and non-phylogenetic signals in the dataset. PMID:19341461

Small animal models of cardiovascular disease: tools for the study of the roles of metabolic syndrome, dyslipidemia, and atherosclerosis.

PubMed

Russell, James C; Proctor, Spencer D

2006-01-01

Cardiovascular disease, the leading cause of death in much of the modern world, is the common symptomatic end stage of a number of distinct diseases and, therefore, is multifactorial and polygenetic in character. The two major underlying causes are disorders of lipid metabolism and metabolic syndrome. The ability to develop preventative and ameliorative treatments will depend on animal models that mimic human disease processes. The focus of this review is to identify suitable animal models and insights into cardiovascular disease achieved to date using such models. The ideal animal model of cardiovascular disease will mimic the human subject metabolically and pathophysiologically, will be large enough to permit physiological and metabolic studies, and will develop end-stage disease comparable to those in humans. Given the complex multifactorial nature of cardiovascular disease, no one species will be suitable for all studies. Potential larger animal models are problematic due to cost, ethical considerations, or poor pathophysiological comparability to humans. Rabbits require high-cholesterol diets to develop cardiovascular disease, and there are no rabbit models of metabolic syndrome. Spontaneous mutations in rats provide several complementary models of obesity, hyperlipidemia, insulin resistance, and type 2 diabetes, one of which spontaneously develops cardiovascular disease and ischemic lesions. The mouse, like normal rats, is characteristically resistant to cardiovascular disease, although genetically altered strains respond to cholesterol feeding with atherosclerosis, but not with end-stage ischemic lesions. The most useful and valid species/strains for the study of cardiovascular disease appear to be small rodents, rats, and mice. This fragmented field would benefit from a consensus on well-characterized appropriate models for the study of different aspects of cardiovascular disease and a renewed emphasis on the biology of underlying diseases.

Progress in the development of animal models of acute kidney injury and its impact on drug discovery.

PubMed

Sanz, Ana B; Sanchez-Niño, María Dolores; Martín-Cleary, Catalina; Ortiz, Alberto; Ramos, Adrián M

2013-07-01

Acute kidney injury (AKI) is a clinical syndrome characterized by the acute loss of kidney function. AKI is increasingly frequent and is associated with impaired survival and chronic kidney disease progression. Experimental AKI models have contributed to a better understanding of pathophysiological mechanisms but they have not yet resulted in routine clinical application of novel therapeutic approaches. The authors present the advances in experimental AKI models over the last decade. Furthermore, the authors review their current and expected impact on novel drug discovery. New AKI models have been developed in rodents and non-rodents. Non-rodents allow the evaluation of specific aspects of AKI in both bigger animals and simpler organisms such as drosophila and zebrafish. New rodent models have recently reproduced described clinical entities, such as aristolochic and warfarin nephropathies, and have also provided better models for old entities such as thrombotic microangiopathy-induced AKI. Several therapies identified in animal models are now undergoing clinical trials in human AKI, including p53 RNAi and bone-marrow derived mesenchymal stem cells. It is conceivable that further refinement of animal models in combination with ongoing trials and novel trials based on already identified potential targets will eventually yield effective therapies for clinical AKI.

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

PubMed

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.

A Syrian golden hamster model recapitulating ebola hemorrhagic fever.

PubMed

Ebihara, Hideki; Zivcec, Marko; Gardner, Donald; Falzarano, Darryl; LaCasse, Rachel; Rosenke, Rebecca; Long, Dan; Haddock, Elaine; Fischer, Elizabeth; Kawaoka, Yoshihiro; Feldmann, Heinz

2013-01-15

Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs.

A Syrian Golden Hamster Model Recapitulating Ebola Hemorrhagic Fever

PubMed Central

Ebihara, Hideki; Zivcec, Marko; Gardner, Donald; Falzarano, Darryl; LaCasse, Rachel; Rosenke, Rebecca; Long, Dan; Haddock, Elaine; Fischer, Elizabeth; Kawaoka, Yoshihiro; Feldmann, Heinz

2013-01-01

Ebola hemorrhagic fever (EHF) is a severe viral infection for which no effective treatment or vaccine is currently available. While the nonhuman primate (NHP) model is used for final evaluation of experimental vaccines and therapeutic efficacy, rodent models have been widely used in ebolavirus research because of their convenience. However, the validity of rodent models has been questioned given their low predictive value for efficacy testing of vaccines and therapeutics, a result of the inconsistent manifestation of coagulopathy seen in EHF. Here, we describe a lethal Syrian hamster model of EHF using mouse-adapted Ebola virus. Infected hamsters displayed most clinical hallmarks of EHF, including severe coagulopathy and uncontrolled host immune responses. Thus, the hamster seems to be superior to the existing rodent models, offering a better tool for understanding the critical processes in pathogenesis and providing a new model for evaluating prophylactic and postexposure interventions prior to testing in NHPs. PMID:23045629

Dietary Factors Modulate Helicobacter-Associated Gastric Cancer in Rodent Models

PubMed Central

Fox, James G.; Wang, Timothy C.

2014-01-01

Since its discovery in 1982, the global importance of H. pylori-induced disease, particularly in developing countries, remains high. The use of rodent models particularly mice, and the unanticipated usefulness of the gerbil to study H. pylori pathogenesis have been used extensively to study the interactions of the host, the pathogen and the environmental conditions influencing the outcome of persistent H. pylori infection. Dietary factors in humans are increasingly recognized as being important factors in modulating progression and severity of H. pylori-induced gastric cancer. Studies using rodent models to verify and help explain mechanisms whereby various dietary ingredients impact disease outcome should continue to be extremely productive. PMID:24301796

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

PubMed

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.

Modeling the Lymphocytic Choriomeningitis Virus: Insights into understanding its epidemiology in the wild

NASA Astrophysics Data System (ADS)

Contreras, Christy; McKay, John; Blattman, Joseph; Holechek, Susan

2015-03-01

The lymphocytic choriomenigitis virus (LCMV) is a rodent-spread virus commonly recognized as causing neurological disease that exhibits asymptomatic pathology. The virus is a pathogen normally carried among rodents that can be transmitted to humans by direct or indirect contact with the virus in excretions and secretions from rodents and can cause aseptic meningitis and other conditions in humans. We consider an epidemiological system within rodent populations modeled by a system of ordinary differential equations that captures the dynamics of the diseases transmission and present our findings. The asymptotic nature of the pathogen plays a large role in its spread within a given population, which has motivated us to expand upon an existing SIRC model (Holechek et al in preparation) that accounts for susceptible-, infected-, recovered-, and carrier-mice on the basis of their gender. We are interested in observing and determining the conditions under which the carrier population will reach a disease free equilibrium, and we focus our investigation on the sensitivity of our model to gender, pregnancy related infection, and reproduction rate conditions.

Novel Method to Assess Arterial Insufficiency in Rodent Hindlimb

PubMed Central

Ziegler, Matthew A.; DiStasi, Matthew R.; Miller, Steven J.; Dalsing, Michael C.; Unthank, Joseph L.

2015-01-01

Background Lack of techniques to assess maximal blood flow capacity thwarts the use of rodent models of arterial insufficiency to evaluate therapies for intermittent claudication. We evaluated femoral vein outflow (VO) in combination with stimulated muscle contraction as a potential method to assess functional hindlimb arterial reserve and therapeutic efficacy in a rodent model of subcritical limb ischemia. Materials and methods VO was measured with perivascular flow probes at rest and during stimulated calf muscle contraction in young healthy rats (Wistar Kyoto, WKY; lean Zucker, LZR) and rats with cardiovascular risk factors (Spontaneously Hypertensive, SHR; Obese Zucker, OZR) with acute and/or chronic femoral arterial occlusion. Therapeutic efficacy was assessed by administration of Ramipril or Losartan to SHR after femoral artery excision. Results VO measurement in WKY demonstrated the utility of this method to assess hindlimb perfusion at rest and during calf muscle contraction. While application to diseased models (OZR, SHR) demonstrated normal resting perfusion compared to contralateral limbs, a significant reduction in reserve capacity was uncovered with muscle stimulation. Administration of Ramipril and Losartan demonstrated significant improvement in functional arterial reserve. Conclusion The results demonstrate that this novel method to assess distal limb perfusion in small rodents with subcritical limb ischemia is sufficient to unmask perfusion deficits not apparent at rest, detect impaired compensation in diseased animal models with risk factors, and assess therapeutic efficacy. The approach provides a significant advance in methods to investigate potential mechanisms and novel therapies for subcritical limb ischemia in pre-clinical rodent models. PMID:26850199

Analysis of enamel development using murine model systems: approaches and limitations

PubMed Central

Pugach, Megan K.; Gibson, Carolyn W.

2014-01-01

A primary goal of enamel research is to understand and potentially treat or prevent enamel defects related to amelogenesis imperfecta (AI). Rodents are ideal models to assist our understanding of how enamel is formed because they are easily genetically modified, and their continuously erupting incisors display all stages of enamel development and mineralization. While numerous methods have been developed to generate and analyze genetically modified rodent enamel, it is crucial to understand the limitations and challenges associated with these methods in order to draw appropriate conclusions that can be applied translationally, to AI patient care. We have highlighted methods involved in generating and analyzing rodent enamel and potential approaches to overcoming limitations of these methods: (1) generating transgenic, knockout, and knockin mouse models, and (2) analyzing rodent enamel mineral density and functional properties (structure and mechanics) of mature enamel. There is a need for a standardized workflow to analyze enamel phenotypes in rodent models so that investigators can compare data from different studies. These methods include analyses of gene and protein expression, developing enamel histology, enamel pigment, degree of mineralization, enamel structure, and mechanical properties. Standardization of these methods with regard to stage of enamel development and sample preparation is crucial, and ideally investigators can use correlative and complementary techniques with the understanding that developing mouse enamel is dynamic and complex. PMID:25278900

Temperature Variations Recorded During Interinstitutional Air Shipments of Laboratory Mice

PubMed Central

Syversen, Eric; Pineda, Fernando J; Watson, Julie

2008-01-01

Despite extensive guidelines and regulations that govern most aspects of rodent shipping, few data are available on the physical environment experienced by rodents during shipment. To document the thermal environment experienced by mice during air shipments, we recorded temperatures at 1-min intervals throughout 103 routine interinstitutional shipments originating at our institution. We found that 49.5% of shipments were exposed to high temperatures (greater than 29.4 °C), 14.6% to low temperatures (less than 7.2 °C), and 61% to temperature variations of 11 °C or more. International shipments were more likely than domestic shipments to experience temperature extremes and large variations in temperature. Freight forwarders using passenger airlines rather than their own airplanes were more likely to have shipments that experienced temperature extremes or variations. Temperature variations were most common during stopovers. Some airlines were more likely than others to experience inflight temperature extremes or swings. Most domestic shipments lasted at least 24 h, whereas international shipments lasted 48 to 72 h. Despite exposure to high and low temperatures, animals in all but 1 shipment arrived alive. We suggest that simple measures, such as shipping at night during hot weather, provision of nesting material in shipping crates, and specifying aircraft cargo-hold temperatures that are suitable for rodents, could reduce temperature-induced stress. Measures such as additional training for airport ground crews, as previously recommended by the American Veterinary Medical Association, could further reduce exposure of rodents to extreme ambient temperatures during airport stopovers. PMID:18210996

Temperature variations recorded during interinstitutional air shipments of laboratory mice.

PubMed

Syversen, Eric; Pineda, Fernando J; Watson, Julie

2008-01-01

Despite extensive guidelines and regulations that govern most aspects of rodent shipping, few data are available on the physical environment experienced by rodents during shipment. To document the thermal environment experienced by mice during air shipments, we recorded temperatures at 1-min intervals throughout 103 routine interinstitutional shipments originating at our institution. We found that 49.5% of shipments were exposed to high temperatures (greater than 29.4 degrees C), 14.6% to low temperatures (less than 7.2 degrees C), and 61% to temperature variations of 11 degrees C or more. International shipments were more likely than domestic shipments to experience temperature extremes and large variations in temperature. Freight forwarders using passenger airlines rather than their own airplanes were more likely to have shipments that experienced temperature extremes or variations. Temperature variations were most common during stopovers. Some airlines were more likely than others to experience inflight temperature extremes or swings. Most domestic shipments lasted at least 24 h, whereas international shipments lasted 48 to 72 h. Despite exposure to high and low temperatures, animals in all but 1 shipment arrived alive. We suggest that simple measures, such as shipping at night during hot weather, provision of nesting material in shipping crates, and specifying aircraft cargo-hold temperatures that are suitable for rodents, could reduce temperature-induced stress. Measures such as additional training for airport ground crews, as previously recommended by the American Veterinary Medical Association, could further reduce exposure of rodents to extreme ambient temperatures during airport stopovers.

A prenatal nicotine exposure mouse model of methylphenidate responsive ADHD-associated cognitive phenotypes.

PubMed

Zhu, Jinmin; Fan, Fangfang; McCarthy, Deirdre M; Zhang, Lin; Cannon, Elisa N; Spencer, Thomas J; Biederman, Joseph; Bhide, Pradeep G

2017-05-01

Prenatal exposure to nicotine via cigarette smoke or other forms of tobacco use is a significant environmental risk factor for attention deficit hyperactivity disorder (ADHD). The neurobiological mechanisms underlying the link between prenatal nicotine exposure (PNE) and ADHD are not well understood. Animal models, especially rodent models, are beginning to bridge this gap in knowledge. Although ADHD is characterized by hyperactivity, inattention, impulsivity and working memory deficits, the majority of the animal models are based on only one or two ADHD associated phenotypes, in particular, hyperactivity or inattention. We report a PNE mouse model that displays the full range of ADHD associated behavioral phenotypes including working memory deficit, attention deficit and impulsive-like behavior. All of the ADHD-associated phenotypes respond to a single administration of a therapeutic equivalent dose of methylphenidate. In an earlier study, we showed that PNE produces hyperactivity, frontal cortical hypodopaminergic state and thinning of the cingulate cortex. Collectively, these data suggest that the PNE mouse model recapitulates key features of ADHD and may be a suitable preclinical model for ADHD research. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity.

PubMed

Chin, Melanie; Lee, Chun-Yue Ivy; Chuang, Jen-Chieh; Bumeister, Ron; Wigley, W Christian; Sonis, Stephen T; Ward, Keith W; Meyer, Colin

2013-06-15

Bardoxolone methyl and related triterpenoids are well tolerated and efficacious in numerous animal models potentially relevant to patients with Type 2 diabetes and chronic kidney disease. These agents enhance glucose control and regulate lipid accumulation in rodent models of diabetes and obesity, and improve renal function, reduce inflammation, and prevent structural injury in models of renal disease. However, a recent study in Zucker diabetic fatty (ZDF) rats noted poor tolerability with the bardoxolone methyl analog RTA 405 within 1 mo after treatment initiation, although this study was confounded in part by the use of an impure RTA 405 batch. To investigate these discordant observations, the present studies were conducted to further characterize triterpenoids in rodent models of diabetes and obesity. A follow-up study was conducted in ZDF rats with two related triterpenoids (RTA 405 and dh404) for 1.5 mo. Consistent with previous rodent experience, and in contrast to the more recent ZDF report, ZDF rats administered RTA 405 or dh404 exhibited no adverse clinical signs, had laboratory values similar to controls, and exhibited no evidence of adverse liver or kidney histopathology. Additionally, RTA 405 was well tolerated in streptozotocin-induced Type 1 diabetic rats and high-fat-diet-induced obese mice. The present results are consistent with the overall published body of data obtained with triterpenoids and provide further evidence that these molecules are well tolerated without adverse effects on hepatobiliary or renal function in rodent models of diabetes and obesity.

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

PubMed Central

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

Optimizing Cardiovascular Benefits of Exercise: A Review of Rodent Models

PubMed Central

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

The Revised Neurobehavioral Severity Scale (NSS-R) for Rodents.

PubMed

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.

Structural Magnetic Resonance Imaging Markers of Alzheimer's Disease and Its Retranslation to Rodent Models.

PubMed

Kincses, Zsigmond Tamas; Király, András; Veréb, Dániel; Vécsei, László

2015-01-01

The importance of imaging biomarkers has been acknowledged in the diagnosis and in the follow-up of Alzheimer's disease (AD), one of the major causes of dementia. Next to the molecular biomarkers and PET imaging investigations, structural MRI approaches provide important information about the disease progression and about the pathomechanism. Furthermore,a growing body of literature retranslates these imaging biomarkers to various rodent models of the disease. The goal of this review is to provide an overview of the macro- and microstructural imaging biomarkers of AD, concentrating on atrophy measures and diffusion MRI alterations. A survey is also given of the imaging approaches used in rodent models of dementias that can promote drug development.

Synthesis of Macroporous Poly(dimethylsiloxane) Scaffolds for Tissue Engineering Applications

PubMed Central

Pedraza, Eileen; Brady, Ann-Christina; Fraker, Christopher A.

2015-01-01

Macroporous, biostable scaffolds with controlled porous architecture were prepared from poly(dimethylsiloxane) (PDMS) using sodium chloride particles (NaCl) and a solvent casting and particulate leaching (SCPL) technique. The effect of particulate size range and overall porosity on the resulting structure was evaluated. Results found 90% v/v scaffolds and particulate ranges above 100 µm to have the most optimal open framework and porosity. Resulting hydrophobic PDMS scaffolds were coated with fibronectin and evaluated as a platform for adherent cell culture using human mesenchymal stem cells. Biocompatibility of PDMS scaffolds was also evaluated in a rodent model, where implants were found to be highly biocompatibile and biostable, with positive extracellular matrix deposition throughout the scaffold. These results demonstrate the suitability of macroporous PDMS scaffolds for tissue engineering applications where strong integration with the host is desired. PMID:23683037

Distributional ecology of Andes hantavirus: a macroecological approach.

PubMed

Astorga, Francisca; Escobar, Luis E; Poo-Muñoz, Daniela; Escobar-Dodero, Joaquin; Rojas-Hucks, Sylvia; Alvarado-Rybak, Mario; Duclos, Melanie; Romero-Alvarez, Daniel; Molina-Burgos, Blanca E; Peñafiel-Ricaurte, Alexandra; Toro, Frederick; Peña-Gómez, Francisco T; Peterson, A Townsend

2018-06-22

Hantavirus pulmonary syndrome (HPS) is an infection endemic in Chile and Argentina, caused by Andes hantavirus (ANDV). The rodent Oligoryzomys longicaudatus is suggested as the main reservoir, although several other species of Sigmodontinae are known hosts of ANDV. Here, we explore potential ANDV transmission risk to humans in southern South America, based on eco-epidemiological associations among: six rodent host species, seropositive rodents, and human HPS cases. We used ecological niche modeling and macroecological approaches to determine potential geographic distributions and assess environmental similarity among rodents and human HPS cases. Highest numbers of rodent species (five) were in Chile between 35° and 41°S latitude. Background similarity tests showed niche similarity in 14 of the 56 possible comparisons: similarity between human HPS cases and the background of all species and seropositive rodents was supported (except for Abrothrix sanborni). Of interest among the results is the likely role of O. longicaudatus, Loxodontomys micropus, Abrothrix olivaceus, and Abrothrix longipilis in HPS transmission to humans. Our results support a role of rodent species' distributions as a risk factor for human HPS at coarse scales, and suggest that the role of the main reservoir (O. longicaudatus) may be supported by the broader rodent host community in some areas.

Evidence for Pyronaridine as a Highly Effective Partner Drug for Treatment of Artemisinin-Resistant Malaria in a Rodent Model

PubMed Central

Henrich, Philipp P.; O'Brien, Connor; Sáenz, Fabián E.; Cremers, Serge; Kyle, Dennis E.

2014-01-01

The increasing prevalence in Southeast Asia of Plasmodium falciparum infections with delayed parasite clearance rates, following treatment of malaria patients with the artemisinin derivative artesunate, highlights an urgent need to identify which of the currently available artemisinin-based combination therapies (ACTs) are most suitable to treat populations with emerging artemisinin resistance. Here, we demonstrate that the rodent Plasmodium berghei SANA strain has acquired artemisinin resistance following drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of artesunate or the active metabolite dihydroartemisinin. Using the SANA strain and the parental drug-sensitive N strain, we have interrogated the antimalarial activity of five ACTs, namely, artemether-lumefantrine, artesunate-amodiaquine, artesunate-mefloquine, dihydroartemisinin-piperaquine, and the newest combination artesunate-pyronaridine. By monitoring parasitemia and outcome for 30 days following initiation of treatment, we found that infections with artemisinin-resistant P. berghei SANA parasites can be successfully treated with artesunate-pyronaridine used at doses that are curative for the parental drug-sensitive N strain. No other partner drug combination was as effective in resolving SANA infections. Of the five partner drugs tested, pyronaridine was also the most effective at suppressing the recrudescence of SANA parasites. These data support the potential benefit of implementing ACTs with pyronaridine in regions affected by artemisinin-resistant malaria. PMID:24145526

Establishing a Mouse Model of a Pure Small Fiber Neuropathy with the Ultrapotent Agonist of Transient Receptor Potential Vanilloid Type 1.

PubMed

Lee, Yi-Chen; Lu, Shui-Chin; Hsieh, Yu-Lin

2018-02-13

Patients with diabetes mellitus (DM) or those experiencing the neurotoxic effects of chemotherapeutic agents may develop sensation disorders due to degeneration and injury of small-diameter sensory neurons, referred to as small fiber neuropathy. Present animal models of small fiber neuropathy affect both large- and small-diameter sensory fibers and thus create a neuropathology too complex to properly assess the effects of injured small-diameter sensory fibers. Therefore, it is necessary to develop an experimental model of pure small fiber neuropathy to adequately examine these issues. This protocol describes an experimental model of small fiber neuropathy specifically affecting small-diameter sensory nerves with resiniferatoxin (RTX), an ultrapotent agonist of transient receptor potential vanilloid type 1 (TRPV1), through a single dose of intraperitoneal injection, referred to as RTX neuropathy. This RTX neuropathy showed pathological manifestations and behavioral abnormalities that mimic the clinical characteristics of patients with small fiber neuropathy, including intraepidermal nerve fiber (IENF) degeneration, specifically injury in small-diameter neurons, and induction of thermal hypoalgesia and mechanical allodynia. This protocol tested three doses of RTX (200, 50, and 10 µg/kg, respectively) and concluded that a critical dose of RTX (50 µg/kg) is required for the development of typical small fiber neuropathy manifestations, and prepared a modified immunostaining procedure to investigate IENF degeneration and neuronal soma injury. The modified procedure is fast, systematic, and economic. Behavioral evaluation of neuropathic pain is critical to reveal the function of small-diameter sensory nerves. The evaluation of mechanical thresholds in experimental rodents is particularly challenging and this protocol describes a customized metal mesh that is suitable for this type of assessment in rodents. In summary, RTX neuropathy is a new and easily established experimental model to evaluate the molecular significance and intervention underlying neuropathic pain for the development of therapeutic agents.

Investigating the influence of chromatic aberration and optical illumination bandwidth on fundus imaging in rats

NASA Astrophysics Data System (ADS)

Li, Hao; Liu, Wenzhong; Zhang, Hao F.

2015-10-01

Rodent models are indispensable in studying various retinal diseases. Noninvasive, high-resolution retinal imaging of rodent models is highly desired for longitudinally investigating the pathogenesis and therapeutic strategies. However, due to severe aberrations, the retinal image quality in rodents can be much worse than that in humans. We numerically and experimentally investigated the influence of chromatic aberration and optical illumination bandwidth on retinal imaging. We confirmed that the rat retinal image quality decreased with increasing illumination bandwidth. We achieved the retinal image resolution of 10 μm using a 19 nm illumination bandwidth centered at 580 nm in a home-built fundus camera. Furthermore, we observed higher chromatic aberration in albino rat eyes than in pigmented rat eyes. This study provides a design guide for high-resolution fundus camera for rodents. Our method is also beneficial to dispersion compensation in multiwavelength retinal imaging applications.

Evaluation of porcine reproductive and respiratory syndrome virus replication in laboratory rodents

PubMed Central

Rosenfeld, Paul; Turner, Patricia V.; MacInnes, Janet I.; Nagy, Éva; Yoo, Dongwan

2009-01-01

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major cause of economic losses in the swine industry. The disease is widespread worldwide, and so PRRSV-negative pigs are often difficult to find for the study of PRRSV in vivo. To determine if a small animal model could be developed for PRRSV, 3 strains of laboratory rodent were examined for their susceptibility to the virus. No virus replication was detected in BALB/c or SCID (severe combined immunodeficiency) mice after intraperitoneal inoculation. Moderate replication of PRRSV was detected in primary cotton rat lung cell cultures, but no viral replication was detected following intranasal or intraperitoneal inoculation. Following intratracheal inoculation, viral transcripts were detected in the lungs of cotton rats, but only for 1 day. This study indicates that PRRSV replication in common laboratory rodent species is inefficient, and suggests that a rodent model for this virus is not appropriate. PMID:20046635

Is there room for all of us? Renewable energy and Xerospermophilus mohavensis

USGS Publications Warehouse

Inman, Richard D.; Esque, Todd C.; Nussear, Kenneth E.; Leitner, Philip; Matocq, Marjorie D.; Weisberg, Peter J.; Dilts, Tomas E.; Vandergast, Amy G.

2013-01-01

Mohave ground squirrels Xerospermophilus mohavensis Merriam are small ground-dwelling rodents that have a highly restricted range in the northwest Mojave Desert, California, USA. Their small natural range is further reduced by habitat loss from agriculture, urban development, military training and recreational activities. Development of wind and solar resources for renewable energy has the potential to further reduce existing habitat. We used maximum entropy habitat models with observation data to describe current potential habitat in the context of future renewable energy development in the region. While 16% of historic habitat has been impacted by, or lost to, urbanization at present, an additional 10% may be affected by renewable energy development in the near future. Our models show that X. mohavensis habitat suitability is higher in areas slated for renewable energy development than in surrounding areas. We provide habitat maps that can be used to develop sampling designs, evaluate conservation corridors and inform development planning in the region.

Spatial Segregation between Invasive and Native Commensal Rodents in an Urban Environment: A Case Study in Niamey, Niger

PubMed Central

Garba, Madougou; Dalecky, Ambroise; Kadaoure, Ibrahima; Kane, Mamadou; Hima, Karmadine; Veran, Sophie; Gagare, Sama; Gauthier, Philippe; Tatard, Caroline; Rossi, Jean-Pierre; Dobigny, Gauthier

2014-01-01

Invasive rodents have been responsible for the diffusion worldwide of many zoonotic agents, thus representing major threats for public health. Cities are important hubs for people and goods exchange and are thus expected to play a pivotal role in invasive commensal rodent dissemination. Yet, data about urban rodents' ecology, especially invasive vs. native species interactions, are dramatically scarce. Here, we provide results of an extensive survey of urban rodents conducted in Niamey, Niger, depicting the early stages of rodent bioinvasions within a city. We explore the species-specific spatial distributions throughout the city using contrasted approaches, namely field sampling, co-occurrence analysis, occupancy modelling and indicator geostatistics. We show that (i) two species (i.e. rural-like vs. truly commensal) assemblages can be identified, and that (ii) within commensal rodents, invasive (Rattus rattus and Mus musculus) and native (Mastomys natalensis) species are spatially segregated. Moreover, several pieces of arguments tend to suggest that these exclusive distributions reflect an ongoing native-to-invasive species turn over. The underlying processes as well as the possible consequences for humans are discussed. PMID:25379785

In vitro perturbations of targets in cancer hallmark processes predict rodent chemical carcinogenesis.

PubMed

Kleinstreuer, Nicole C; Dix, David J; Houck, Keith A; Kavlock, Robert J; Knudsen, Thomas B; Martin, Matthew T; Paul, Katie B; Reif, David M; Crofton, Kevin M; Hamilton, Kerry; Hunter, Ronald; Shah, Imran; Judson, Richard S

2013-01-01

Thousands of untested chemicals in the environment require efficient characterization of carcinogenic potential in humans. A proposed solution is rapid testing of chemicals using in vitro high-throughput screening (HTS) assays for targets in pathways linked to disease processes to build models for priority setting and further testing. We describe a model for predicting rodent carcinogenicity based on HTS data from 292 chemicals tested in 672 assays mapping to 455 genes. All data come from the EPA ToxCast project. The model was trained on a subset of 232 chemicals with in vivo rodent carcinogenicity data in the Toxicity Reference Database (ToxRefDB). Individual HTS assays strongly associated with rodent cancers in ToxRefDB were linked to genes, pathways, and hallmark processes documented to be involved in tumor biology and cancer progression. Rodent liver cancer endpoints were linked to well-documented pathways such as peroxisome proliferator-activated receptor signaling and TP53 and novel targets such as PDE5A and PLAUR. Cancer hallmark genes associated with rodent thyroid tumors were found to be linked to human thyroid tumors and autoimmune thyroid disease. A model was developed in which these genes/pathways function as hypothetical enhancers or promoters of rat thyroid tumors, acting secondary to the key initiating event of thyroid hormone disruption. A simple scoring function was generated to identify chemicals with significant in vitro evidence that was predictive of in vivo carcinogenicity in different rat tissues and organs. This scoring function was applied to an external test set of 33 compounds with carcinogenicity classifications from the EPA's Office of Pesticide Programs and successfully (p = 0.024) differentiated between chemicals classified as "possible"/"probable"/"likely" carcinogens and those designated as "not likely" or with "evidence of noncarcinogenicity." This model represents a chemical carcinogenicity prioritization tool supporting targeted testing and functional validation of cancer pathways.

Epigenetic modification in neurons of the mollusc Pomacea canaliculata after immune challenge.

PubMed

Ottaviani, Enzo; Accorsi, Alice; Rigillo, Giovanna; Malagoli, Davide; Blom, Joan M C; Tascedda, Fabio

2013-11-06

In human and rodents, the transcriptional response of neurons to stress is related to epigenetic modifications of both DNA and histone proteins. To assess the suitability of simple invertebrate models in studying the basic mechanisms of stress-related epigenetic modifications, we analyzed epigenetic modifications in neurons of the freshwater snail Pomacea canaliculata after the injection of Escherichia coli-derived lipopolysaccharide (LPS). The phospho-acetylation of histone H3, together with the induction of stress-related factors, c-Fos and HSP70, were evaluated in large and small neurons of the pedal ganglia of sham- and LPS-injected snails. Immunocytochemical investigations showed that after LPS injection, the immunopositivity towards phospho (Ser10)-acetyl (Lys14)-histone H3 and c-Fos increases in the nuclei of small gangliar neurons. Western blot analysis confirmed a significant increase of phospho (Ser10)-acetyl (Lys14)-histone H3 in nuclear extracts from 2h LPS-injected animals. c-Fos protein levels were significantly augmented 6h after LPS injection. Immunocytochemistry and western blot indicated that no changes occurred in HSP70 distribution and protein levels. To our knowledge this is the first demonstration of epigenetic changes in molluscan neurons after an immune challenge and indicate the gastropod P. canaliculata as a suitable model for evolutionary and translational studies on stress-related epigenetic modifications. © 2013 Published by Elsevier B.V.

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

PubMed

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.

Methods to Induce Chronic Ocular Hypertension

PubMed Central

Dey, Ashim; Manthey, Abby L.; Chiu, Kin; Do, Chi-Wai

2018-01-01

Glaucoma, a form of progressive optic neuropathy, is the second leading cause of blindness worldwide. Being a prominent disease affecting vision, substantial efforts are being made to better understand glaucoma pathogenesis and to develop novel treatment options including neuroprotective and neuroregenerative approaches. Cell transplantation has the potential to play a neuroprotective and/or neuroregenerative role for various ocular cell types (e.g., retinal cells, trabecular meshwork). Notably, glaucoma is often associated with elevated intraocular pressure, and over the past 2 decades, several rodent models of chronic ocular hypertension (COH) have been developed that reflect these changes in pressure. However, the underlying pathophysiology of glaucoma in these models and how they compare to the human condition remains unclear. This limitation is the primary barrier for using rodent models to develop novel therapies to manage glaucoma and glaucoma-related blindness. Here, we review the current techniques used to induce COH-related glaucoma in various rodent models, focusing on the strengths and weaknesses of the each, in order to provide a more complete understanding of how these models can be best utilized. To so do, we have separated them based on the target tissue (pre-trabecular, trabecular, and post-trabecular) in order to provide the reader with an encompassing reference describing the most appropriate rodent COH models for their research. We begin with an initial overview of the current use of these models in the evaluation of cell transplantation therapies. PMID:29637819

Lurking in the Shadows: Emerging Rodent Infectious Diseases

PubMed Central

Besselsen, David G.; Franklin, Craig L.; Livingston, Robert S.; Riley, Lela K.

2013-01-01

Rodent parvoviruses, Helicobacter spp., murine norovirus, and several other previously unknown infectious agents have “emerged” in laboratory rodents relatively recently. These agents have been discovered serendipitously or through active investigation of atypical serology results, cell culture contamination, unexpected histopathology, or previously unrecognized clinical disease syndromes. The potential research impact of these agents is not fully known. Infected rodents have demonstrated immunomodulation, tumor suppression, clinical disease (particularly in immunodeficient rodents), and histopathology. Perturbations of organismal and cellular physiology also likely occur. These agents posed unique challenges to laboratory animal resource programs once discovered; it was necessary to develop specific diagnostic assays and an understanding of their epidemiology and transmission routes before attempting eradication, and then evaluate eradication methods for efficacy. Even then management approaches varied significantly, from apathy to total exclusion, and such inconsistency has hindered the sharing and transfer of rodents among institutions, particularly for genetically modified rodent models that may not be readily available. As additional infectious agents are discovered in laboratory rodents in coming years, much of what researchers have learned from experiences with the recently identified pathogens will be applicable. This article provides an overview of the discovery, detection, and research impact of infectious agents recently identified in laboratory rodents. We also discuss emerging syndromes for which there is a suspected infectious etiology, and the unique challenges of managing newly emerging infectious agents. PMID:18506061

A rodent model for the study of invariant visual object recognition

PubMed Central

Zoccolan, Davide; Oertelt, Nadja; DiCarlo, James J.; Cox, David D.

2009-01-01

The human visual system is able to recognize objects despite tremendous variation in their appearance on the retina resulting from variation in view, size, lighting, etc. This ability—known as “invariant” object recognition—is central to visual perception, yet its computational underpinnings are poorly understood. Traditionally, nonhuman primates have been the animal model-of-choice for investigating the neuronal substrates of invariant recognition, because their visual systems closely mirror our own. Meanwhile, simpler and more accessible animal models such as rodents have been largely overlooked as possible models of higher-level visual functions, because their brains are often assumed to lack advanced visual processing machinery. As a result, little is known about rodents' ability to process complex visual stimuli in the face of real-world image variation. In the present work, we show that rats possess more advanced visual abilities than previously appreciated. Specifically, we trained pigmented rats to perform a visual task that required them to recognize objects despite substantial variation in their appearance, due to changes in size, view, and lighting. Critically, rats were able to spontaneously generalize to previously unseen transformations of learned objects. These results provide the first systematic evidence for invariant object recognition in rats and argue for an increased focus on rodents as models for studying high-level visual processing. PMID:19429704

Nutraceuticals in rodent models as potential treatments for human Inflammatory Bowel Disease.

PubMed

Ghattamaneni, Naga K R; Panchal, Sunil K; Brown, Lindsay

2018-04-20

Inflammatory Bowel Disease (IBD) is characterized by chronic inflammation of all or part of the digestive tract. Nutraceuticals include bioactive compounds such as polyphenols with anti-inflammatory activities, thus these products have the potential to treat chronic inflammatory diseases. We have emphasized the role of nutraceuticals in ameliorating the symptoms of IBD in rodent models of human IBD through modulation of key pathogenic mechanisms including dysbiosis, oxidative stress, increased inflammatory cytokines, immune system dysregulation, and inflammatory cell signaling pathways. Nutraceuticals have an important role in IBD patients as a preventive approach to extend remission phases and as a therapeutic intervention to suppress active IBD. Further clinical trials on nutraceuticals with positive results in rodent models are warranted. Copyright © 2018. Published by Elsevier Ltd.

Using Geographic Information System-based Ecologic Niche Models to Forecast the Risk of Hantavirus Infection in Shandong Province, China

PubMed Central

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

Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species

PubMed Central

Semple, Bridgette D.; Blomgren, Klas; Gimlin, Kayleen; Ferriero, Donna M.; Noble-Haeusslein, Linda J.

2013-01-01

Hypoxic-ischemic and traumatic brain injuries are leading causes of long-term mortality and disability in infants and children. Although several preclinical models using rodents of different ages have been developed, species differences in the timing of key brain maturation events can render comparisons of vulnerability and regenerative capacities difficult to interpret. Traditional models of developmental brain injury have utilized rodents at postnatal day 7–10 as being roughly equivalent to a term human infant, based historically on the measurement of post-mortem brain weights during the 1970s. Here we will examine fundamental brain development processes that occur in both rodents and humans, to delineate a comparable time course of postnatal brain development across species. We consider the timing of neurogenesis, synaptogenesis, gliogenesis, oligodendrocyte maturation and age-dependent behaviors that coincide with developmentally regulated molecular and biochemical changes. In general, while the time scale is considerably different, the sequence of key events in brain maturation is largely consistent between humans and rodents. Further, there are distinct parallels in regional vulnerability as well as functional consequences in response to brain injuries. With a focus on developmental hypoxicischemic encephalopathy and traumatic brain injury, this review offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development. PMID:23583307

Autoclave sterilization produces acrylamide in rodent diets: implications for toxicity testing.

PubMed

Twaddle, Nathan C; Churchwell, Mona I; McDaniel, L Patrice; Doerge, Daniel R

2004-06-30

Acrylamide (AA) is a neurotoxic and carcinogenic contaminant that is formed during the cooking of starchy foods. Assessment of human risks from toxicants is routinely performed using laboratory rodents, and such testing requires careful control of unintended exposures, particularly through the diet. This study describes an analytical method based on liquid chromatography with electrospray tandem mass spectrometry that was used to measure endogenous AA in rodent diets and to survey a number of commercial products for contamination. Method sensitivity permitted accurate quantification of endogenous levels of AA in raw diets below 20 ppb. Autoclaving a standard rodent diet (NIH-31) increased the AA content 14-fold, from 17 to 240 ppb. A nutritionally equivalent diet that was sterilized by irradiation was found to contain approximately 10 ppb of AA (NIH-31IR). A toxicokinetic study of AA and its epoxide metabolite, glycidamide, was performed by switching mice from NIH-31IR to the autoclaved diet for a 30 min feeding period (average AA dose administered was 4.5 microg/kg of body weight). The concentrations of AA and glycidamide were measured in serum collected at various times. The elimination half-lives and the areas under the respective concentration-time curves were similar for AA and glycidamide. Mice maintained on autoclaved NIH-31 diet, but otherwise untreated, showed elevated steady state levels of a glycidamide-derived DNA adduct in liver relative to mice maintained on the irradiated diet. This study demonstrates that a heat sterilization procedure used in laboratory animal husbandry (i.e., autoclaving) can lead to the formation of significant levels of AA in basal diets used for toxicity testing. AA in rodent diets is bioavailable, is distributed to tissues, and is metabolically activated to a genotoxic metabolite, which produces quantifiable cumulative DNA damage. Although the contribution of endogenous AA to the incidence of tumors in multiple organs of rodents otherwise untreated in chronic carcinogenicity bioassays (i.e., control groups) is not known, the reduction of endogenous AA through the use of a suitable irradiated diet was deemed to be critical for ongoing studies of AA carcinogenicity and neurotoxicity.

Modeling insulin resistance in rodents by alterations in diet: what have high-fat and high-calorie diets revealed?

PubMed

Small, Lewin; Brandon, Amanda E; Turner, Nigel; Cooney, Gregory J

2018-03-01

For over half a century, researchers have been feeding different diets to rodents to examine the effects of macronutrients on whole body and tissue insulin action. During this period, the number of different diets and the source of macronutrients employed have grown dramatically. Because of the large heterogeneity in both the source and percentage of different macronutrients used for studies, it is not surprising that different high-calorie diets do not produce the same changes in insulin action. Despite this, diverse high-calorie diets continue to be employed in an attempt to generate a "generic" insulin resistance. The high-fat diet in particular varies greatly between studies with regard to the source, complexity, and ratio of dietary fat, carbohydrate, and protein. This review examines the range of rodent dietary models and methods for assessing insulin action. In almost all studies reviewed, rodents fed diets that had more than 45% of dietary energy as fat or simple carbohydrates had reduced whole body insulin action compared with chow. However, different high-calorie diets produced significantly different effects in liver, muscle, and whole body insulin action when insulin action was measured by the hyperinsulinemic-euglycemic clamp method. Rodent dietary models remain an important tool for exploring potential mechanisms of insulin resistance, but more attention needs to be given to the total macronutrient content and composition when interpreting dietary effects on insulin action.

A Review of the Molecular Mechanisms of Chemically-Induced Neoplasia in Rat and Mouse Models in National Toxicology Program Bioassays and Their Relevance to Human Cancer

PubMed Central

Hoenerhoff, Mark J.; Hong, Hue Hua; Ton, Tai-Vu; Lahousse, Stephanie A.; Sills, Robert C.

2012-01-01

Tumor response in the B6C3F1 mouse, F344 rat, and other animal models following exposure to various compounds provides evidence that people exposed to these or similar compounds may be at risk for developing cancer. Although tumors in rodents and humans are often morphologically similar, underlying mechanisms of tumorigenesis are often unknown and may be different between the species. Therefore, the relevance of an animal tumor response to human health would be better determined if the molecular pathogenesis were understood. The underlying molecular mechanisms leading to carcinogenesis are complex and involve multiple genetic and epigenetic events and other factors. To address the molecular pathogenesis of environmental carcinogens, we examine rodent tumors (e.g., lung, colon, mammary gland, skin, brain, mesothelioma) for alterations in cancer genes and epigenetic events that are associated with human cancer. Our NTP studies have identified several genetic alterations in chemically induced rodent neoplasms that are important in human cancer. Identification of such alterations in rodent models of chemical carcinogenesis caused by exposure to environmental contaminants, occupational chemicals, and other compounds lends further support that they are of potential human health risk. These studies also emphasize the importance of molecular evaluation of chemically induced rodent tumors for providing greater public health significance for NTP evaluated compounds. PMID:19846892

Highly impulsive rats: modelling an endophenotype to determine the neurobiological, genetic and environmental mechanisms of addiction

PubMed Central

Jupp, Bianca; Caprioli, Daniele; Dalley, Jeffrey W.

2013-01-01

Impulsivity describes the tendency of an individual to act prematurely without foresight and is associated with a number of neuropsychiatric co-morbidities, including drug addiction. As such, there is increasing interest in the neurobiological mechanisms of impulsivity, as well as the genetic and environmental influences that govern the expression of this behaviour. Tests used on rodent models of impulsivity share strong parallels with tasks used to assess this trait in humans, and studies in both suggest a crucial role of monoaminergic corticostriatal systems in the expression of this behavioural trait. Furthermore, rodent models have enabled investigation of the causal relationship between drug abuse and impulsivity. Here, we review the use of rodent models of impulsivity for investigating the mechanisms involved in this trait, and how these mechanisms could contribute to the pathogenesis of addiction. PMID:23355644

Nonhuman primate models of focal cerebral ischemia

PubMed Central

Fan, Jingjing; Li, Yi; Fu, Xinyu; Li, Lijuan; Hao, Xiaoting; Li, Shasha

2017-01-01

Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model. PMID:28400817

Robust optical fiber patch-cords for in vivo optogenetic experiments in rats.

PubMed

Trujillo-Pisanty, Ivan; Sanio, Christian; Chaudhri, Nadia; Shizgal, Peter

2015-01-01

In vivo optogenetic experiments commonly employ long lengths of optical fiber to connect the light source (commonly a laser) to the optical fiber implants in the brain. Commercially available patch cords are expensive and break easily. Researchers have developed methods to build these cables in house for in vivo experiments with rodents [1-4]. However, the half-life of those patch cords is greatly reduced when they are used with behaving rats, which are strong enough to break the delicate cable tip and to bite through the optical fiber and furcation tubing. Based on [3] we have strengthened the patch-cord tip that connects to the optical implant, and we have incorporated multiple layers of shielding to produce more robust and resistant cladding. Here, we illustrate how to build these patch cords with FC or M3 connectors. However, the design can be adapted for use with other common optical-fiber connectors. We have saved time and money by using this design in our optical self-stimulation experiments with rats, which are commonly several months long and last four to eleven hours per session. The main advantages are: •Long half-life.•Resistant to moderate rodent bites.•Suitable for long in vivo optogenetic experiments with large rodents.

Mathematical Modeling for Scrub Typhus and Its Implications for Disease Control.

PubMed

Min, Kyung Duk; Cho, Sung Il

2018-03-19

The incidence rate of scrub typhus has been increasing in the Republic of Korea. Previous studies have suggested that this trend may have resulted from the effects of climate change on the transmission dynamics among vectors and hosts, but a clear explanation of the process is still lacking. In this study, we applied mathematical models to explore the potential factors that influence the epidemiology of tsutsugamushi disease. We developed mathematical models of ordinary differential equations including human, rodent and mite groups. Two models, including simple and complex models, were developed, and all parameters employed in the models were adopted from previous articles that represent epidemiological situations in the Republic of Korea. The simulation results showed that the force of infection at the equilibrium state under the simple model was 0.236 (per 100,000 person-months), and that in the complex model was 26.796 (per 100,000 person-months). Sensitivity analyses indicated that the most influential parameters were rodent and mite populations and contact rate between them for the simple model, and trans-ovarian transmission for the complex model. In both models, contact rate between humans and mites is more influential than morality rate of rodent and mite group. The results indicate that the effect of controlling either rodents or mites could be limited, and reducing the contact rate between humans and mites is more practical and effective strategy. However, the current level of control would be insufficient relative to the growing mite population. © 2018 The Korean Academy of Medical Sciences.

Chromosomal evolution in Rodentia

PubMed Central

Romanenko, S A; Perelman, P L; Trifonov, V A; Graphodatsky, A S

2012-01-01

Rodentia is the most species-rich mammalian order and includes several important laboratory model species. The amount of new information on karyotypic and phylogenetic relations within and among rodent taxa is rapidly increasing, but a synthesis of these data is currently lacking. Here, we have integrated information drawn from conventional banding studies, recent comparative painting investigations and molecular phylogenetic reconstructions of different rodent taxa. This permitted a revision of several ancestral karyotypic reconstructions, and a more accurate depiction of rodent chromosomal evolution. PMID:22086076

Probing for Neuroadaptations to Unpredictable Stressors in Addiction: Translational Methods and Emerging Evidence

PubMed Central

Kaye, Jesse T.; Bradford, Daniel E.; Magruder, Katherine P.; Curtin, John J.

2017-01-01

Stressors clearly contribute to addiction etiology and relapse in humans, but our understanding of specific mechanisms remains limited. Rodent models of addiction offer the power, flexibility, and precision necessary to delineate the causal role and specific mechanisms through which stressors influence alcohol and other drug use. This review describes a program of research using startle potentiation to unpredictable stressors that is well positioned to translate between animal models and clinical research with humans on stress neuroadaptations in addiction. This research rests on a solid foundation provided by three separate pillars of evidence from (a) rodent behavioral neuroscience on stress neuroadaptations in addiction, (b) rodent affective neuroscience on startle potentiation, and (c) human addiction and affective science with startle potentiation. Rodent stress neuroadaptation models implicate adaptations in corticotropin-releasing factor and norepinephrine circuits within the central extended amygdala following chronic alcohol and other drug use that mediate anxious behaviors and stress-induced reinstatement among drug-dependent rodents. Basic affective neuroscience indicates that these same neural mechanisms are involved in startle potentiation to unpredictable stressors in particular (vs. predictable stressors). We believe that synthesis of these evidence bases should focus us on the role of unpredictable stressors in addiction etiology and relapse. Startle potentiation in unpredictable stressor tasks is proposed to provide an attractive and flexible test bed to encourage tight translation and reverse translation between animal models and human clinical research on stress neuroadaptations. Experimental therapeutics approaches focused on unpredictable stressors hold high promise to identify, repurpose, or refine pharmacological and psychosocial interventions for addiction. PMID:28499100

Probing for Neuroadaptations to Unpredictable Stressors in Addiction: Translational Methods and Emerging Evidence.

PubMed

Kaye, Jesse T; Bradford, Daniel E; Magruder, Katherine P; Curtin, John J

2017-05-01

Stressors clearly contribute to addiction etiology and relapse in humans, but our understanding of specific mechanisms remains limited. Rodent models of addiction offer the power, flexibility, and precision necessary to delineate the causal role and specific mechanisms through which stressors influence alcohol and other drug use. This review describes a program of research using startle potentiation to unpredictable stressors that is well positioned to translate between animal models and clinical research with humans on stress neuroadaptations in addiction. This research rests on a solid foundation provided by three separate pillars of evidence from (a) rodent behavioral neuroscience on stress neuroadaptations in addiction, (b) rodent affective neuroscience on startle potentiation, and (c) human addiction and affective science with startle potentiation. Rodent stress neuroadaptation models implicate adaptations in corticotropin-releasing factor and norepinephrine circuits within the central extended amygdala following chronic alcohol and other drug use that mediate anxious behaviors and stress-induced reinstatement among drug-dependent rodents. Basic affective neuroscience indicates that these same neural mechanisms are involved in startle potentiation to unpredictable stressors in particular (vs. predictable stressors). We believe that synthesis of these evidence bases should focus us on the role of unpredictable stressors in addiction etiology and relapse. Startle potentiation in unpredictable stressor tasks is proposed to provide an attractive and flexible test bed to encourage tight translation and reverse translation between animal models and human clinical research on stress neuroadaptations. Experimental therapeutics approaches focused on unpredictable stressors hold high promise to identify, repurpose, or refine pharmacological and psychosocial interventions for addiction.

Stem cells--clinical application and perspectives.

PubMed

Brehm, Michael; Zeus, Tobias; Strauer, Bodo Eckehard

2002-11-01

Augmentation of myocardial performance in experimental models of therapeutic infarction and heart failure has been achieved by transplantation of exogenous cells into damaged myocardium. The quest for suitable donor cells has prompted research into the use of both embryonic stem cells and adult somatic stem cells. Recently, there has been a growing body of evidence that multipotent somatic stem cells in adult bone marrow exhibit tremendous functional plasticity and can reprogram in a new environmental tissue niche to give rise to cell lineages specific for new organ site. This phenomenon has made huge impact on myocardial biology, while multipotent adult bone marrow hematopoeitic stem cells and mesechymal stem cells can repopulate infarcted rodent myocardium and differentiate into both cardiomyocytes and new blood vessels. These data, coupled with the identification of a putative primitive cardiac stem cell population in the adult human heart, may open the way for novel therapeutic modalities for enhancing myocardial performance and treating heart failure.

Effects of Humidity Variation on the Hantavirus Infection and Hemorrhagic Fever with Renal Syndrome Occurrence in Subtropical China

PubMed Central

Xiao, Hong; Huang, Ru; Gao, Li-Dong; Huang, Cun-Rui; Lin, Xiao-Ling; Li, Na; Liu, Hai-Ning; Tong, Shi-Lu; Tian, Huai-Yu

2016-01-01

Infection rates of rodents have a significant influence on the transmission of hemorrhagic fever with renal syndrome (HFRS). In this study, four cities and two counties with high HFRS incidence in eastern Hunan Province in China were studied, and surveillance data of rodents, as well as HFRS cases and related environmental variables from 2007 to 2010, were collected. Results indicate that the distribution and infection rates of rodents are closely associated with environmental conditions. Hantavirus infections in rodents were positively correlated with temperature vegetation dryness index and negatively correlated with elevation. The predictive risk maps based on multivariate regression model revealed that the annual variation of infection risks is small, whereas monthly variation is large and corresponded well to the seasonal variation of human HFRS incidence. The identification of risk factors and risk prediction provides decision support for rodent surveillance and the prevention and control of HFRS. PMID:26711521

Bone morphology of the hind limbs in two caviomorph rodents.

PubMed

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.

Magnetic Capture of a Molecular Biomarker from Synovial Fluid in a Rat Model of Knee Osteoarthritis

PubMed Central

Yarmola, Elena G.; Shah, Yash; Arnold, David P.; Dobson, Jon; Allen, Kyle D.

2015-01-01

Biomarker development for osteoarthritis (OA) often begins in rodent models, but can be limited by an inability to aspirate synovial fluid from a rodent stifle (similar to the human knee). To address this limitation, we have developed a magnetic nanoparticle-based technology to collect biomarkers from a rodent stifle, termed magnetic capture. Using a common OA biomarker - the c-terminus telopeptide of type II collagen (CTXII) - magnetic capture was optimized in vitro using bovine synovial fluid and then tested in a rat model of knee OA. Anti-CTXII antibodies were conjugated to the surface of superparamagnetic iron oxide-containing polymeric particles. Using these anti-CTXII particles, magnetic capture was able to estimate the level of CTXII in 25 µL aliquots of bovine synovial fluid; and under controlled conditions, this estimate was unaffected by synovial fluid viscosity. Following in vitro testing, anti-CTXII particles were tested in a rat monoiodoacetate model of knee OA. CTXII could be magnetically captured from a rodent stifle without the need to aspirate fluid and showed 10 fold changes in CTXII levels from OA-affected joints relative to contralateral control joints. Combined, these data demonstrate the ability and sensitivity of magnetic capture for post-mortem analysis of OA biomarkers in the rat. PMID:26136062

Magnetic Capture of a Molecular Biomarker from Synovial Fluid in a Rat Model of Knee Osteoarthritis.

PubMed

Yarmola, Elena G; Shah, Yash; Arnold, David P; Dobson, Jon; Allen, Kyle D

2016-04-01

Biomarker development for osteoarthritis (OA) often begins in rodent models, but can be limited by an inability to aspirate synovial fluid from a rodent stifle (similar to the human knee). To address this limitation, we have developed a magnetic nanoparticle-based technology to collect biomarkers from a rodent stifle, termed magnetic capture. Using a common OA biomarker--the c-terminus telopeptide of type II collagen (CTXII)--magnetic capture was optimized in vitro using bovine synovial fluid and then tested in a rat model of knee OA. Anti-CTXII antibodies were conjugated to the surface of superparamagnetic iron oxide-containing polymeric particles. Using these anti-CTXII particles, magnetic capture was able to estimate the level of CTXII in 25 μL aliquots of bovine synovial fluid; and under controlled conditions, this estimate was unaffected by synovial fluid viscosity. Following in vitro testing, anti-CTXII particles were tested in a rat monoiodoacetate model of knee OA. CTXII could be magnetically captured from a rodent stifle without the need to aspirate fluid and showed tenfold changes in CTXII levels from OA-affected joints relative to contralateral control joints. Combined, these data demonstrate the ability and sensitivity of magnetic capture for post-mortem analysis of OA biomarkers in the rat.

Ex vivo human pancreatic slice preparations offer a valuable model for studying pancreatic exocrine biology.

PubMed

Liang, Tao; Dolai, Subhankar; Xie, Li; Winter, Erin; Orabi, Abrahim I; Karimian, Negar; Cosen-Binker, Laura I; Huang, Ya-Chi; Thorn, Peter; Cattral, Mark S; Gaisano, Herbert Y

2017-04-07

A genuine understanding of human exocrine pancreas biology and pathobiology has been hampered by a lack of suitable preparations and reliance on rodent models employing dispersed acini preparations. We have developed an organotypic slice preparation of the normal portions of human pancreas obtained from cancer resections. The preparation was assessed for physiologic and pathologic responses to the cholinergic agonist carbachol (Cch) and cholecystokinin (CCK-8), including 1) amylase secretion, 2) exocytosis, 3) intracellular Ca 2+ responses, 4) cytoplasmic autophagic vacuole formation, and 5) protease activation. Cch and CCK-8 both dose-dependently stimulated secretory responses from human pancreas slices similar to those previously observed in dispersed rodent acini. Confocal microscopy imaging showed that these responses were accounted for by efficient apical exocytosis at physiologic doses of both agonists and by apical blockade and redirection of exocytosis to the basolateral plasma membrane at supramaximal doses. The secretory responses and exocytotic events evoked by CCK-8 were mediated by CCK-A and not CCK-B receptors. Physiologic agonist doses evoked oscillatory Ca 2+ increases across the acini. Supraphysiologic doses induced formation of cytoplasmic autophagic vacuoles and activation of proteases (trypsin, chymotrypsin). Maximal atropine pretreatment that completely blocked all the Cch-evoked responses did not affect any of the CCK-8-evoked responses, indicating that rather than acting on the nerves within the pancreas slice, CCK cellular actions directly affected human acinar cells. Human pancreas slices represent excellent preparations to examine pancreatic cell biology and pathobiology and could help screen for potential treatments for human pancreatitis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Map making in the 21st century: charting breast cancer susceptibility pathways in rodent models.

PubMed

Blackburn, Anneke C; Jerry, D Joseph

2011-04-01

Genetic factors play an important role in determining risk and resistance to increased breast cancer. Recent technological advances have made it possible to analyze hundreds of thousands of single nucleotide polymorphisms in large-scale association studies in humans and have resulted in identification of alleles in over 20 genes that influence breast cancer risk. Despite these advances, the challenge remains in identifying what the functional polymorphisms are that confer the increased risk, and how these genetic variants interact with each other and with environmental factors. In rodents, the incidence of mammary tumors varies among strains, such that they can provide alternate ideas for candidate pathways involved in humans. Mapping studies in animals have unearthed numerous loci for breast cancer susceptibility that have been validated in human populations. In a reciprocal manner, knockin and knockout mice have been used to validate the tumorigenicity of risk alleles found in population studies. Rodent studies also underscore the complexity of interactions among alleles. The fact that genes affecting risk and resistance to mammary tumors in rodents depend greatly upon the carcinogenic challenge emphasizes the importance of gene x environment interactions. The challenge to rodent geneticists now is to capitalize on the ability to control the genetics and environment in rodent models of tumorigenesis to better understand the biology of breast cancer development, to identify those polymorphisms most relevant to human susceptibility and to identify compensatory pathways that can be targeted for improved prevention in women at highest risk of developing breast cancer.

Teratology studies in the minipig.

PubMed

McAnulty, Peter A

2013-01-01

The minipig is a suitable species for regulatory teratology testing and may be regarded as an alternative to the rabbit, dog, and primate. The first successful regulatory teratology studies in the minipig were performed in the 1990s. It became clear that minipigs have several benefits over the other non-rodents, as they are purpose-bred for laboratory use, they are sexually mature at approximately 5 months of age, and they produce multiple offspring. The minipig has subsequently gained regulatory acceptance in the teratology testing of new drugs.

COMPARATIVE MICROARRAY EXPRESSION ANALYSIS OF SELECTED CANCER RELEVANT GENES IN HYPERTENSIVE RESISTANT VERSUS SUSCEPTIBLE RODENT STRAINS

EPA Science Inventory

Hypertension and cancer are prevalent diseases. Epidemiological studies suggest that hypertension may increase the long term risk of cancer. Identification of resistance and/or susceptibility genes using rodent models could provide important insights into the management and treat...

Cardiac Radionuclide Imaging in Rodents: A Review of Methods, Results, and Factors at Play

PubMed Central

Cicone, Francesco; Viertl, David; Quintela Pousa, Ana Maria; Denoël, Thibaut; Gnesin, Silvano; Scopinaro, Francesco; Vozenin, Marie-Catherine; Prior, John O.

2017-01-01

The interest around small-animal cardiac radionuclide imaging is growing as rodent models can be manipulated to allow the simulation of human diseases. In addition to new radiopharmaceuticals testing, often researchers apply well-established probes to animal models, to follow the evolution of the target disease. This reverse translation of standard radiopharmaceuticals to rodent models is complicated by technical shortcomings and by obvious differences between human and rodent cardiac physiology. In addition, radionuclide studies involving small animals are affected by several extrinsic variables, such as the choice of anesthetic. In this paper, we review the major cardiac features that can be studied with classical single-photon and positron-emitting radiopharmaceuticals, namely, cardiac function, perfusion and metabolism, as well as the results and pitfalls of small-animal radionuclide imaging techniques. In addition, we provide a concise guide to the understanding of the most frequently used anesthetics such as ketamine/xylazine, isoflurane, and pentobarbital. We address in particular their mechanisms of action and the potential effects on radionuclide imaging. Indeed, cardiac function, perfusion, and metabolism can all be significantly affected by varying anesthetics and animal handling conditions. PMID:28424774

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

PubMed

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.

Temporal distribution and weather correlates of Norway rat (Rattus norvegicus) infestations in the city of Madrid, Spain.

PubMed

Tamayo Uria, Ibon; Mateu Mahiques, Jorge; Mughini Gras, Lapo

2013-06-01

Urban Norway rats are challenging pests, posing significant health and economic threats. Implementing ecologically based integrated rodent management (EBIRM) programmes relies primarily on the understanding of ecological relationships between rodents and their environments, with emphasis on the processes influencing rodent populations in the target ecosystem. We investigated the temporal distribution of urban Norway rat infestations in Madrid, Spain, and tested for the association of such infestations with temperature, relative humidity and precipitation by fitting a multivariate Poisson generalized linear model to a 3-year (2006-2008) daily time series of 4,689 Norway rat sightings. Norway rat infestations showed a marked seasonality, peaking in the summer. Most Norway rat sightings were reported on Mondays. Minimum temperature and relative humidity were positively associated with Norway rat infestation, whereas the association with precipitation was negative. The time series was adequately explained by the model. We identified previously unrecognized time periods that are more prone to Norway rat infestation than others and generated hypotheses about the association between weather, human outdoor activity, resource availability, rodent activity and population size. This provided local authorities engaged in preserving urban ecosystem health with basic research information to predict future rodent outbreaks and support the implementation of EBIRM programmes in urban areas.

Detection of genotoxic and non-genotoxic carcinogens in Xpc{sup −/−}p53{sup +/−} mice

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

Melis, Joost P.M.; Leiden University Medical Center, Department of Toxicogenetics, Leiden; Speksnijder, Ewoud N.

2013-01-15

An accurate assessment of the carcinogenic potential of chemicals and pharmaceutical drugs is essential to protect humans and the environment. Therefore, substances are extensively tested before they are marketed to the public. Currently, the rodent two-year bioassay is still routinely used to assess the carcinogenic potential of substances. However, over time it has become clear that this assay yields false positive results and also has several economic and ethical drawbacks including the use of large numbers of animals, the long duration, and the high cost. The need for a suitable alternative assay is therefore high. Previously, we have proposed themore » Xpa*p53 mouse model as a very suitable alternative to the two-year bioassay. We now show that the Xpc*p53 mouse model preserves all the beneficial traits of the Xpa*p53 model for sub-chronic carcinogen identification and can identify both genotoxic and non-genotoxic carcinogens. Moreover, Xpc*p53 mice appear to be more responsive than Xpa*p53 mice towards several genotoxic and non-genotoxic carcinogens. Furthermore, Xpc*p53 mice are far less sensitive than Xpa*p53 mice for the toxic activity of DNA damaging agents and as such clearly respond in a similar way as wild type mice do. These advantageous traits of the Xpc*p53 model make it a better alternative for in vivo carcinogen testing than Xpa*p53. This pilot study suggests that Xpc*p53 mice are suited for routine sub-chronic testing of both genotoxic and non-genotoxic carcinogens and as such represent a suitable alternative to possibly replace the murine life time cancer bioassay. Highlights: ► The Xpc*p53 mouse model is able to identify genotoxic and non-genotoxic carcinogens. ► Time, animals and cost can be significantly reduced compared to the 2-year bioassay. ► Xpc*p53 mice are more advantageous for carcinogen identification than Xpa*p53 mice. ► Xpc*p53 mice exhibit a wild type response upon exposure to genotoxicants.« less

Zebrafish as a model for acetylcholinesterase-inhibiting organophosphorus agent exposure and oxime reactivation

PubMed Central

Koenig, Jeffrey A.; Dao, Thuy L.; Kan, Robert K.; Shih, Tsung-Ming

2016-01-01

The current research progression efforts for investigating novel treatments for exposure to organophosphorus (OP) compounds that inhibit acetylcholinesterase (AChE), including pesticides and chemical warfare nerve agents (CWNAs), rely solely on in vitro cell assays and in vivo rodent models. The zebrafish (Danio rerio) is a popular, well-established vertebrate model in biomedical research that offers high-throughput capabilities and genetic manipulation not readily available with rodents. A number of research studies have investigated the effects of subacute developmental exposure to OP pesticides in zebrafish, observing detrimental effects on gross morphology, neuronal development, and behavior. Few studies, however, have utilized this model to evaluate treatments, such as oxime reactivators, anticholinergics, or anticonvulsants, following acute exposure. Preliminary work has investigated the effects of CWNA exposure. The results clearly demonstrated relative toxicity and oxime efficacy similar to that reported for the rodent model. This review surveys the current literature utilizing zebrafish as a model for OP exposure and highlights its potential use as a high-throughput system for evaluating AChE reactivator antidotal treatments to acute pesticide and CWNA exposure. PMID:27123828

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

PubMed Central

2011-01-01

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. PMID:21288352

Methods for Dissecting Motivation and Related Psychological Processes in Rodents.

PubMed

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.

New rodent models for studies of chemopreventive agents.

PubMed

Lipkin, M

1997-01-01

Some recent studies of the effects of chemopreventive agents have begun to use new rodent models to improve the analysis of stages of colonic preneoplasia, and how chemopreventive agents modify progressive abnormal cell development. In one of the models of inherited predisposition to colon cancer, mice carrying a truncated Apc allele with a nonsense mutation in exon 15 have been generated by gene targeting and embryonic stem cell technology (Apc1638 mice). These mice develop multiple gastrointestinal lesions, including adenomas and carcinomas, focal areas of high-grade dysplasia (FAD), and polypoid hyperplasias with FADS. The incidence of inherited colonic neoplasms has now been modulated by a chemopreventive regimen. Colonic lesions significantly increased in Apc1638 mice on a Western-style diet, which has higher fat content and lower calcium and vitamin D compared to the same mice on AIN-76A diet. In another rodent model, Min mice were treated with sulindac, which markedly reduced the incidence of intestinal tumors. A third new rodent model containing a targeted mutation in the gene Mcc (mutated in colorectal cancer) recently became available for chemoprevention studies. These mice develop multiple types of neoplasms including adenocarcinomas, focal areas of gastrointestinal dysplasia, papillomas of the forestomach, and tumors in other organs including lung, liver, and lymphoid tissue. Feeding a Western-style diet to the Mcc mutant mice also resulted in significantly increased gastrointestinal lesions. These nutrient modifications also have been given to normal mice, demonstrating without any chemical carcinogen that a Western-style diet induced colonic tumorigenesis. Western-style diets also have now induced modulation of cell proliferation in other organs including mammary gland, pancreas, and prostate. These findings help develop new preclinical rodent models to aid the analysis of genetic and environmental factors leading to neoplasia, as well as new methods for evaluating the chemopreventive efficacy of specific nutrients and pharmacological agents.

Quadrupedal rodent gait compensations in a low dose monoiodoacetate model of osteoarthritis.

PubMed

Lakes, Emily H; Allen, Kyle D

2018-06-01

Rodent gait analysis provides robust, quantitative results for preclinical musculoskeletal and neurological models. In prior work, surgical models of osteoarthritis have been found to result in a hind limb shuffle-stepping gait compensation, while a high dose monoiodoacetate (MIA, 3 mg) model resulted in a hind limb antalgic gait. However, it is unknown whether the antalgic gait caused by MIA is associated with severity of degeneration from the high dosage or the whole-joint degeneration associated with glycolysis inhibition. This study evaluates rodent gait changes resulting from a low dose, 1 mg unilateral intra-articular injection of MIA compared to saline injected and naïve rats. Spatiotemporal and dynamic gait parameters were collected from a total of 42 male Lewis rats spread across 3 time points: 1, 2, and 4 weeks post-injection. To provide a detailed analysis of this low dose MIA model, gait analysis was used to uniquely quantify both fore and hind limb gait parameters. Our data indicate that 1 mg of MIA caused relatively minor degeneration and a shuffle-step gait compensation, similar to the compensation observed in prior surgical models. These data from a 1 mg MIA model show a different gait compensation compared to a previously studied 3 mg model. This 1 mg MIA model resulted in gait compensations more similar to a previously studied surgical model of osteoarthritis. Additionally, this study provides detailed 4 limb analysis of rodent gait that includes spatiotemporal and dynamic data from the same gait trial. These data highlight the importance of measuring dynamic data in combination with spatiotemporal data, since compensatory gait patterns may not be captured by spatial, temporal, or dynamic characterizations alone. Copyright © 2018 Elsevier B.V. All rights reserved.

Effect of environment on the long-term consequences of chronic pain

PubMed Central

Bushnell, MC; Case, LK; Ceko, M; Cotton, VA; Gracely, JL; Low, LA; Pitcher, MH; Villemure, C

2014-01-01

Much evidence from pain patients and animal models shows that chronic pain does not exist in a vacuum, but has varied co-morbidities and far-reaching consequences. Patients with long-term pain often develop anxiety and depression and can manifest changes in cognitive functioning, particularly with working memory. Longitudinal studies in rodent models also show the development of anxiety-like behavior and cognitive changes weeks to months after an injury causing long-term pain. Brain imaging studies in pain patients and rodent models find that chronic pain is associated with anatomical and functional alterations in the brain. Nevertheless, studies in humans reveal that life-style choices, such as the practice of meditation or yoga, can reduce pain perception and have the opposite effect on the brain as does chronic pain. In rodent models, studies show that physical activity and a socially enriched environment reduce pain behavior and normalize brain function. Together, these studies suggest that the burden of chronic pain can be reduced by non-pharmacological interventions. PMID:25789436

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

PubMed

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.

Rodent models of congenital and hereditary cataract in man.

PubMed

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.

A Multi-Scale Distribution Model for Non-Equilibrium Populations Suggests Resource Limitation in an Endangered Rodent

PubMed Central

Bean, William T.; Stafford, Robert; Butterfield, H. Scott; Brashares, Justin S.

2014-01-01

Species distributions are known to be limited by biotic and abiotic factors at multiple temporal and spatial scales. Species distribution models, however, frequently assume a population at equilibrium in both time and space. Studies of habitat selection have repeatedly shown the difficulty of estimating resource selection if the scale or extent of analysis is incorrect. Here, we present a multi-step approach to estimate the realized and potential distribution of the endangered giant kangaroo rat. First, we estimate the potential distribution by modeling suitability at a range-wide scale using static bioclimatic variables. We then examine annual changes in extent at a population-level. We define “available” habitat based on the total suitable potential distribution at the range-wide scale. Then, within the available habitat, model changes in population extent driven by multiple measures of resource availability. By modeling distributions for a population with robust estimates of population extent through time, and ecologically relevant predictor variables, we improved the predictive ability of SDMs, as well as revealed an unanticipated relationship between population extent and precipitation at multiple scales. At a range-wide scale, the best model indicated the giant kangaroo rat was limited to areas that received little to no precipitation in the summer months. In contrast, the best model for shorter time scales showed a positive relation with resource abundance, driven by precipitation, in the current and previous year. These results suggest that the distribution of the giant kangaroo rat was limited to the wettest parts of the drier areas within the study region. This multi-step approach reinforces the differing relationship species may have with environmental variables at different scales, provides a novel method for defining “available” habitat in habitat selection studies, and suggests a way to create distribution models at spatial and temporal scales relevant to theoretical and applied ecologists. PMID:25237807

Concerns about the widespread use of rodent models for human risk assessments of endocrine disruptors

PubMed Central

Habert, René; Muczynski, Vincent; Grisin, Tiphany; Moison, Delphine; Messiaen, Sébastien; Frydman, René; Benachi, Alexandra; Delbes, Géraldine; Lambrot, Romain; Lehraiki, Abdelali; N'Tumba-Byn, Thierry; Guerquin, Marie-Justine; Levacher, Christine; Rouiller-Fabre, Virginie; Livera, Gabriel

2014-01-01

Fetal testis is a major target of endocrine disruptors (EDs). During the last 20 years, we have developed an organotypic culture system that maintains the function of the different fetal testis cell types and have used this approach as a toxicological test to evaluate the effects of various compounds on gametogenesis and steroidogenesis in rat, mouse and human testes. We named this test rat, mouse and human fetal testis assay. With this approach, we compared the effects of six potential EDs ((mono-(2-ethylhexyl) phthalate (MEHP), cadmium, depleted uranium, diethylstilboestrol (DES), bisphenol A (BPA) and metformin) and one signalling molecule (retinoic acid (RA)) on the function of rat, mouse and human fetal testis at a comparable developmental stage. We found that the response is similar in humans and rodents for only one third of our analyses. For instance, RA and MEHP have similar negative effects on gametogenesis in the three species. For another third of our analyses, the threshold efficient concentrations that disturb gametogenesis and/or steroidogenesis differ as a function of the species. For instance, BPA and metformin have similar negative effects on steroidogenesis in human and rodents, but at different threshold doses. For the last third of our analyses, the qualitative response is species specific. For instance, MEHP and DES affect steroidogenesis in rodents, but not in human fetal testis. These species differences raise concerns about the extrapolation of data obtained in rodents to human health risk assessment and highlight the need of rigorous comparisons of the effects in human and rodent models, when assessing ED risk. PMID:24497529

Long-term Hyperglycemia Naturally Induces Dental Caries but Not Periodontal Disease in Type 1 and Type 2 Diabetic Rodents.

PubMed

Nakahara, Yutaka; Ozaki, Kiyokazu; Matsuura, Tetsuro

2017-11-01

Periodontal disease (PD) in patients with diabetes is described as the sixth complication of diabetes. We have previously shown that diabetes increases dental caries, and carious inflammation might have a strong effect on the adjacent periodontal tissue in diabetic rodent models. However, the possibility that hyperglycemia may induce PD in diabetic animals could not be completely eliminated. The goal of this study was to confirm the presence of PD in diabetic animal models by preventing carious inflammation with fluoride administration. F344 rats injected with alloxan (type 1 diabetic model) and db/db mice (type 2 diabetic model) were given either tap water alone or tap water containing fluoride. A cariostatic effect of fluoride was evident in the diabetic animals. Meanwhile, fluoride treatment drastically attenuated periodontal inflammation in addition to preventing dental caries. Furthermore, with fluoride treatment, periodontitis was notably nonexistent in the periodontal tissue surrounding the normal molars, whereas the caries-forming process was clearly observed in the teeth that were enveloped with persistent periodontitis, suggesting that enhanced periodontal inflammation might have been derived from the dental caries in the diabetic rodents rather than from the PD. In conclusion, long-term hyperglycemia naturally induces dental caries but not PD in type 1 and type 2 diabetic rodents. © 2017 by the American Diabetes Association.

Lyme disease bacterium does not affect attraction to rodent odour in the tick vector.

PubMed

Berret, Jérémy; Voordouw, Maarten Jeroen

2015-04-28

Vector-borne pathogens experience a conflict of interest when the arthropod vector chooses a vertebrate host that is incompetent for pathogen transmission. The qualitative manipulation hypothesis suggests that vector-borne pathogens can resolve this conflict in their favour by manipulating the host choice behaviour of the arthropod vector. European Lyme disease is a model system for studying this conflict because Ixodes ricinus is a generalist tick species that vectors Borrelia pathogens that are specialized on different classes of vertebrate hosts. Avian specialists like B. garinii cannot survive in rodent reservoir hosts and vice versa for rodent specialists like B. afzelii. The present study tested whether Borrelia genospecies influenced the attraction of field-collected I. ricinus nymphs to rodent odours. Nymphs were significantly attracted to questing perches that had been scented with mouse odours. However, there was no difference in questing behaviour between nymphs infected with rodent- versus bird-specialized Borrelia genospecies. Our study suggests that the tick, and not the pathogen, controls the early stages of host choice behaviour.

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

PubMed

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.

Genetically engineered pigs as models for human disease

PubMed Central

Perleberg, Carolin; Kind, Alexander

2018-01-01

ABSTRACT Genetically modified animals are vital for gaining a proper understanding of disease mechanisms. Mice have long been the mainstay of basic research into a wide variety of diseases but are not always the most suitable means of translating basic knowledge into clinical application. The shortcomings of rodent preclinical studies are widely recognised, and regulatory agencies around the world now require preclinical trial data from nonrodent species. Pigs are well suited to biomedical research, sharing many similarities with humans, including body size, anatomical features, physiology and pathophysiology, and they already play an important role in translational studies. This role is set to increase as advanced genetic techniques simplify the generation of pigs with precisely tailored modifications designed to replicate lesions responsible for human disease. This article provides an overview of the most promising and clinically relevant genetically modified porcine models of human disease for translational biomedical research, including cardiovascular diseases, cancers, diabetes mellitus, Alzheimer's disease, cystic fibrosis and Duchenne muscular dystrophy. We briefly summarise the technologies involved and consider the future impact of recent technical advances. PMID:29419487

A potential role for imaging technology in anticancer efficacy evaluations.

PubMed

Hollingshead, M G; Bonomi, C A; Borgel, S D; Carter, J P; Shoemaker, R; Melillo, G; Sausville, E A

2004-04-01

The introduction of imaging methods suitable for rodents offers opportunities for new anticancer efficacy models. Traditional models do not provide the level of sensitivity afforded by these precise and quantitative techniques. Bioluminescent endpoints, now feasible because of sensitive charge-coupled device cameras, can be non-invasively detected in live animals. Currently, the most common luminescence endpoint is firefly luciferase, which, in the presence of O(2) and ATP, catalyses the cleavage of the substrate luciferin and results in the emission of a photon of light. In vivo implantation of tumour cells transfected with the luciferase gene allows sequential monitoring of tumour growth within the viscera by measuring these photon signals. Furthermore, tumour cell lines containing the luciferase gene transcribed from an inducible promoter offer opportunities to study molecular-target modulation without the need for ex vivo evaluations of serial tumour samples. In conjunction with this, transgenic mice bearing a luciferase reporter mechanism can be used to monitor the tumour microenvironment as well as to signal when transforming events occur. This technology has the potential to reshape the efficacy evaluations and drug-testing algorithms of the future.

Cardiac remodelling in a baboon model of intrauterine growth restriction mimics accelerated ageing.

PubMed

Kuo, Anderson H; Li, Cun; Li, Jinqi; Huber, Hillary F; Nathanielsz, Peter W; Clarke, Geoffrey D

2017-02-15

Rodent models of intrauterine growth restriction (IUGR) successfully identify mechanisms that can lead to short-term and long-term detrimental cardiomyopathies but differences between rodent and human cardiac physiology and placental-fetal development indicate a need for models in precocial species for translation to human development. We developed a baboon model for IUGR studies using a moderate 30% global calorie restriction of pregnant mothers and used cardiac magnetic resonance imaging to evaluate offspring heart function in early adulthood. Impaired diastolic and systolic cardiac function was observed in IUGR offspring with differences between male and female subjects, compared to their respective controls. Aspects of cardiac impairment found in the IUGR offspring were similar to those found in normal controls in a geriatric cohort. Understanding early cardiac biomarkers of IUGR using non-invasive imaging in this susceptible population, especially taking into account sexual dimorphisms, will aid recognition of the clinical presentation, development of biomarkers suitable for use in humans and management of treatment strategies. Extensive rodent studies have shown that reduced perinatal nutrition programmes chronic cardiovascular disease. To enable translation to humans, we developed baboon offspring cohorts from mothers fed ad libitum (control) or 70% of the control ad libitum diet in pregnancy and lactation, which were growth restricted at birth. We hypothesized that intrauterine growth restriction (IUGR) offspring hearts would show impaired function and a premature ageing phenotype. We studied IUGR baboons (8 male, 8 female, 5.7 years), control offspring (8 male, 8 female, 5.6 years - human equivalent approximately 25 years), and normal elderly (OLD) baboons (6 male, 6 female, mean 15.9 years). Left ventricular (LV) morphology and systolic and diastolic function were evaluated with cardiac MRI and normalized to body surface area. Two-way ANOVA by group and sex (with P < 0.05) indicated ejection fraction, 3D sphericity indices, cardiac index, normalized systolic volume, normalized LV wall thickness, and average filling rate differed by group. Group and sex differences were found for normalized LV wall thickening and normalized myocardial mass, without interactions. Normalized peak LV filling rate and diastolic sphericity index were not correlated in control but strongly correlated in OLD and IUGR baboons. IUGR programming in baboons produces myocardial remodelling, reduces systolic and diastolic function, and results in the emergence of a premature ageing phenotype in the heart. To our knowledge, this is the first demonstration of the specific characteristics of cardiac programming and early life functional decline with ageing in an IUGR non-human primate model. Further studies across the life span will determine progression of cardiac dysfunction. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

A semiarid fruit agroecosystem as a conservation-friendly option for small mammals in an anthropized landscape in Mexico.

PubMed

Riojas-López, Mónica E; Mellink, Eric; Luévano, Jaime

2018-03-01

Many studies have addressed the potential of low-input agroecosystems for biological conservation. However, most have been carried out on annual agroecosystems in temperate, developed countries. As agricultural surface will increase and natural protected areas alone will not warrant the conservation of biodiversity, it is crucial to include different types of agroecosystems in research and conservation efforts. In Mexico, perennial, low-input, fruit-oriented nopal orchards (Opuntia spp.), one of the few crops suitable for semiarid areas, are the 10th out of 61 most important fruit crops grown in the country. We assessed their value for conservation in an anthropized landscape by comparing their rodent assemblages with those in adjacent habitats and determined the influence of the latter on the rodent communities inside them. We live-trapped rodents in 12 orchards and adjacent natural xeric shrubland, grassland, and cropland. We captured 19 different species, of which 17 used the orchards. Four are Mexican endemics. Orchards have higher α diversity, species richness, and abundance than cropland and grassland and are not different from shrubland. The dominant rodent species are the same in orchards and shrubland, and where these two meet they integrate into one habitat. Within-habitat quality is a critical driver of the composition and diversity of rodent communities in the orchards studied, and the neighboring habitats do not modify them substantially. Increasing within-patch heterogeneity beyond a certain level is at the expense of habitat integrity and produces small-scale fragmentation reducing habitat quality. At a landscape scale, orchards contribute importantly to regional rodent diversity compared with other land use types, and appear to increase habitat connectivity between patches of shrubland. Orchards' higher α diversity would give them higher ecological resilience and make them better suited than grassland and cropland to contribute to the conservation of local biota. Nopal orchards should be considered conservation allies and incorporated in regional conservation plans. Regrettably, their future is unwarranted as producers face low revenues and lack of governmental support. Our confirmation that orchards have an important, positive impact on biodiversity can be used as a strong argument to lobby for incentives to safeguard this environmental friendly, low-input agroecosystem. © 2017 by the Ecological Society of America.

PCP-induced deficits in murine nest building activity: employment of an ethological rodent behavior to mimic negative-like symptoms of schizophrenia.

PubMed

Pedersen, Christian Spang; Sørensen, Dorte Bratbo; Parachikova, Anna I; Plath, Niels

2014-10-15

Schizophrenia is a severe psychiatric disorder characterized by three symptom domains, positive (hallucinations, obsession), negative (social withdrawal, apathy, self-neglect) and cognitive (impairment in attention, memory and executive function). Whereas current medication ameliorates positive symptomatology, negative symptoms as well as cognitive dysfunctions remain untreated. The development of improved therapies for negative symptoms has proven particularly difficult, in part due to the inability of mimicking these in rodents. Here, we address the predictive validity of combining an ethologically well preserved behavior in rodents, namely nest building activity, with an established animal model of schizophrenia, the sub-chronic PCP model, for negative symptoms. Decline in rodent nesting activity has been suggested to mirror domains of negative symptoms of schizophrenia, including social withdrawal, anhedonia and self-neglect, whereas repeated treatment with the NMDAR antagonist PCP induces and exacerbates schizophrenia-like symptoms in rodents and human subjects. Using a back-translational approach of pharmacological validation, we tested the effects of two agents targeting the nicotinic α7 receptor (EVP-6124 and TC-5619) that were reported to exert some beneficial effect on negative symptoms in schizophrenic patients. Sub-chronic PCP treatment resulted in a significant nest building deficit in mice and treatment with EVP-6124 and TC-5619 reversed this PCP-induced deficit. In contrast, the atypical antipsychotic drug risperidone remained ineffective in this assay. In addition, EVP-6124, TC-5619 and risperidone were tested in the Social Interaction Test (SIT), an assay suggested to address negative-like symptoms. Results obtained in SIT were comparable to results in the nest building test (NEST). Based on these findings, we propose nest building in combination with the sub-chronic PCP model as a novel approach to assess negative-like symptoms of schizophrenia in rodents. Copyright © 2014 Elsevier B.V. All rights reserved.

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

PubMed Central

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, Allemann C, Reibel S, Sage-Ciocca D, Bourgin P. Arvicanthis ansorgei, a novel model for the study of sleep and waking in diurnal rodents. SLEEP 2015;38(6):979–988. PMID:25409107

Toxicological Assessment of Inhaled Nanoparticles: Role of in Vivo, ex Vivo, in Vitro, and in Silico Studies

PubMed Central

Fröhlich, Eleonore; Salar-Behzadi, Sharareh

2014-01-01

The alveolar epithelium of the lung is by far the most permeable epithelial barrier of the human body. The risk for adverse effects by inhaled nanoparticles (NPs) depends on their hazard (negative action on cells and organism) and on exposure (concentration in the inhaled air and pattern of deposition in the lung). With the development of advanced in vitro models, not only in vivo, but also cellular studies can be used for toxicological testing. Advanced in vitro studies use combinations of cells cultured in the air-liquid interface. These cultures are useful for particle uptake and mechanistic studies. Whole-body, nose-only, and lung-only exposures of animals could help to determine retention of NPs in the body. Both approaches also have their limitations; cellular studies cannot mimic the entire organism and data obtained by inhalation exposure of rodents have limitations due to differences in the respiratory system from that of humans. Simulation programs for lung deposition in humans could help to determine the relevance of the biological findings. Combination of biological data generated in different biological models and in silico modeling appears suitable for a realistic estimation of potential risks by inhalation exposure to NPs. PMID:24646916

A reproducible radiation delivery method for unanesthetized rodents during periods of hind limb unloading

NASA Astrophysics Data System (ADS)

Walb, M. C.; Black, P. J.; Payne, V. S.; Munley, M. T.; Willey, J. S.

2015-07-01

Exposure to the spaceflight environment has long been known to be a health challenge concerning many body systems. Both microgravity and/or ionizing radiation can cause acute and chronic effects in multiple body systems. The hind limb unloaded (HLU) rodent model is a ground-based analogue for microgravity that can be used to simulate and study the combined biologic effects of reduced loading with spaceflight radiation exposure. However, studies delivering radiation to rodents during periods of HLU are rare. Herein we report the development of an irradiation protocol using a clinical linear accelerator that can be used with hind limb unloaded, unanesthetized rodents that is capable of being performed at most academic medical centers. A 30.5 cm × 30.5 cm × 40.6 cm rectangular chamber was constructed out of polymethyl methacrylate (PMMA) sheets (0.64 cm thickness). Five centimeters of water-equivalent material were placed outside of two PMMA inserts on either side of the rodent that permitted the desired radiation dose buildup (electronic equilibrium) and helped to achieve a flatter dose profile. Perforated aluminum strips permitted the suspension dowel to be placed at varying heights depending on the rodent size. Radiation was delivered using a medical linear accelerator at an accelerating potential of 10 MV. A calibrated PTW Farmer ionization chamber, wrapped in appropriately thick tissue-equivalent bolus material to simulate the volume of the rodent, was used to verify a uniform dose distribution at various regions of the chamber. The dosimetry measurements confirmed variances typically within 3%, with maximum variance <10% indicated through optically stimulated luminescent dosimeter (OSLD) measurements, thus delivering reliable spaceflight-relevant total body doses and ensuring a uniform dose regardless of its location within the chamber. Due to the relative abundance of LINACs at academic medical centers and the reliability of their dosimetry properties, this method may find great utility in the implementation of future ground-based studies that examine the combined spaceflight challenges of reduced loading and radiation while using the HLU rodent model.

New Developments in NASA's Rodent Research Hardware for Conducting Long Duration Biomedical and Basic Research in Space

NASA Technical Reports Server (NTRS)

Shirazi, Yasaman; Choi, S.; Harris, C.; Gong, C.; Fisher, R. J.; Beegle, J. E.; Stube, K. C.; Martin, K. J.; Nevitt, R. G.; Globus, R. K.

2017-01-01

Animal models, particularly rodents, are the foundation of pre-clinical research to understand human diseases and evaluate new therapeutics, and play a key role in advancing biomedical discoveries both on Earth and in space. The National Research Councils Decadal survey emphasized the importance of expanding NASA's life sciences research to perform long duration, rodent experiments on the International Space Station (ISS) to study effects of the space environment on the musculoskeletal and neurological systems of mice as model organisms of human health and disease, particularly in areas of muscle atrophy, bone loss, and fracture healing. To accomplish this objective, flight hardware, operations, and science capabilities were developed at NASA Ames Research Center (ARC) to enhance science return for both commercial (CASIS) and government-sponsored rodent research. The Rodent Research Project at NASA ARC has pioneered a new research capability on the International Space Station and has progressed toward translating research to the ISS utilizing commercial rockets, collaborating with academia and science industry, while training crewmembers to assist in performing research on orbit. The Rodent Research Habitat provides a living environment for animals on ISS according to standard animal welfare requirements, and daily health checks can be performed using the habitats camera system. Results from these studies contribute to the science community via both the primary investigation and banked samples that are shared in publicly available data repository such as GeneLab. Following each flight, through the Biospecimen Sharing Program (BSP), numerous tissues and thousands of samples will be harvested, and distributed from the Space Life and Physical Sciences (SLPS) to Principal Investigators (PIs) through the Ames Life Science Data Archive (ALSDA). Every completed mission sets a foundation to build and design greater complexity into future research and answer questions about common human diseases. Together, the hardware improvements (enrichment, telemetry sensors, cameras), new capabilities (live animal return), and experience that the Rodent Research team has gained working with principal investigator teams and ISS crew to conduct complex experiments on orbit are expanding capabilities for long duration rodent research on the ISS to achieve both basic science and biomedical research objectives.

The Neonatal Ventral Hippocampal Lesion (NVHL) Rodent Model of Schizophrenia

PubMed Central

Brady, Anne Marie

2016-01-01

Animal models are crucial to the study of the neurobiological bases of psychiatric disorders, but schizophrenia is a particularly challenging disorder to model given the complexity and heavily verbal nature of its symptoms. This article describes a developmental surgical rodent model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model. This widely used model produces reliable behavioral abnormalities that are comparable to those observed in patients, as well as anatomical and neurophysiological disruptions in forebrain areas that are also implicated in schizophrenia. A brief background of the development and validity of the NVHL model is discussed here, along with detailed procedures for producing the model in rats. Critical issues particular to neonatal surgery are discussed, and representative histological and behavioral results are presented. PMID:27696361

Modeling of mouse eye and errors in ocular parameters affecting refractive state

NASA Astrophysics Data System (ADS)

Bawa, Gurinder

Rodents eye are particularly used to study refractive error state of an eye and development of refractive eye. Genetic organization of rodents is similar to that of humans, which makes them interesting candidates to be researched upon. From rodents family mice models are encouraged over rats because of availability of genetically engineered models. Despite of extensive work that has been performed on mice and rat models, still no one is able to quantify an optical model, due to variability in the reported ocular parameters. In this Dissertation, we have extracted ocular parameters and generated schematics of eye from the raw data from School of Medicine, Detroit. In order to see how the rays would travel through an eye and the defects associated with an eye; ray tracing has been performed using ocular parameters. Finally we have systematically evaluated the contribution of various ocular parameters, such as radii of curvature of ocular surfaces, thicknesses of ocular components, and refractive indices of ocular refractive media, using variational analysis and a computational model of the rodent eye. Variational analysis revealed that variation in all the ocular parameters does affect the refractive status of the eye, but depending upon the magnitude of the impact those parameters are listed as critical or non critical. Variation in the depth of the vitreous chamber, thickness of the lens, radius of the anterior surface of the cornea, radius of the anterior surface of the lens, as well as refractive indices for the lens and vitreous, appears to have the largest impact on the refractive error and thus are categorized as critical ocular parameters. The radii of the posterior surfaces of the cornea and lens have much smaller contributions to the refractive state, while the radii of the anterior and posterior surfaces of the retina have no effect on the refractive error. These data provide the framework for further refinement of the optical models of the rat and mouse eye and suggest that extra efforts should be directed towards increasing the linear resolution of the rodent eye biometry and obtaining more accurate data for the refractive indices of the lens and vitreous.

Modeling menopause: The utility of rodents in translational behavioral endocrinology research.

PubMed

Koebele, Stephanie V; Bimonte-Nelson, Heather A

2016-05-01

The human menopause transition and aging are each associated with an increase in a variety of health risk factors including, but not limited to, cardiovascular disease, osteoporosis, cancer, diabetes, stroke, sexual dysfunction, affective disorders, sleep disturbances, and cognitive decline. It is challenging to systematically evaluate the biological underpinnings associated with the menopause transition in the human population. For this reason, rodent models have been invaluable tools for studying the impact of gonadal hormone fluctuations and eventual decline on a variety of body systems. While it is essential to keep in mind that some of the mechanisms associated with aging and the transition into a reproductively senescent state can differ when translating from one species to another, animal models provide researchers with opportunities to gain a fundamental understanding of the key elements underlying reproduction and aging processes, paving the way to explore novel pathways for intervention associated with known health risks. Here, we discuss the utility of several rodent models used in the laboratory for translational menopause research, examining the benefits and drawbacks in helping us to better understand aging and the menopause transition in women. The rodent models discussed are ovary-intact, ovariectomy, and 4-vinylcylohexene diepoxide for the menopause transition. We then describe how these models may be implemented in the laboratory, particularly in the context of cognition. Ultimately, we aim to use these animal models to elucidate novel perspectives and interventions for maintaining a high quality of life in women, and to potentially prevent or postpone the onset of negative health consequences associated with these significant life changes during aging. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Leptin- and Leptin Receptor-Deficient Rodent Models: Relevance for Human Type 2 Diabetes

PubMed Central

Wang, Bingxuan; P., Charukeshi Chandrasekera; Pippin, John J.

2014-01-01

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor-based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management. PMID:24809394

Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes.

PubMed

Wang, Bingxuan; Chandrasekera, P Charukeshi; Pippin, John J

2014-03-01

Among the most widely used animal models in obesity-induced type 2 diabetes mellitus (T2DM) research are the congenital leptin- and leptin receptor-deficient rodent models. These include the leptin-deficient ob/ob mice and the leptin receptor-deficient db/db mice, Zucker fatty rats, Zucker diabetic fatty rats, SHR/N-cp rats, and JCR:LA-cp rats. After decades of mechanistic and therapeutic research schemes with these animal models, many species differences have been uncovered, but researchers continue to overlook these differences, leading to untranslatable research. The purpose of this review is to analyze and comprehensively recapitulate the most common leptin/leptin receptor-based animal models with respect to their relevance and translatability to human T2DM. Our analysis revealed that, although these rodents develop obesity due to hyperphagia caused by abnormal leptin/leptin receptor signaling with the subsequent appearance of T2DM-like manifestations, these are in fact secondary to genetic mutations that do not reflect disease etiology in humans, for whom leptin or leptin receptor deficiency is not an important contributor to T2DM. A detailed comparison of the roles of genetic susceptibility, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and diabetic complications as well as leptin expression, signaling, and other factors that confound translation are presented here. There are substantial differences between these animal models and human T2DM that limit reliable, reproducible, and translatable insight into human T2DM. Therefore, it is imperative that researchers recognize and acknowledge the limitations of the leptin/leptin receptor- based rodent models and invest in research methods that would be directly and reliably applicable to humans in order to advance T2DM management.

Support for targeted sampling of red fox (Vulpes vulpes) feces in Sweden: a method to improve the probability of finding Echinococcus multilocularis.

PubMed

Miller, Andrea L; Olsson, Gert E; Sollenberg, Sofia; Skarin, Moa; Wahlström, Helene; Höglund, Johan

2016-11-29

Localized concentrations of Echinococcus multilocularis eggs from feces of infected red fox (Vulpes vulpes) can create areas of higher transmission risk for rodent hosts and possibly also for humans; therefore, identification of these areas is important. However, in a low prevalence environment, such as Sweden, these areas could be easily overlooked. As part of a project investigating the role of different rodents in the epidemiology of E. multilocularis in Sweden, fox feces were collected seasonally from rodent trapping sites in two regions with known parasite status and in two regions with unknown parasite status, 2013-2015. The aim was to evaluate background contamination in rodent trapping sites from parasite eggs in these regions. To maximize the likelihood of finding fox feces positive for the parasite, fecal collection was focused in habitats with the assumed presence of suitable rodent intermediate hosts (i.e. targeted sampling). Parasite eggs were isolated from feces through sieving-flotation, and parasite species were then confirmed using PCR and sequencing. Most samples were collected in the late winter/early spring and in open fields where both Arvicola amphibius and Microtus agrestis were captured. Fox feces positive for E. multilocularis (41/714) were found within 1-3 field collection sites within each of the four regions. The overall proportion of positive samples was low (≤5.4%) in three regions, but was significantly higher in one region (22.5%, P < 0.001). There was not a significant difference between seasons or years. Compared to previous national screenings, our sampling strategy identified multiple E. multilocularis positive feces in all four regions, including the two regions with previously unknown parasite status. These results further suggest that the distribution of E. multilocularis is highly aggregated in the environment and provide support for further development of a targeted sampling strategy. Our results show that it was possible to identify new areas of high contamination in low endemic environments. After further elaboration, such a strategy may be particularly useful for countries designing surveillance to document freedom from disease.

A PK-PD model of ketamine-induced high-frequency oscillations

NASA Astrophysics Data System (ADS)

Flores, Francisco J.; Ching, ShiNung; Hartnack, Katharine; Fath, Amanda B.; Purdon, Patrick L.; Wilson, Matthew A.; Brown, Emery N.

2015-10-01

Objective. Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a high-frequency oscillation (HFO) which power is modulated nonlinearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PDs) of ketamine and the observed HFO power. Approach. In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by an HFO observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results. We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance. Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent range of effects that ketamine has.

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

PubMed

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.

Predators, Prey and Habitat Structure: Can Key Conservation Areas and Early Signs of Population Collapse Be Detected in Neotropical Forests?

PubMed

de Thoisy, Benoit; Fayad, Ibrahim; Clément, Luc; Barrioz, Sébastien; Poirier, Eddy; Gond, Valéry

2016-01-01

Tropical forests with a low human population and absence of large-scale deforestation provide unique opportunities to study successful conservation strategies, which should be based on adequate monitoring tools. This study explored the conservation status of a large predator, the jaguar, considered an indicator of the maintenance of how well ecological processes are maintained. We implemented an original integrative approach, exploring successive ecosystem status proxies, from habitats and responses to threats of predators and their prey, to canopy structure and forest biomass. Niche modeling allowed identification of more suitable habitats, significantly related to canopy height and forest biomass. Capture/recapture methods showed that jaguar density was higher in habitats identified as more suitable by the niche model. Surveys of ungulates, large rodents and birds also showed higher density where jaguars were more abundant. Although jaguar density does not allow early detection of overall vertebrate community collapse, a decrease in the abundance of large terrestrial birds was noted as good first evidence of disturbance. The most promising tool comes from easily acquired LiDAR data and radar images: a decrease in canopy roughness was closely associated with the disturbance of forests and associated decreasing vertebrate biomass. This mixed approach, focusing on an apex predator, ecological modeling and remote-sensing information, not only helps detect early population declines in large mammals, but is also useful to discuss the relevance of large predators as indicators and the efficiency of conservation measures. It can also be easily extrapolated and adapted in a timely manner, since important open-source data are increasingly available and relevant for large-scale and real-time monitoring of biodiversity.

Predators, Prey and Habitat Structure: Can Key Conservation Areas and Early Signs of Population Collapse Be Detected in Neotropical Forests?

PubMed Central

de Thoisy, Benoit; Fayad, Ibrahim; Clément, Luc; Barrioz, Sébastien; Poirier, Eddy; Gond, Valéry

2016-01-01

Tropical forests with a low human population and absence of large-scale deforestation provide unique opportunities to study successful conservation strategies, which should be based on adequate monitoring tools. This study explored the conservation status of a large predator, the jaguar, considered an indicator of the maintenance of how well ecological processes are maintained. We implemented an original integrative approach, exploring successive ecosystem status proxies, from habitats and responses to threats of predators and their prey, to canopy structure and forest biomass. Niche modeling allowed identification of more suitable habitats, significantly related to canopy height and forest biomass. Capture/recapture methods showed that jaguar density was higher in habitats identified as more suitable by the niche model. Surveys of ungulates, large rodents and birds also showed higher density where jaguars were more abundant. Although jaguar density does not allow early detection of overall vertebrate community collapse, a decrease in the abundance of large terrestrial birds was noted as good first evidence of disturbance. The most promising tool comes from easily acquired LiDAR data and radar images: a decrease in canopy roughness was closely associated with the disturbance of forests and associated decreasing vertebrate biomass. This mixed approach, focusing on an apex predator, ecological modeling and remote-sensing information, not only helps detect early population declines in large mammals, but is also useful to discuss the relevance of large predators as indicators and the efficiency of conservation measures. It can also be easily extrapolated and adapted in a timely manner, since important open-source data are increasingly available and relevant for large-scale and real-time monitoring of biodiversity. PMID:27828993

Neurogenetics of Aggressive Behavior – Studies in Rodents

PubMed Central

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), major inhibitory and excitatory 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 differences in aggression, using the so-called forward genetics approach. PMID:24318936

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

PubMed Central

Nowak, Karl; Mix, Eilhard; Gimsa, Jan; Strauss, Ulf; Sriperumbudur, Kiran Kumar; Benecke, Reiner; Gimsa, Ulrike

2011-01-01

Deep brain stimulation (DBS) has become a treatment for a growing number of neurological and psychiatric disorders, especially for therapy-refractory Parkinson's disease (PD). However, not all of the symptoms of PD are sufficiently improved in all patients, and side effects may occur. Further progress depends on a deeper insight into the mechanisms of action of DBS in the context of disturbed brain circuits. For this, optimized animal models have to be developed. We review not only charge transfer mechanisms at the electrode/tissue interface and strategies to increase the stimulation's energy-efficiency but also the electrochemical, electrophysiological, biochemical and functional effects of DBS. We introduce a hemi-Parkinsonian rat model for long-term experiments with chronically 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. PMID:21603182

Histone Deacetylase Adaptation in Single Ventricle Heart Disease and a Young Animal Model of Right Ventricular Hypertrophy

PubMed Central

Blakeslee, Weston W.; Demos-Davies, Kimberly M.; Lemon, Douglas D.; Lutter, Katharina M.; Cavasin, Maria A.; Payne, Sam; Nunley, Karin; Long, Carlin S.; McKinsey, Timothy A.; Miyamoto, Shelley D.

2017-01-01

Background Histone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac disease. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle heart disease of right ventricular morphology (SV), as well as in a rodent model of right ventricular hypertrophy (RVH). Methods Homogenates of RV explants from non-failing controls and SV children were assayed for HDAC catalytic activity and HDAC isoform expression. Postnatal 1-day old rat pups were placed in hypoxic conditions and echocardiographic analysis, gene expression, HDAC catalytic activity and isoform expression studies of the RV were performed. Results Class I, IIa, and IIb HDAC catalytic activity and protein expression were elevated in hearts of SV children. Hypoxic neonatal rats demonstrated RVH, abnormal gene expression and elevated class I and class IIb HDAC catalytic activity and protein expression in the RV compared to control. Conclusions These data suggest that myocardial HDAC adaptations occur in the SV heart and could represent a novel therapeutic target. While further characterization of the hypoxic neonatal rat is needed, this animal model may be suitable for pre-clinical investigations of pediatric RV disease and could serve as a useful model for future mechanistic studies. PMID:28549058

Long-term Potentiation Decay and Poor Long-lasting Memory Process in the Wild Rodents Proechimys from Brazil’s Amazon Rainforest

PubMed Central

Guimarães Marques, Marcia J.; Reyes-Garcia, Selvin Z.; Marques-Carneiro, José E.; Lopes-Silva, Leonardo B.; Andersen, Monica L.; Cavalheiro, Esper A.; Scorza, Fulvio A.; Scorza, Carla A.

2018-01-01

Proechimys are small terrestrial rodents from Amazon rainforest. Each animal species is adapted to a specific environment in which the animal evolved therefore without comparative approaches unique characteristics of distinct species cannot be fully recognized. Laboratory rodents are exceedingly inbred strains dissociated from their native habitats and their fundamental ecological aspects are abstracted. Thus, the employment of exotic non-model species can be informative and complement conventional animal models. With the aim of promoting comparative studies between the exotic wildlife populations in the laboratory and traditional rodent model, we surveyed a type of synaptic plasticity intimately related to memory encoding in animals. Using theta-burst paradigm, in vitro long-term potentiation (LTP) in the CA1 subfield of hippocampal slices was assessed in the Amazon rodents Proechimys and Wistar rats. Memory, learning and anxiety were investigated through the plus-maze discriminative avoidance task (PM-DAT) and object recognition test. In PM-DAT, both animal species were submitted to two test sessions (3-h and 24-h) after the conditioning training. Proechimys exhibited higher anxiety-like behavior in the training session but during test sessions both species exhibited similar patterns of anxiety-related behavior. After 3-h of the training, Proechimys and Wistar spent significantly less time in the aversive enclosed arm than in the non-aversive arm. But, at 24-h after training, Wistar rats remained less time in the aversive closed arm in comparison with the non-aversive one, while Proechimys rodents spent the same amount of time in both enclosed arms. In the object recognition test, both species were evaluated at 24-h after the acquisition session and similar findings than those of the PM-DAT (24-h) were obtained, suggesting that long-term memory duration did not persist for 24-h in the Amazon rodent. Field excitatory post-synaptic potentials recordings revealed that LTP decays rapidly over time reaching basal levels at 90 min after theta-burst stimulation in Proechimys, contrasting to the stable LTP found in the Wistar rats which was observed throughout 3-h recording period. These findings suggest a link between the LTP decay and the lack of 24-h long-lasting memory process in Proechimys. Nevertheless, why early-phase LTP in Proechimys decays very rapidly remains to be elucidated. PMID:29410617

Long-term Potentiation Decay and Poor Long-lasting Memory Process in the Wild Rodents Proechimys from Brazil's Amazon Rainforest.

PubMed

Guimarães Marques, Marcia J; Reyes-Garcia, Selvin Z; Marques-Carneiro, José E; Lopes-Silva, Leonardo B; Andersen, Monica L; Cavalheiro, Esper A; Scorza, Fulvio A; Scorza, Carla A

2018-01-01

Proechimys are small terrestrial rodents from Amazon rainforest. Each animal species is adapted to a specific environment in which the animal evolved therefore without comparative approaches unique characteristics of distinct species cannot be fully recognized. Laboratory rodents are exceedingly inbred strains dissociated from their native habitats and their fundamental ecological aspects are abstracted. Thus, the employment of exotic non-model species can be informative and complement conventional animal models. With the aim of promoting comparative studies between the exotic wildlife populations in the laboratory and traditional rodent model, we surveyed a type of synaptic plasticity intimately related to memory encoding in animals. Using theta-burst paradigm, in vitro long-term potentiation (LTP) in the CA1 subfield of hippocampal slices was assessed in the Amazon rodents Proechimys and Wistar rats. Memory, learning and anxiety were investigated through the plus-maze discriminative avoidance task (PM-DAT) and object recognition test. In PM-DAT, both animal species were submitted to two test sessions (3-h and 24-h) after the conditioning training. Proechimys exhibited higher anxiety-like behavior in the training session but during test sessions both species exhibited similar patterns of anxiety-related behavior. After 3-h of the training, Proechimys and Wistar spent significantly less time in the aversive enclosed arm than in the non-aversive arm. But, at 24-h after training, Wistar rats remained less time in the aversive closed arm in comparison with the non-aversive one, while Proechimys rodents spent the same amount of time in both enclosed arms. In the object recognition test, both species were evaluated at 24-h after the acquisition session and similar findings than those of the PM-DAT (24-h) were obtained, suggesting that long-term memory duration did not persist for 24-h in the Amazon rodent. Field excitatory post-synaptic potentials recordings revealed that LTP decays rapidly over time reaching basal levels at 90 min after theta-burst stimulation in Proechimys , contrasting to the stable LTP found in the Wistar rats which was observed throughout 3-h recording period. These findings suggest a link between the LTP decay and the lack of 24-h long-lasting memory process in Proechimys . Nevertheless, why early-phase LTP in Proechimys decays very rapidly remains to be elucidated.

Maripa Hantavirus in French Guiana: Phylogenetic Position and Predicted Spatial Distribution of Rodent Hosts

PubMed Central

de Thoisy, Benoît; Matheus, Séverine; Catzeflis, François; Clément, Luc; Barrioz, Sébastien; Guidez, Amandine; Donato, Damien; Cornu, Jean-François; Brunaux, Olivier; Guitet, Stéphane; Lacoste, Vincent; Lavergne, Anne

2014-01-01

A molecular screening of wild-caught rodents was conducted in French Guiana, South America to identify hosts of the hantavirus Maripa described in 2008 in a hantavirus pulmonary syndrome (HPS) case. Over a 9-year period, 418 echimyids and murids were captured. Viral RNA was detected in two sigmodontine rodents, Oligoryzomys fulvescens and Zygodontomys brevicauda, trapped close to the house of a second HPS case that occurred in 2009 and an O. fulvescens close to the fourth HPS case identified in 2013. Sequences from the rodents had 96% and 97% nucleotide identity (fragment of S and M segments, respectively) with the sequence of the first human HPS case. Phylogenetic reconstructions based on the complete sequence of the S segment show that Maripa virus is closely related to Rio Mamore hantavirus. Using environmental descriptors of trapping sites, including vegetation, landscape units, rain, and human disturbance, a maximal entropy-based species distribution model allowed for identification of areas of higher predicted occurrence of the two rodents, where emergence risks of Maripa virus are expected to be higher. PMID:24752689

Maripa hantavirus in French Guiana: phylogenetic position and predicted spatial distribution of rodent hosts.

PubMed

de Thoisy, Benoît; Matheus, Séverine; Catzeflis, François; Clément, Luc; Barrioz, Sébastien; Guidez, Amandine; Donato, Damien; Cornu, Jean-François; Brunaux, Olivier; Guitet, Stéphane; Lacoste, Vincent; Lavergne, Anne

2014-06-01

A molecular screening of wild-caught rodents was conducted in French Guiana, South America to identify hosts of the hantavirus Maripa described in 2008 in a hantavirus pulmonary syndrome (HPS) case. Over a 9-year period, 418 echimyids and murids were captured. Viral RNA was detected in two sigmodontine rodents, Oligoryzomys fulvescens and Zygodontomys brevicauda, trapped close to the house of a second HPS case that occurred in 2009 and an O. fulvescens close to the fourth HPS case identified in 2013. Sequences from the rodents had 96% and 97% nucleotide identity (fragment of S and M segments, respectively) with the sequence of the first human HPS case. Phylogenetic reconstructions based on the complete sequence of the S segment show that Maripa virus is closely related to Rio Mamore hantavirus. Using environmental descriptors of trapping sites, including vegetation, landscape units, rain, and human disturbance, a maximal entropy-based species distribution model allowed for identification of areas of higher predicted occurrence of the two rodents, where emergence risks of Maripa virus are expected to be higher. © The American Society of Tropical Medicine and Hygiene.

Rat infestation associated with environmental deficiencies in an urban slum community with high risk of leptospirosis transmission.

PubMed

Santos, Norlan de Jesus; Sousa, Erica; Reis, Mitermayer G; Ko, Albert I; Costa, Federico

2017-03-09

We analyzed environmental factors that provide food, water and harborage to rodents and the risk of household rodent infestation in a slum community with a high risk of leptospirosis transmission. Detailed environmental surveys were performed in 221 households. Multivariate regression models evaluated the association between rodent infestation and socioeconomic status and environmental attributes obtained from Geographical Information System surveys. The general household infestation rate was 45.9%. Rattus norvegicus signs were the most prevalent, present in 74% of the infested households. The risk for rodent infestation was associated with environmental factors supporting harborage for rats, such as dilapidated fences/walls (OR: 8.95; 95%CI: 2.42-33.12) and households built on an earthen slope (OR: 4.68; 95%CI: 2.23-9.81). An increase of 1 meter from the nearest sewer was associated with a 3% (95%CI: 1%-5%) decrease in the risk of rodent infestation. A lack of sanitation where poor people live provides factors for rat infestation and could the target of educational interventions.

Chronic Unpredictable Stress (CUS)-Induced Anxiety and Related Mood Disorders in a Zebrafish Model: Altered Brain Proteome Profile Implicates Mitochondrial Dysfunction

PubMed Central

Chakravarty, Sumana; Reddy, Bommana R.; Sudhakar, Sreesha R.; Saxena, Sandeep; Das, Tapatee; Meghah, Vuppalapaty; Brahmendra Swamy, Cherukuvada V.; Kumar, Arvind; Idris, Mohammed M.

2013-01-01

Anxiety and depression are major chronic mood disorders, and the etiopathology for each appears to be repeated exposure to diverse unpredictable stress factors. Most of the studies on anxiety and related mood disorders are performed in rodents, and a good model is chronic unpredictable stress (CUS). In this study, we have attempted to understand the molecular basis of the neuroglial and behavioral changes underlying CUS-induced mood disorders in the simplest vertebrate model, the zebrafish, Danio rerio. Zebrafish were subjected to a CUS paradigm in which two different stressors were used daily for 15 days, and thorough behavioral analyses were performed to assess anxiety and related mood disorder phenotypes using the novel tank test, shoal cohesion and scototaxis. Fifteen days of exposure to chronic stressors appears to induce an anxiety and related mood disorder phenotype. Decreased neurogenesis, another hallmark of anxiety and related disorders in rodents, was also observed in this zebrafish model. The common molecular markers of rodent anxiety and related disorders, corticotropin-releasing factor (CRF), calcineurin (ppp3r1a) and phospho cyclic AMP response element binding protein (pCREB), were also replicated in the fish model. Finally, using 2DE FTMS/ITMSMS proteomics analyses, 18 proteins were found to be deregulated in zebrafish anxiety and related disorders. The most affected process was mitochondrial function, 4 of the 18 differentially regulated proteins were mitochondrial proteins: PHB2, SLC25A5, VDAC3 and IDH2, as reported in rodent and clinical samples. Thus, the zebrafish CUS model and proteomics can facilitate not only uncovering new molecular targets of anxiety and related mood disorders but also the routine screening of compounds for drug development. PMID:23691016

Evolving Communicative Complexity: Insight from Rodents and Beyond

DTIC Science & Technology

2012-01-01

Group size in animal societies: the potential role of social and ecological limitations in the group-living fish , Paragobiodon xanthosomus. Ethology... Ecology and Evolutionary Biology, University of California, Los Angeles, CA 90095, USA 2Human Research and Engineering Directorate, Perceptual Sciences...evolve is an active question in behavioural ecology . Sciurid rodents (ground squirrels, prairie dogs and marmots) provide an excellent model system for

State-dependent μ-opioid modulation of social motivation

PubMed Central

Loseth, Guro E.; Ellingsen, Dan-Mikael; Leknes, Siri

2014-01-01

Social mammals engage in affiliative interactions both when seeking relief from negative affect and when searching for pleasure and joy. These two motivational states are both modulated by μ-opioid transmission. The μ-opioid receptor (MOR) system in the brain mediates pain relief and reward behaviors, and is implicated in social reward processing and affiliative bonding across mammalian species. However, pharmacological manipulation of the μ-opioid system has yielded opposite effects on rodents and primates: in rodents, social motivation is generally increased by MOR agonists and reduced by antagonists, whereas the opposite pattern has been shown in primates. Here, we address this paradox by taking into account differences in motivational state. We first review evidence for μ-opioid mediation of reward processing, emotion regulation, and affiliation in humans, non-human primates, rodents and other species. Based on the consistent cross-species similarities in opioid functioning, we propose a unified, state-dependent model for μ-opioid modulation of affiliation across the mammalian species. Finally, we show that this state-dependent model is supported by evidence from both rodent and primate studies, when species and age differences in social separation response are taken into account. PMID:25565999

Rodentia and lagomorpha

USGS Publications Warehouse

Sheffield, S.R.; Sawicka-Kapusta, K.; Cohen, J.B.; Rattner, B.A.; Shore, Richard F.; Rattner, Barnett A.

2001-01-01

This comprehensive review examines the extensive literature on wild rodents and lagomorphs as biomonitors of environmental contamination. This chapter covers studies dealing with exposure and effects of environmental contaminants on rodent and lagomorph species, including pesticides (organochlorines, organophosphorus and carbamate compounds, herbicides, plant growth regulators, fungicides, and rodenticides), other organic chemicals, metals, radionuclides, and other miscellaneous contaminants. Many research needs become evident when reviewing ecotoxicological data for rodents and lagomorphs, the most striking being the paucity of information on rodent families other than Muridae (mice and rats). While our ability to qualitatively extrapolate effects observed in laboratory studies to field situations is good for a variety of contaminants, quantitative predictions of dose-response relationships are poor because inter-specific variation and differences in exposure patterns between laboratory and wild species to toxicants are for the most part unknown. More sophisticated comparative toxicity studies need to be undertaken that build on previous work in order to develop a database of information, to account for and model differences in exposure pathways, to document interactions among multiple stressors, to generate data establishing thresholds, critical concentrations, and diagnostic guidelines, and even to develop physiologically-based toxicokinetic models. Such efforts may enhance our ability to predict effects on wild populations, including threatened and endangered species.

Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model

PubMed Central

Canal, Clint E.; Morgan, Drake

2013-01-01

Two primary animal models persist for assessing hallucinogenic potential of novel compounds and for examining the pharmacological and neurobiological substrates underlying the actions of classical hallucinogens, the two-lever drug discrimination procedure and the drug-induced head-twitch response (HTR) in rodents. The substituted amphetamine hallucinogen, serotonin 2 (5-HT2) receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) has emerged as the most popular pharmacological tool used in HTR studies of hallucinogens. Synthesizing classic, recent, and relatively overlooked findings, addressing ostensibly conflicting observations, and considering contemporary theories in receptor and behavioural pharmacology, this review provides an up-to-date and comprehensive synopsis of DOI and the HTR model, from neural mechanisms to utility for understanding psychiatric diseases. Also presented is support for the argument that, although both the two-lever drug discrimination and the HTR models in rodents are useful for uncovering receptors, interacting proteins, intracellular signalling pathways, and neurochemical processes affected by DOI and related classical hallucinogens, results from both models suggest they are not reporting hallucinogenic experiences in animals. PMID:22517680

The yin and yang of cannabis-induced psychosis: the actions of Δ(9)-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia.

PubMed

Arnold, J C; Boucher, A A; Karl, T

2012-01-01

The link between cannabis and psychosis has often been debated with polarized views on the topic. There is substantial epidemiological evidence showing that cannabis increases the risk of psychosis, whereas other research suggests that schizophrenia patients self-medicate with the substance. These conflicting accounts may at least be partially explained by the two phytocannabinoids cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC) and their opposing actions on schizophrenia-related symptoms. In the present review we will first focus on how traditional rodent models of schizophrenia have been used to improve our understanding of the propsychotic actions of THC and the antipsychotic actions of CBD. We will also review novel rodent models used to address genetic vulnerability to cannabis-induced schizophrenia and show that specific genes are being uncovered that modulate cannabinoid action (e.g. the schizophrenia susceptibility gene neuregulin 1). We will also review rodent studies that have addressed interactions between THC and CBD. These animal studies underscore great complexity with some studies showing that CBD antagonises the neurobehavioural effects of THC, while others show the opposite, that CBD potentiates the actions of THC. Various mechanisms are put forth to explain these divergent effects such as CBD antagonism at central CB1 receptors or that CBD inhibits proteins that regulate THC disposition and metabolism (e.g. the ABC transporter, P-glycoprotein).

Pulsed food resources, but not forest cover, determine lifetime reproductive success in a forest-dwelling rodent.

PubMed

Hoset, Katrine S; Villers, Alexandre; Wistbacka, Ralf; Selonen, Vesa

2017-09-01

The relative contributions of habitat and food availability on fitness may provide evidence for key habitat features needed to safeguard population persistence. However, defining habitat quality for a species can be a complex task, especially if knowledge on the relationship between individual performance and habitat quality is lacking. Here, we determined the relative importance of the availability of suitable forest habitat, body mass and food from masting tree species on female lifetime reproductive success (LRS) of Siberian flying squirrels (Pteromys volans). We calculated LRS of 500 female flying squirrels based on a 22-year-long longitudinal dataset of two populations from western Finland. We assessed with generalised additive models the potential effects of availability of suitable habitat and cumulative lifetime availability of food from masting tree species on female LRS, longevity and fecundity. On a reduced dataset, we evaluated the importance of female winter body mass and conducted a piecewise path analysis to determine how variables were connected. According to generalised additive models female longevity, fecundity and LRS were mainly determined by variation in cumulative lifetime availability of food from masting alder and birch. Instead, habitat and body mass had a smaller role. The path analysis indicated that lifetime food availability had a direct effect on longevity and fecundity, and these had an equal effect on LRS at both study sites. Our results on LRS show that the occurrence of tree masting events during a female flying squirrel's lifetime has a profoundly larger effect on LRS than the cover of suitable forest habitat. Furthermore, this study emphasises the importance of both fecundity and longevity, and the indirect effects of food availability via those components, as determinants of lifetime fitness in female flying squirrels. © 2017 The Authors. Journal of Animal Ecology © 2017 British Ecological Society.

Brain and Behavioral Pathology in an Animal Model of Wernicke’s Encephalopathy and Wernicke-Korsakoff Syndrome

PubMed Central

Vetreno, Ryan P.; Ramos, Raddy L.; Anzalone, Steven; Savage, Lisa M.

2012-01-01

Animal models provide the opportunity for in-depth and experimental investigation into the anatomical and physiological underpinnings of human neurological disorders. Rodent models of thiamine deficiency have yielded significant insight into the structural, neurochemical and cognitive deficits associated with thiamine deficiency as well as proven useful toward greater understanding of memory function in the intact brain. In this review, we discuss the anatomical, neurochemical and behavioral changes that occur during the acute and chronic phases of thiamine deficiency and describe how rodent models of Wernicke-Korsakoff Syndrome aid in developing a more detailed picture of brain structures involved in learning and memory. PMID:22192411

Brain and behavioral pathology in an animal model of Wernicke's encephalopathy and Wernicke-Korsakoff Syndrome.

PubMed

Vetreno, Ryan P; Ramos, Raddy L; Anzalone, Steven; Savage, Lisa M

2012-02-03

Animal models provide the opportunity for in-depth and experimental investigation into the anatomical and physiological underpinnings of human neurological disorders. Rodent models of thiamine deficiency have yielded significant insight into the structural, neurochemical and cognitive deficits associated with thiamine deficiency as well as proven useful toward greater understanding of memory function in the intact brain. In this review, we discuss the anatomical, neurochemical and behavioral changes that occur during the acute and chronic phases of thiamine deficiency and describe how rodent models of Wernicke-Korsakoff Syndrome aid in developing a more detailed picture of brain structures involved in learning and memory. Copyright © 2011 Elsevier B.V. All rights reserved.

Dendritic spine dynamics in synaptogenesis after repeated LTP inductions: Dependence on pre-existing spine density

PubMed Central

Oe, Yuki; Tominaga-Yoshino, Keiko; Hasegawa, Sho; Ogura, Akihiko

2013-01-01

Not only from our daily experience but from learning experiments in animals, we know that the establishment of long-lasting memory requires repeated practice. However, cellular backgrounds underlying this repetition-dependent consolidation of memory remain largely unclear. We reported previously using organotypic slice cultures of rodent hippocampus that the repeated inductions of LTP (long-term potentiation) lead to a slowly developing long-lasting synaptic enhancement accompanied by synaptogenesis distinct from LTP itself, and proposed this phenomenon as a model system suitable for the analysis of the repetition-dependent consolidation of memory. Here we examined the dynamics of individual dendritic spines after repeated LTP-inductions and found the existence of two phases in the spines' stochastic behavior that eventually lead to the increase in spine density. This spine dynamics occurred preferentially in the dendritic segments having low pre-existing spine density. Our results may provide clues for understanding the cellular bases underlying the repetition-dependent consolidation of memory. PMID:23739837

Material Characterization and Computer Model Simulation of Low Density Polyurethane Foam Used in a Rodent Traumatic Brain Injury Model

PubMed Central

Zhang, Liying; Gurao, Manish; Yang, King H.; King, Albert I.

2011-01-01

Computer models of the head can be used to simulate the events associated with traumatic brain injury (TBI) and quantify biomechanical response within the brain. Marmarou’s impact acceleration rodent model is a widely used experimental model of TBI mirroring axonal pathology in humans. The mechanical properties of the low density polyurethane (PU) foam, an essential piece of energy management used in Marmarou’s impact device, has not been fully characterized. The foam used in Marmarou’s device was tested at seven strain rates ranging from quasi-static to dynamic (0.014 ~ 42.86 s−1) to quantify the stress-strain relationships in compression. Recovery rate of the foam after cyclic compression was also determined through the periods of recovery up to three weeks. The experimentally determined stress-strain curves were incorporated into a material model in an explicit Finite Element (FE) solver to validate the strain rate dependency of the FE foam model. Compression test results have shown that the foam used in the rodent impact acceleration model is strain rate dependent. The foam has been found to be reusable for multiple impacts. However the stress resistance of used foam is reduced to 70% of the new foam. The FU_CHANG_FOAM material model in an FE solver has been found to be adequate to simulate this rate sensitive foam. PMID:21459114

Material characterization and computer model simulation of low density polyurethane foam used in a rodent traumatic brain injury model.

PubMed

Zhang, Liying; Gurao, Manish; Yang, King H; King, Albert I

2011-05-15

Computer models of the head can be used to simulate the events associated with traumatic brain injury (TBI) and quantify biomechanical response within the brain. Marmarou's impact acceleration rodent model is a widely used experimental model of TBI mirroring axonal pathology in humans. The mechanical properties of the low density polyurethane (PU) foam, an essential piece of energy management used in Marmarou's impact device, has not been fully characterized. The foam used in Marmarou's device was tested at seven strain rates ranging from quasi-static to dynamic (0.014-42.86 s⁻¹) to quantify the stress-strain relationships in compression. Recovery rate of the foam after cyclic compression was also determined through the periods of recovery up to three weeks. The experimentally determined stress-strain curves were incorporated into a material model in an explicit Finite Element (FE) solver to validate the strain rate dependency of the FE foam model. Compression test results have shown that the foam used in the rodent impact acceleration model is strain rate dependent. The foam has been found to be reusable for multiple impacts. However the stress resistance of used foam is reduced to 70% of the new foam. The FU_CHANG_FOAM material model in an FE solver has been found to be adequate to simulate this rate sensitive foam. Copyright © 2011 Elsevier B.V. All rights reserved.

ExNOTic: Should We Be Keeping Exotic Pets?

PubMed Central

Grant, Rachel A.; Montrose, V. Tamara; Wills, Alison P.

2017-01-01

There has been a recent trend towards keeping non-traditional companion animals, also known as exotic pets. These pets include parrots, reptiles, amphibians and rabbits, as well as small species of rodent such as degus and guinea pigs. Many of these exotic pet species are not domesticated, and often have special requirements in captivity, which many owners do not have the facilities or knowledge to provide. Keeping animals in settings to which they are poorly adapted is a threat to their welfare. Additionally, owner satisfaction with the animal may be poor due to a misalignment of expectations, which further impacts on welfare, as it may lead to repeated rehoming or neglect. We investigate a range of commonly kept exotic species in terms of their suitability as companion animals from the point of view of animal welfare and owner satisfaction, and make recommendations on the suitability of various species as pets. PMID:28629177

Animal models of serotonergic psychedelics.

PubMed

Hanks, James B; González-Maeso, Javier

2013-01-16

The serotonin 5-HT(2A) receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects.

Animal Models of Serotonergic Psychedelics

PubMed Central

2012-01-01

The serotonin 5-HT2A receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects. PMID:23336043

In vitro and in vivo evaluation of N-{2-[4-(3-Cyanopyridin-2-yl)piperazin-1-yl]ethyl}-3-[(11) C]methoxybenz-amide, a positron emission tomography (PET) radioligand for dopamine D4 receptors, in rodents.

PubMed

Leopoldo, Marcello; Selivanova, Svetlana V; Müller, Adrienne; Lacivita, Enza; Schetz, John A; Ametamey, Simon M

2014-09-01

The D4 dopamine receptor belongs to the D2 -like family of dopamine receptors, and its exact regional distribution in the central nervous system is still a matter of considerable debate. The availability of a selective radioligand for the D4 receptor with suitable properties for positron emission tomography (PET) would help resolve issues of D4 receptor localization in the brain, and the presumed diurnal change of expressed protein in the eye and pineal gland. We report here on in vitro and in vivo characteristics of the high-affinity D4 receptor-selective ligand N-{2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl}-3-[(11) C]methoxybenzamide ([(11) C]2) in rat. The results provide new insights on the in vitro properties that a brain PET dopamine D4 radioligand should possess in order to have improved in vivo utility in rodents. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

In vivo transgenic bioassays and assessment of the carcinogenic potential of pharmaceuticals.

PubMed Central

Contrera, J F; DeGeorge, J J

1998-01-01

There is general agreement in the scientific community on the need to improve carcinogenicity testing and the assessment of human carcinogenic risk and to incorporate more information on mechanisms and modes of action into the risk assessment process. Advances in molecular biology have identified a growing number of genes such as protooncogenes and tumor-suppressor genes that are highly conserved across species and are associated with a wide variety of human and animal cancers. In vivo transgenic rodent models incorporating such mechanisms are used to identify mechanisms involved in tumor formation and as selective tests for carcinogens. Transgenic methods can be considered an extension of genetic manipulation by selective breeding, which long has been employed in science and agriculture. The use of two rodent species in carcinogenicity testing is especially important for identifying transspecies carcinogens. The capacity of a substance to induce neoplasia across species suggests that the mechanism(s) involved in the induction of the neoplasia are conserved and therefore may have significance for humans. Based on available information there is sufficient experience with some in vivo transgenic rodent carcinogenicity models to support their application as complementary second species studies in conjunction with a single 2-year rodent carcinogenicity study. The optional substitution of a second 2-year rodent carcinogenicity study with an alternative study such as an in vivo transgenic carcinogenicity study is part of the International Conference on Harmonization guidance S1B: Testing for Carcinogenicity of Pharmaceuticals. This guidance is intended to be flexible enough to accommodate a wide range of possible carcinogenicity assessment models currently under consideration or models that may be developed in the future. The use of an in vivo transgenic mouse model in place of a second 2-year mouse study will improve the assessment of carcinogenic risk by contributing insights into the mechanisms of tumorigenesis and potential human relevance not available from a standard 2-year bioassay. It is envisioned that this will stimulate the further development of more efficient and relevant methods for identifying and assessing potential human carcinogenic risk, which will benefit public health. PMID:9539006

Application of MODIS GPP to Forecast Risk of Hantavirus Pulmonary Syndrome Based on Fluctuations in Reservoir Population Density

NASA Astrophysics Data System (ADS)

Loehman, R.; Heinsch, F. A.; Mills, J. N.; Wagoner, K.; Running, S.

2003-12-01

Recent predictive models for hantavirus pulmonary syndrome (HPS) have used remotely sensed spectral reflectance data to characterize risk areas with limited success. We present an alternative method using gross primary production (GPP) from the MODIS sensor to estimate the effects of biomass accumulation on population density of Peromyscus maniculatus (deer mouse), the principal reservoir species for Sin Nombre virus (SNV). The majority of diagnosed HPS cases in North America are attributed to SNV, which is transmitted to humans through inhalation of excretions and secretions from infected rodents. A logistic model framework is used to evaluate MODIS GPP, temperature, and precipitation as predictors of P. maniculatus density at established trapping sites across the western United States. Rodent populations are estimated using monthly minimum number alive (MNA) data for 2000 through 2002. Both local meteorological data from nearby weather stations and 1.25 degree x 1 degree gridded data from the NASA DAO were used in the regression model to determine the spatial sensitivity of the response. MODIS eight-day GPP data (1-km resolution) were acquired and binned to monthly average and monthly sum GPP for 3km x 3km grids surrounding each rodent trapping site. The use of MODIS GPP to forecast HPS risk may result in a marked improvement over past reflectance-based risk area characterizations. The MODIS GPP product provides a vegetation dynamics estimate that is unique to disease models, and targets the fundamental ecological processes responsible for increased rodent density and amplified disease risk.

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

PubMed Central

Alemu, Asnakech

2018-01-01

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. PMID:29675050

Construction of vapor chambers used to expose mice to alcohol during the equivalent of all three trimesters of human development.

PubMed

Morton, Russell A; Diaz, Marvin R; Topper, Lauren A; Valenzuela, C Fernando

2014-07-13

Exposure to alcohol during development can result in a constellation of morphological and behavioral abnormalities that are collectively known as Fetal Alcohol Spectrum Disorders (FASDs). At the most severe end of the spectrum is Fetal Alcohol Syndrome (FAS), characterized by growth retardation, craniofacial dysmorphology, and neurobehavioral deficits. Studies with animal models, including rodents, have elucidated many molecular and cellular mechanisms involved in the pathophysiology of FASDs. Ethanol administration to pregnant rodents has been used to model human exposure during the first and second trimesters of pregnancy. Third trimester ethanol consumption in humans has been modeled using neonatal rodents. However, few rodent studies have characterized the effect of ethanol exposure during the equivalent to all three trimesters of human pregnancy, a pattern of exposure that is common in pregnant women. Here, we show how to build vapor chambers from readily obtainable materials that can each accommodate up to six standard mouse cages. We describe a vapor chamber paradigm that can be used to model exposure to ethanol, with minimal handling, during all three trimesters. Our studies demonstrate that pregnant dams developed significant metabolic tolerance to ethanol. However, neonatal mice did not develop metabolic tolerance and the number of fetuses, fetus weight, placenta weight, number of pups/litter, number of dead pups/litter, and pup weight were not significantly affected by ethanol exposure. An important advantage of this paradigm is its applicability to studies with genetically-modified mice. Additionally, this paradigm minimizes handling of animals, a major confound in fetal alcohol research.

The Feasibility of HIFU Liver Ablation Through the Ribcage and Cartilage in a Rodent Model

NASA Astrophysics Data System (ADS)

King, Randy; Rieke, Viola; Pauly, Kim Butts

2009-04-01

We examined the feasibility of the rat model for the study of HIFU treatment of liver cancer. Significance: HIFU is being developed for the minimally invasive treatment of primary and metastatic liver cancer. In patients, obstruction of the ultrasound by the ribs poses a significant problem, and current studies are under way which investigate the efficacy of focusing around or sonicating between the ribs. Such techniques show promise for patient treatments, but are not feasible when using rodent models. Results: Six recently euthanized (within the hour) Sprague-Dewey rats were used. The hair over the anterior surface was removed. Sonications were performed with the InSightec ExAblate system at 0.95 MHz, 1.1 MHz, and 1.35MHz through the rib cage. Temperature rise was monitored with MRI-based thermometry. Lesions were created in the livers of 5/6 rats. In the five rats, energy levels between 572-1194 Joules produced lesions every time. With energies greater than 1393 Joules, skin damaged was observed which prevented the ultrasound from propagating to the liver on subsequent sonications, accounting for the one study that failed to produce lesions. No thermal damage was observed at the skin with sonications that resulted in liver lesions, and no significant heating was observed at or near the skin in the MRI temperature maps. Conclusions: It is possible to ignore the effect of ribs and sternum in rodents and create lesions within the rat liver. This technique opens the door to using hepatocellular carcinoma rodent models in HIFU studies.

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

PubMed

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.

Investigation of brain science and neurological/psychiatric disorders using genetically modified non-human primates.

PubMed

Okano, Hideyuki; Kishi, Noriyuki

2018-06-01

Although mice have been the most frequently used experimental animals in many research fields due to well-established gene manipulation techniques, recent evidence has revealed that rodent models do not always recapitulate pathophysiology of human neurological and psychiatric diseases due to the differences between humans and rodents. The recent developments in gene manipulation of non-human primate have been attracting much attention in the biomedical research field, because non-human primates have more applicable brain structure and function than rodents. In this review, we summarize recent progress on genetically-modified non-human primates including transgenic and knockout animals using genome editing technology. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

PubMed

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.

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

PubMed Central

Golden, Joseph W.; Hammerbeck, Christopher D.; Mucker, Eric M.; Brocato, Rebecca L.

2015-01-01

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. PMID:26266264

An integrated analysis of genes and functional pathways for aggression in human and rodent models.

PubMed

Zhang-James, Yanli; Fernàndez-Castillo, Noèlia; Hess, Jonathan L; Malki, Karim; Glatt, Stephen J; Cormand, Bru; Faraone, Stephen V

2018-06-01

Human genome-wide association studies (GWAS), transcriptome analyses of animal models, and candidate gene studies have advanced our understanding of the genetic architecture of aggressive behaviors. However, each of these methods presents unique limitations. To generate a more confident and comprehensive view of the complex genetics underlying aggression, we undertook an integrated, cross-species approach. We focused on human and rodent models to derive eight gene lists from three main categories of genetic evidence: two sets of genes identified in GWAS studies, four sets implicated by transcriptome-wide studies of rodent models, and two sets of genes with causal evidence from online Mendelian inheritance in man (OMIM) and knockout (KO) mice reports. These gene sets were evaluated for overlap and pathway enrichment to extract their similarities and differences. We identified enriched common pathways such as the G-protein coupled receptor (GPCR) signaling pathway, axon guidance, reelin signaling in neurons, and ERK/MAPK signaling. Also, individual genes were ranked based on their cumulative weights to quantify their importance as risk factors for aggressive behavior, which resulted in 40 top-ranked and highly interconnected genes. The results of our cross-species and integrated approach provide insights into the genetic etiology of aggression.

Conspecific Interactions in Adult Laboratory Rodents: Friends or Foes?

PubMed

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.

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

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

The Hindlimb Unloading Rat Model: Literature Overview, Comparison with Spaceflight Data, and Technique Update

NASA Technical Reports Server (NTRS)

Morey-Holton, Emily; Globus, Ruth K.; Kaplansky, Alexander; Durnova, Galina

2004-01-01

The hindlimb unloading (HU) rodent model is used extensively to study the response of many physiological systems to certain aspects of spaceflight, as well as to disuse and recovery from disuse for Earth benefits. This chapter describes the evolution of HU, and is divided into three sections. The first section examines the characteristics of 1063 articles using or reviewing the HU model, published between 1976 and April 1, 2004. The characteristics include number of publications, journals, countries, major physiological systems, method modifications, species, gender, genetic strains and ages of rodents, experiment duration, and countermeasures. The second section provides a comparison of results between space flown and Hu animals from the 14-day Cosmos 2044 mission. The final section describes modifications to HU required by different experimental paradigms and a method to protect the tail harness for long duration studies. HU in rodents has enabled improved understanding of the responses of the musculoskeletal, cardiovascular, immune, renal, neural, metabolic, and reproductive systems to unloading and/or to reloading on Earth with implications for both long-duration human spaceflight and disuse on Earth.

The cognitive cost of sleep lost

PubMed Central

McCoy, John G.; Strecker, Robert E.

2013-01-01

A substantial body of literature supports the intuitive notion that a good night’s sleep can facilitate human cognitive performance the next day. Deficits in attention, learning & memory, emotional reactivity, and higher-order cognitive processes, such as executive function and decision making, have all been documented following sleep disruption in humans. Thus, whilst numerous clinical and experimental studies link human sleep disturbance to cognitive deficits, attempts to develop valid and reliable rodent models of these phenomena are fewer, and relatively more recent. This review focuses primarily on the cognitive impairments produced by sleep disruption in rodent models of several human patterns of sleep loss/sleep disturbance. Though not an exclusive list, this review will focus on four specific types of sleep disturbance: total sleep deprivation, experimental sleep fragmentation, selective REM sleep deprivation, and chronic sleep restriction. The use of rodent models can provide greater opportunities to understand the neurobiological changes underlying sleep loss induced cognitive impairments. Thus, this review concludes with a description of recent neurobiological findings concerning the neuroplastic changes and putative brain mechanisms that may underlie the cognitive deficits produced by sleep disturbances. PMID:21875679

Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy.

PubMed

Reddy, Doodipala Samba

2016-01-01

Catamenial epilepsy is a type of refractory epilepsy characterized by seizure clusters around perimenstrual or periovulatory period. The pathophysiology of catamenial epilepsy still remains unclear, yet there are few animal models to study this gender-specific disorder. The pathophysiology of perimenstrual catamenial epilepsy involves the withdrawal of the progesterone-derived GABAergic neurosteroids due to the decline in progesterone level at the time of menstruation. These manifestations can be faithfully reproduced in rodents by specific neuroendocrine manipulations. Since mice and rats, like humans, have ovarian cycles with circulating hormones, they appear to be suitable animal models for studies of perimenstrual seizures. Recently, we created specific experimental models to mimic perimenstrual seizures. Studies in rat and mouse models of catamenial epilepsy show enhanced susceptibility to seizures or increased seizure exacerbations following neurosteroid withdrawal. During such a seizure exacerbation period, there is a striking decrease in the anticonvulsant effect of commonly prescribed antiepileptics, such as benzodiazepines, but an increase in the anticonvulsant potency of exogenous neurosteroids. We discovered an extrasynaptic molecular mechanism of catamenial epilepsy. In essence, extrasynaptic δGABA-A receptors are upregulated during perimenstrual-like neuroendocrine milieu. Consequently, there is enhanced antiseizure efficacy of neurosteroids in catamenial models because δGABA-A receptors confer neurosteroid sensitivity and greater seizure protection. Molecular mechanisms such as these offer a strong rationale for the clinical development of a neurosteroid replacement therapy for catamenial epilepsy.

Jaagsiekte Sheep Retrovirus Envelope Efficiently Pseudotypes Human Immunodeficiency Virus Type 1-Based Lentiviral Vectors

PubMed Central

Liu, Shan-Lu; Halbert, Christine L.; Miller, A. Dusty

2004-01-01

Jaagsiekte sheep retrovirus (JSRV) infects lung epithelial cells in sheep, and oncoretroviral vectors bearing JSRV Env can mediate transduction of human cells, suggesting that such vectors might be useful for lung-directed gene therapy. Here we show that JSRV Env can also efficiently pseudotype a human immunodeficiency virus type 1-based lentiviral vector, a more suitable vector for transduction of slowly dividing lung epithelial cells. We created several chimeric Env proteins that, unlike the parental Env, do not transform rodent fibroblasts but are still capable of pseudotyping lentiviral and oncoretroviral vectors. PMID:14963173

Advances in cytogenetics of Brazilian rodents: cytotaxonomy, chromosome evolution and new karyotypic data

PubMed Central

Di-Nizo, Camilla Bruno; Banci, Karina Rodrigues da Silva; Sato-Kuwabara, Yukie; Silva, Maria José de J.

2017-01-01

Abstract Rodents constitute one of the most diversified mammalian orders. Due to the morphological similarity in many of the groups, their taxonomy is controversial. Karyotype information proved to be an important tool for distinguishing some species because some of them are species-specific. Additionally, rodents can be an excellent model for chromosome evolution studies since many rearrangements have been described in this group.This work brings a review of cytogenetic data of Brazilian rodents, with information about diploid and fundamental numbers, polymorphisms, and geographical distribution. We point out that, even with the recent efforts on cytogenetic studies in this group, many species lack karyotypic data. Moreover, we describe for the first time the karyotype of Carterodon sulcidens (Lund, 1838) (Family Echimyidae), a new fundamental number for an undescribed species of Neacomys Thomas, 1900 (Family Cricetidae, Subfamily Sigmodontinae), and illustrate the karyotype of a Brazilian specimen of Mus musculus Linnaeus, 1758 (Family Muridae). This review compiles the cytogenetic data on Brazilian rodents reported in the last three decades, after the last revision published in 1984, including synonyms, chromosomal variations, and geographic distribution. Additionally, it also reinforces that Brazilian biodiversity is still poorly known, considering the new data reported here. PMID:29362668

Effects of rodent community diversity and composition on prevalence of an endemic bacterial pathogen - Bartonella

USGS Publications Warehouse

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.

Temporal and spatial host abundance and prevalence of Andes hantavirus in southern Argentina.

PubMed

Polop, Francisco J; Provensal, María C; Pini, Noemí; Levis, Silvana C; Priotto, José W; Enría, Delia; Calderón, Gladys E; Costa, Federico; Polop, Jaime J

2010-06-01

Andes virus (AND) is a hantavirus hosted by the sigmodontine rodent Oligoryzomys longicaudatus in southern Argentina, where it is responsible for most cases of hantavirus pulmonary syndrome (HPS). Our study provides data about the spatial variation in abundance of the rodent host of AND hantavirus. We report results of a longitudinal study performed in a locality of the Andean region of Chubut Province. From November 2003 (spring) to July 2006 (winter), O. longicaudatus was the most common species captured (63%) and it showed significant differences in abundance among habitats and seasons. Most antibody-positive rodents were O. longicaudatus (9.2%), followed by A. longipilis (3.6%) and A. olivaceus (1.5%). The highest number of antibody-positive animals was observed for males that belonged to the heaviest mass classes. Antibody-positive O. longicaudatus were more abundant in brush habitats. We found low richness of rodents and abundance of O. longicaudatus in areas affected by anthropogenic activity. The infection seems to be regionally persistent, but the risk to humans in a landscape would be localized. To develop accurate models for predicting HPS outbreaks, further research is needed to characterize rodent movement patterns across the landscape.

Understanding spatio-temporal strategies of adult zebrafish exploration in the open field test.

PubMed

Stewart, Adam Michael; Gaikwad, Siddharth; Kyzar, Evan; Kalueff, Allan V

2012-04-27

Zebrafish (Danio rerio) are emerging as a useful model organism for neuroscience research. Mounting evidence suggests that various traditional rodent paradigms may be adapted for testing zebrafish behavior. The open field test is a popular rodent test of novelty exploration, recently applied to zebrafish research. To better understand fish novelty behavior, we exposed adult zebrafish to two different open field arenas for 30 min, assessing the amount and temporal patterning of their exploration. While (similar to rodents) zebrafish scale their locomotory activity depending on the size of the tank, the temporal patterning of their activity was independent of arena size. These observations strikingly parallel similar rodent behaviors, suggesting that spatio-temporal strategies of animal exploration may be evolutionarily conserved across vertebrate species. In addition, we found interesting oscillations in zebrafish exploration, with the per-minute distribution of their horizontal activity demonstrating sinusoidal-like patterns. While such patterning is not reported for rodents and other higher vertebrates, a nonlinear regression analysis confirmed the oscillation patterning of all assessed zebrafish behavioral endpoints in both open field arenas, revealing a potentially important aspect of novelty exploration in lower vertebrates. Copyright © 2012 Elsevier B.V. All rights reserved.

Response of brown treesnakes to reduction of their rodent prey

USGS Publications Warehouse

Gragg, J.E.; Rodda, G.H.; Savidge, J.A.; White, Gary C.; Dean-Bradley, K.; Ellingson, A.R.

2007-01-01

Trapping brown treesnakes (Boiga irregularis; BTS) with live-mouse (Mus domesticus) lures is the principal control technique for this invasive species on Guam. Lure-based trapping is also used on other islands as a precaution against undetected arrivals and in response to verified BTS sightings. However, the effectiveness of lure-based trapping on other islands is questionable, as it has yielded no BTS despite other evidence of their presence. Some evidence suggests that high rodent numbers may interfere with BTS control. To test the relationship between rodent abundance and snake trappability, we conducted a controlled, replicated field experiment incorporating a rodenticide treatment during a BTS mark-recapture study. Using open population modeling in Program MARK, we estimated BTS apparent survival and recapture probabilities. Rodent reduction increased BTS recapture probabilities by 52-65% in 2002 and 22-36% in 2003, and it decreased apparent survival by <1% both years. This appears to be the first published instance of manipulating wild prey to influence snake behavior. Rodent reduction may enhance detection and control of BTS with traps on Guam and other islands. It may also amplify the effectiveness of oral toxicants against BTS.

Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

PubMed Central

Kazdoba, Tatiana M.; Leach, Prescott T.; Yang, Mu; Silverman, Jill L.; Solomon, Marjorie

2016-01-01

Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism. PMID:27305922

Neuropeptides and the social brain: potential rodent models of autism.

PubMed

Lim, Miranda M; Bielsky, Isadora F; Young, Larry J

2005-01-01

Conducting basic scientific research on a complex psychiatric disorder, such as autism, is a challenging prospect. It is difficult to dissociate the fundamental neurological and psychological processes that are disturbed in autism and, therefore, it is a challenge to discover accurate and reliable animal models of the disease. Because of their role in animal models of social processing and social bonding, the neuropeptides oxytocin and vasopressin are strong candidates for dysregulation in autism. In this review, we discuss the current animal models which have investigated oxytocin and vasopressin systems in the brain and their effects on social behavior. For example, mice lacking the oxytocin gene have profound deficits in social processing and social recognition, as do rats lacking vasopressin or mice lacking the vasopressin V1a receptor (V1aR). In another rodent model, monogamous prairie voles are highly social and form strong pair bonds with their mates. Pair bonds can be facilitated or disrupted by perturbing the oxytocin and vasopressin systems. Non-monogamous vole species that do not pair bond have different oxytocin and V1aR distribution patterns in the brain than monogamous vole species. Potential ties from these rodent models to the human autistic condition are then discussed. Given the hallmark disturbances in social function, the study of animal models of social behavior may provide novel therapeutic targets for the treatment of autism.

Finite element modelling of squirrel, guinea pig and rat skulls: using geometric morphometrics to assess sensitivity.

PubMed

Cox, P G; Fagan, M J; Rayfield, E J; Jeffery, N

2011-12-01

Rodents are defined by a uniquely specialized dentition and a highly complex arrangement of jaw-closing muscles. Finite element analysis (FEA) is an ideal technique to investigate the biomechanical implications of these specializations, but it is essential to understand fully the degree of influence of the different input parameters of the FE model to have confidence in the model's predictions. This study evaluates the sensitivity of FE models of rodent crania to elastic properties of the materials, loading direction, and the location and orientation of the models' constraints. Three FE models were constructed of squirrel, guinea pig and rat skulls. Each was loaded to simulate biting on the incisors, and the first and the third molars, with the angle of the incisal bite varied over a range of 45°. The Young's moduli of the bone and teeth components were varied between limits defined by findings from our own and previously published tests of material properties. Geometric morphometrics (GMM) was used to analyse the resulting skull deformations. Bone stiffness was found to have the strongest influence on the results in all three rodents, followed by bite position, and then bite angle and muscle orientation. Tooth material properties were shown to have little effect on the deformation of the skull. The effect of bite position varied between species, with the mesiodistal position of the biting tooth being most important in squirrels and guinea pigs, whereas bilateral vs. unilateral biting had the greatest influence in rats. A GMM analysis of isolated incisor deformations showed that, for all rodents, bite angle is the most important parameter, followed by elastic properties of the tooth. The results here elucidate which input parameters are most important when defining the FE models, but also provide interesting glimpses of the biomechanical differences between the three skulls, which will be fully explored in future publications. © 2011 The Authors. Journal of Anatomy © 2011 Anatomical Society of Great Britain and Ireland.

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease.

PubMed

Orr, Adam L; Rutaganira, Florentine U; de Roulet, Daniel; Huang, Eric J; Hertz, Nicholas T; Shokat, Kevan M; Nakamura, Ken

2017-10-01

Mutations in the mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) cause Parkinson's disease (PD), likely by disrupting PINK1's kinase activity. Although the mechanism(s) underlying how this loss of activity causes degeneration remains unclear, increasing PINK1 activity may therapeutically benefit some forms of PD. However, we must first learn whether restoring PINK1 function prevents degeneration in patients harboring PINK1 mutations, or whether boosting PINK1 function can offer protection in more common causes of PD. To test these hypotheses in preclinical rodent models of PD, we used kinetin triphosphate, a small-molecule that activates both wild-type and mutant forms of PINK1, which affects mitochondrial function and protects neural cells in culture. We chronically fed kinetin, the precursor of kinetin triphosphate, to PINK1-null rats in which PINK1 was reintroduced into their midbrain, and also to rodent models overexpressing α-synuclein. The highest tolerated dose of oral kinetin increased brain levels of kinetin for up to 6 months, without adversely affecting the survival of nigrostriatal dopamine neurons. However, there was no degeneration of midbrain dopamine neurons lacking PINK1, which precluded an assessment of neuroprotection and raised questions about the robustness of the PINK1 KO rat model of PD. In two rodent models of α-synuclein-induced toxicity, boosting PINK1 activity with oral kinetin provided no protective effects. Our results suggest that oral kinetin is unlikely to protect against α-synuclein toxicity, and thus fail to provide evidence that kinetin will protect in sporadic models of PD. Kinetin may protect in cases of PINK1 deficiency, but this possibility requires a more robust PINK1 KO model that can be validated by proof-of-principle genetic correction in adult animals. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Therapeutic Potential of Induced Pluripotent Stem Cells After Stroke: Evidence from Rodent Models.

PubMed

Zents, Karlijn; Copray, Sjef

2016-01-01

Stroke is the second most common cause of death and the leading cause of disability in the world. About 30% of the people that are affected by stroke die within a year; 25% of the patients that survive stroke remain in need of care after a year. Therefore, stroke is a major burden for health care costs. The most common subtype is ischemic stroke. This type is characterized by a reduced and insufficient blood supply to a certain part of the brain. Despite the high prevalence of stroke, the currently used therapeutic interventions are limited. No therapies that aim to restore damaged neuronal tissue or to promote recovery are available nowadays. Transplantation of stem cell-derived cells has been investigated as a potential regenerative and protective treatment. Embryonic stem cell (ESC)-based cell therapy in rodent models of stroke has been shown to improve functional outcome. However, the clinical use of ESCs still raises ethical questions and implantation of ESC-derived cells requires continuous immunosuppression. The groundbreaking detection of induced pluripotent stem cells (iPSCs) has provided a most promising alternative. This mini-review summarizes current literature in which the potential use of iPSC-derived cells has been tested in rodent models of stroke. iPSC-based cell therapy has been demonstrated to improve motor function, decrease stroke volume, promote neurogenesis and angiogenesis and to exert immunomodulatory, anti-inflammatory effects in the brain of stroke-affected rodents.

New Insights from Rodent Models of Fatty Liver Disease

PubMed Central

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

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

PubMed

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.

Optogenetic manipulation of neural circuits in awake marmosets

PubMed Central

MacDougall, Matthew; Nummela, Samuel U.; Coop, Shanna; Disney, Anita; Mitchell, Jude F.

2016-01-01

Optogenetics has revolutionized the study of functional neuronal circuitry (Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Nat Neurosci 8: 1263–1268, 2005; Deisseroth K. Nat Methods 8: 26–29, 2011). Although these techniques have been most successfully implemented in rodent models, they have the potential to be similarly impactful in studies of nonhuman primate brains. Common marmosets (Callithrix jacchus) have recently emerged as a candidate primate model for gene editing, providing a potentially powerful model for studies of neural circuitry and disease in primates. The application of viral transduction methods in marmosets for identifying and manipulating neuronal circuitry is a crucial step in developing this species for neuroscience research. In the present study we developed a novel, chronic method to successfully induce rapid photostimulation in individual cortical neurons transduced by adeno-associated virus to express channelrhodopsin (ChR2) in awake marmosets. We found that large proportions of neurons could be effectively photoactivated following viral transduction and that this procedure could be repeated for several months. These data suggest that techniques for viral transduction and optical manipulation of neuronal populations are suitable for marmosets and can be combined with existing behavioral preparations in the species to elucidate the functional neural circuitry underlying perceptual and cognitive processes. PMID:27334951

A PK-PD Model of Ketamine-Induced High-Frequency Oscillations

PubMed Central

Flores, Francisco J.; Ching, ShiNung; Hartnack, Katharine; Fath, Amanda B.; Purdon, Patrick L.; Wilson, Matthew A.; Brown, Emery N.

2017-01-01

Objective Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a High-Frequency Oscillation (HFO) which power is modulated non-linearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PD) of ketamine and the observed HFO power. Approach In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by a high-frequency oscillation (HFO) observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent range of effects that ketamine has. PMID:26268223

Rodent Models of Experimental Endometriosis: Identifying Mechanisms of Disease and Therapeutic Targets

PubMed Central

Bruner-Tran, Kaylon L.; Mokshagundam, Shilpa; Herington, Jennifer L.; Ding, Tianbing; Osteen, Kevin G.

2018-01-01

Background: Although it has been more than a century since endometriosis was initially described in the literature, understanding the etiology and natural history of the disease has been challenging. However, the broad utility of murine and rat models of experimental endometriosis has enabled the elucidation of a number of potentially targetable processes which may otherwise promote this disease. Objective: To review a variety of studies utilizing rodent models of endometriosis to illustrate their utility in examining mechanisms associated with development and progression of this disease. Results: Use of rodent models of endometriosis has provided a much broader understanding of the risk factors for the initial development of endometriosis, the cellular pathology of the disease and the identification of potential therapeutic targets. Conclusion: Although there are limitations with any animal model, the variety of experimental endometriosis models that have been developed has enabled investigation into numerous aspects of this disease. Thanks to these models, our under-standing of the early processes of disease development, the role of steroid responsiveness, inflammatory processes and the peritoneal environment has been advanced. More recent models have begun to shed light on how epigenetic alterations con-tribute to the molecular basis of this disease as well as the multiple comorbidities which plague many patients. Continued de-velopments of animal models which aid in unraveling the mechanisms of endometriosis development provide the best oppor-tunity to identify therapeutic strategies to prevent or regress this enigmatic disease.

Emergence of transformation-tolerant representations of visual objects in rat lateral extrastriate cortex

PubMed Central

Tafazoli, Sina; Safaai, Houman; De Franceschi, Gioia; Rosselli, Federica Bianca; Vanzella, Walter; Riggi, Margherita; Buffolo, Federica; Panzeri, Stefano; Zoccolan, Davide

2017-01-01

Rodents are emerging as increasingly popular models of visual functions. Yet, evidence that rodent visual cortex is capable of advanced visual processing, such as object recognition, is limited. Here we investigate how neurons located along the progression of extrastriate areas that, in the rat brain, run laterally to primary visual cortex, encode object information. We found a progressive functional specialization of neural responses along these areas, with: (1) a sharp reduction of the amount of low-level, energy-related visual information encoded by neuronal firing; and (2) a substantial increase in the ability of both single neurons and neuronal populations to support discrimination of visual objects under identity-preserving transformations (e.g., position and size changes). These findings strongly argue for the existence of a rat object-processing pathway, and point to the rodents as promising models to dissect the neuronal circuitry underlying transformation-tolerant recognition of visual objects. DOI: http://dx.doi.org/10.7554/eLife.22794.001 PMID:28395730

Potent and Selective Amidopyrazole Inhibitors of IRAK4 That Are Efficacious in a Rodent Model of Inflammation

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

McElroy, William T.; Tan, Zheng; Ho, Ginny

IRAK4 is a critical upstream kinase in the IL-1R/TLR signaling pathway. Inhibition of IRAK4 is hypothesized to be beneficial in the treatment of autoimmune related disorders. A screening campaign identified a pyrazole class of IRAK4 inhibitors that were determined by X-ray crystallography to exhibit an unusual binding mode. SAR efforts focused on the identification of a potent and selective inhibitor with good aqueous solubility and rodent pharmacokinetics. Pyrazole C-3 piperidines were well tolerated, with N-sulfonyl analogues generally having good rodent oral exposure but poor solubility. N-Alkyl piperidines exhibited excellent solubility and reduced exposure. Pyrazoles possessing N-1 pyridine and fluorophenyl substituentsmore » were among the most active. Piperazine 32 was a potent enzyme inhibitor with good cellular activity. Compound 32 reduced the in vivo production of proinflammatory cytokines and was orally efficacious in a mouse antibody induced arthritis disease model of inflammation.« less

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

PubMed

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

2015-06-01

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. Video-electroencephalogram (EEG), electromyogram (EMG), and electrooculogram (EOG) recordings. Rodent sleep laboratory. Fourteen male Arvicanthis ansorgei, aged 3 mo. 12 h light (L):12 h dark (D) baseline condition, 24-h constant darkness, 6-h sleep deprivation. 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. 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. © 2015 Associated Professional Sleep Societies, LLC.

Increased visceral tissue perfusion with heated, humidified carbon dioxide insufflation during open abdominal surgery in a rodent model.

PubMed

Robson, Jonathan P; Kokhanenko, Pavlo; Marshall, Jean K; Phillips, Anthony R; van der Linden, Jan

2018-01-01

Tissue perfusion during surgery is important in reducing surgical site infections and promoting healing. This study aimed to determine if insufflation of the open abdomen with heated, humidified (HH) carbon dioxide (CO2) increased visceral tissue perfusion and core body temperature during open abdominal surgery in a rodent model. Using two different rodent models of open abdominal surgery, visceral perfusion and core temperature were measured. Visceral perfusion was investigated using a repeated measures crossover experiment with rodents receiving the same sequence of two alternating treatments: exposure to ambient air (no insufflation) and insufflation with HH CO2. Core body temperature was measured using an independent experimental design with three treatment groups: ambient air, HH CO2 and cold, dry (CD) CO2. Visceral perfusion was measured by laser speckle contrast analysis (LASCA) and core body temperature was measured with a rectal thermometer. Insufflation with HH CO2 into a rodent open abdominal cavity significantly increased visceral tissue perfusion (2.4 perfusion units (PU)/min (95% CI 1.23-3.58); p<0.0001) compared with ambient air, which significantly reduced visceral blood flow (-5.20 PU/min (95% CI -6.83- -3.58); p<0.0001). Insufflation of HH CO2 into the open abdominal cavity significantly increased core body temperature (+1.15 ± 0.14°C) compared with open cavities exposed to ambient air (-0.65 ± 0.52°C; p = 0.037), or cavities insufflated with CD CO2 (-0.73 ± 0.33°C; p = 0.006). Abdominal visceral temperatures also increased with HH CO2 insufflation compared with ambient air or CD CO2, as shown by infrared thermography. This study reports for the first time the use of LASCA to measure visceral perfusion in open abdominal surgery and shows that insufflation of open abdominal cavities with HH CO2 significantly increases visceral tissue perfusion and core body temperature.

Hantavirus reservoir Oligoryzomys longicaudatus spatial distribution sensitivity to climate change scenarios in Argentine Patagonia

PubMed Central

Carbajo, Aníbal E; Vera, Carolina; González, Paula LM

2009-01-01

Background Oligoryzomys longicaudatus (colilargo) is the rodent responsible for hantavirus pulmonary syndrome (HPS) in Argentine Patagonia. In past decades (1967–1998), trends of precipitation reduction and surface air temperature increase have been observed in western Patagonia. We explore how the potential distribution of the hantavirus reservoir would change under different climate change scenarios based on the observed trends. Methods Four scenarios of potential climate change were constructed using temperature and precipitation changes observed in Argentine Patagonia between 1967 and 1998: Scenario 1 assumed no change in precipitation but a temperature trend as observed; scenario 2 assumed no changes in temperature but a precipitation trend as observed; Scenario 3 included changes in both temperature and precipitation trends as observed; Scenario 4 assumed changes in both temperature and precipitation trends as observed but doubled. We used a validated spatial distribution model of O. longicaudatus as a function of temperature and precipitation. From the model probability of the rodent presence was calculated for each scenario. Results If changes in precipitation follow previous trends, the probability of the colilargo presence would fall in the HPS transmission zone of northern Patagonia. If temperature and precipitation trends remain at current levels for 60 years or double in the future 30 years, the probability of the rodent presence and the associated total area of potential distribution would diminish throughout Patagonia; the areas of potential distribution for colilargos would shift eastwards. These results suggest that future changes in Patagonia climate may lower transmission risk through a reduction in the potential distribution of the rodent reservoir. Conclusion According to our model the rates of temperature and precipitation changes observed between 1967 and 1998 may produce significant changes in the rodent distribution in an equivalent period of time only in certain areas. Given that changes maintain for 60 years or double in 30 years, the hantavirus reservoir Oligoryzomys longicaudatus may contract its distribution in Argentine Patagonia extensively. PMID:19607707

Using animal models to evaluate the functional consequences of anesthesia during early neurodevelopment.

PubMed

Maloney, Susan E; Creeley, Catherine E; Hartman, Richard E; Yuede, Carla M; Zorumski, Charles F; Jevtovic-Todorovic, Vesna; Dikranian, Krikor; Noguchi, Kevin K; Farber, Nuri B; Wozniak, David F

2018-03-14

Fifteen years ago Olney and colleagues began using animal models to evaluate the effects of anesthetic and sedative agents (ASAs) on neurodevelopment. The results from ongoing studies indicate that, under certain conditions, exposure to these drugs during development induces an acute elevated apoptotic neurodegenerative response in the brain and long-term functional impairments. These animal models have played a significant role in bringing attention to the possible adverse effects of exposing the developing brain to ASAs when few concerns had been raised previously in the medical community. The apoptotic degenerative response resulting from neonatal exposure to ASAs has been replicated in many studies in both rodents and non-human primates, suggesting that a similar effect may occur in humans. In both rodents and non-human primates, significantly increased levels of apoptotic degeneration are often associated with functional impairments later in life. However, behavioral deficits following developmental ASA exposure have not been consistently reported even when significantly elevated levels of apoptotic degeneration have been documented in animal models. In the present work, we review this literature and propose a rodent model for assessing potential functional deficits following neonatal ASA exposure with special reference to experimental design and procedural issues. Our intent is to improve test sensitivity and replicability for detecting subtle behavioral effects, and thus enhance the translational significance of ASA models. Copyright © 2018 Elsevier Inc. All rights reserved.

Assessing the Diversity of Rodent-Borne Viruses: Exploring of High-Throughput Sequencing and Classical Amplification/Sequencing Approaches.

PubMed

Drewes, Stephan; Straková, Petra; Drexler, Jan F; Jacob, Jens; Ulrich, Rainer G

2017-01-01

Rodents are distributed throughout the world and interact with humans in many ways. They provide vital ecosystem services, some species are useful models in biomedical research and some are held as pet animals. However, many rodent species can have adverse effects such as damage to crops and stored produce, and they are of health concern because of the transmission of pathogens to humans and livestock. The first rodent viruses were discovered by isolation approaches and resulted in break-through knowledge in immunology, molecular and cell biology, and cancer research. In addition to rodent-specific viruses, rodent-borne viruses are causing a large number of zoonotic diseases. Most prominent examples are reemerging outbreaks of human hemorrhagic fever disease cases caused by arena- and hantaviruses. In addition, rodents are reservoirs for vector-borne pathogens, such as tick-borne encephalitis virus and Borrelia spp., and may carry human pathogenic agents, but likely are not involved in their transmission to human. In our days, next-generation sequencing or high-throughput sequencing (HTS) is revolutionizing the speed of the discovery of novel viruses, but other molecular approaches, such as generic RT-PCR/PCR and rolling circle amplification techniques, contribute significantly to the rapidly ongoing process. However, the current knowledge still represents only the tip of the iceberg, when comparing the known human viruses to those known for rodents, the mammalian taxon with the largest species number. The diagnostic potential of HTS-based metagenomic approaches is illustrated by their use in the discovery and complete genome determination of novel borna- and adenoviruses as causative disease agents in squirrels. In conclusion, HTS, in combination with conventional RT-PCR/PCR-based approaches, resulted in a drastically increased knowledge of the diversity of rodent viruses. Future improvements of the used workflows, including bioinformatics analysis, will further enhance our knowledge and preparedness in case of the emergence of novel viruses. Classical virological and additional molecular approaches are needed for genome annotation and functional characterization of novel viruses, discovered by these technologies, and evaluation of their zoonotic potential. © 2017 Elsevier Inc. All rights reserved.

Cryptic herbivores mediate the strength and form of ungulate impacts on a long-lived savanna tree.

PubMed

Maclean, Janet E; Goheen, Jacob R; Doak, Daniel F; Palmer, Todd M; Young, Truman P

2011-08-01

Plant populations are regulated by a diverse array of herbivores that impose demographic filters throughout their life cycle. Few studies, however, simultaneously quantify the impacts of multiple herbivore guilds on the lifetime performance or population growth rate of plants. In African savannas, large ungulates (such as elephants) are widely regarded as important drivers of woody plant population dynamics, while the potential impacts of smaller, more cryptic herbivores (such as rodents) have largely been ignored. We combined a large-scale ungulate exclusion experiment with a five-year manipulation of rodent densities to quantify the impacts of three herbivore guilds (wild ungulates, domestic cattle, and rodents) on all life stages of a widespread savanna tree. We utilized demographic modeling to reveal the overall role of each guild in regulating tree population dynamics, and to elucidate the importance of different demographic hurdles in driving population growth under contrasting consumer communities. We found that wild ungulates dramatically reduced population growth, shifting the population trajectory from increase to decline, but that the mechanisms driving these effects were strongly mediated by rodents. The impact of wild ungulates on population growth was predominantly driven by their negative effect on tree reproduction when rodents were excluded, and on adult tree survival when rodents were present. By limiting seedling survival, rodents also reduced population growth; however, this effect was strongly dampened where wild ungulates were present. We suggest that these complex interactions between disparate consumer guilds can have important consequences for the population demography of long-lived species, and that the effects of a single consumer group are often likely to vary dramatically depending on the larger community in which interactions are embedded.

16S rRNA Amplicon Sequencing for Epidemiological Surveys of Bacteria in Wildlife

PubMed Central

Razzauti, Maria; Bard, Emilie; Bernard, Maria; Brouat, Carine; Charbonnel, Nathalie; Dehne-Garcia, Alexandre; Loiseau, Anne; Tatard, Caroline; Tamisier, Lucie; Vayssier-Taussat, Muriel; Vignes, Helene

2016-01-01

ABSTRACT The human impact on natural habitats is increasing the complexity of human-wildlife interactions and leading to the emergence of infectious diseases worldwide. Highly successful synanthropic wildlife species, such as rodents, will undoubtedly play an increasingly important role in transmitting zoonotic diseases. We investigated the potential for recent developments in 16S rRNA amplicon sequencing to facilitate the multiplexing of the large numbers of samples needed to improve our understanding of the risk of zoonotic disease transmission posed by urban rodents in West Africa. In addition to listing pathogenic bacteria in wild populations, as in other high-throughput sequencing (HTS) studies, our approach can estimate essential parameters for studies of zoonotic risk, such as prevalence and patterns of coinfection within individual hosts. However, the estimation of these parameters requires cleaning of the raw data to mitigate the biases generated by HTS methods. We present here an extensive review of these biases and of their consequences, and we propose a comprehensive trimming strategy for managing these biases. We demonstrated the application of this strategy using 711 commensal rodents, including 208 Mus musculus domesticus, 189 Rattus rattus, 93 Mastomys natalensis, and 221 Mastomys erythroleucus, collected from 24 villages in Senegal. Seven major genera of pathogenic bacteria were detected in their spleens: Borrelia, Bartonella, Mycoplasma, Ehrlichia, Rickettsia, Streptobacillus, and Orientia. Mycoplasma, Ehrlichia, Rickettsia, Streptobacillus, and Orientia have never before been detected in West African rodents. Bacterial prevalence ranged from 0% to 90% of individuals per site, depending on the bacterial taxon, rodent species, and site considered, and 26% of rodents displayed coinfection. The 16S rRNA amplicon sequencing strategy presented here has the advantage over other molecular surveillance tools of dealing with a large spectrum of bacterial pathogens without requiring assumptions about their presence in the samples. This approach is therefore particularly suitable to continuous pathogen surveillance in the context of disease-monitoring programs. IMPORTANCE Several recent public health crises have shown that the surveillance of zoonotic agents in wildlife is important to prevent pandemic risks. High-throughput sequencing (HTS) technologies are potentially useful for this surveillance, but rigorous experimental processes are required for the use of these effective tools in such epidemiological contexts. In particular, HTS introduces biases into the raw data set that might lead to incorrect interpretations. We describe here a procedure for cleaning data before estimating reliable biological parameters, such as positivity, prevalence, and coinfection, using 16S rRNA amplicon sequencing on an Illumina MiSeq platform. This procedure, applied to 711 rodents collected in West Africa, detected several zoonotic bacterial species, including some at high prevalence, despite their never before having been reported for West Africa. In the future, this approach could be adapted for the monitoring of other microbes such as protists, fungi, and even viruses. PMID:27822541

Convection-enhanced delivery of SN-38-loaded polymeric micelles (NK012) enables consistent distribution of SN-38 and is effective against rodent intracranial brain tumor models.

PubMed

Zhang, Rong; Saito, Ryuta; Mano, Yui; Sumiyoshi, Akira; Kanamori, Masayuki; Sonoda, Yukihiko; Kawashima, Ryuta; Tominaga, Teiji

2016-10-01

Convection-enhanced delivery (CED) of therapeutic agents is a promising local delivery technique that has been extensively studied as a treatment for CNS diseases over the last two decades. One continuing challenge of CED is accurate and consistent delivery of the agents to the target. The present study focused on a new type of therapeutic agent, NK012, a novel SN-38-loaded polymeric micelle. Local delivery profiles of NK012 and SN-38 were studied using rodent brain and intracranial rodent brain tumor models. First, the cytotoxicity of NK012 against glioma cell lines was determined in vitro. Proliferations of glioma cells were significantly reduced after exposure to NK012. Then, the distribution and local toxicity after CED delivery of NK012 and SN-38 were evaluated in vivo. Volume of distribution of NK012 after CED was much larger than that of SN-38. Histological examination revealed minimum brain tissue damage in rat brains after delivery of 40 µg NK012 but severe damage with SN-38 at the same dose. Subsequently, the efficacy of NK012 delivered via CED was tested in 9L and U87MG rodent orthotopic brain tumor models. CED of NK012 displayed excellent efficacy in the 9L and U87MG orthotopic brain tumor models. Furthermore, NK012 and gadolinium diamide were co-delivered via CED to monitor the NK012 distribution using MRI. Volume of NK012 distribution evaluated by histology and MRI showed excellent agreement. CED of NK012 represents an effective treatment option for malignant gliomas. MRI-guided CED of NK012 has potential for clinical application.

Rodent Models of Genetic Contributions to Motivation to Abuse Alcohol

PubMed Central

Crabbe, John C.

2016-01-01

The distinction between alcohol use (normative) and abuse (unfortunately common) implies dysregulation of motivation directed toward the drug. Genetic contributions to abuse risk are mediated through personality differences, other predispositions to drink excessively, and differences in sensitivity to the acute and chronic consequences of the drug. How to assess motivation in laboratory animals is not straightforward but risk factors for and consequences of alcohol abuse can be modeled with reasonable fidelity in laboratory rodents. Remarkably few rodent studies focus on the genetic contributions to alcohol’s reinforcing value: almost all examine preferential drinking of unflavored alcohol over water. Such studies will likely never avoid the confounding role of taste preferences and most often yield intake levels insufficient to yield a pharmacologically significant blood alcohol level. Genotypes that avoid alcohol probably do so based on pre-ingestive sensory cues; however, post-ingestive consequences are also important. Thus, the quest for improved measures of reinforcing value continues. We have genetic differences aplenty, but still lack evidence that any genotype will readily self-administer alcohol to the devastating extent that many alcoholics will. Encouraging results that are emerging include improved behavioral methods for elevating alcohol intake and inferring alcohol reinforcement, as well as new genetic animal models. Several ingenious assays to index alcohol’s motivational effects have been used extensively. Alcoholic drinking that attempts to prevent or to alleviate withdrawal symptoms has been modeled. Another characteristic of alcoholic drinking is its persistence despite abundant evidence to the drinker of the damaging effects of the excessive drinking on work, relationships, and/or health. Modeling such persistence in rodents has been uncommon to date. New genetic animal models include lines of mice selectively bred for chronic high drinking, and other bred for high binge-like drinking. We have a much more clear idea now about some important experiments remaining to be performed. PMID:25306777

Diet before and during Pregnancy and Offspring Health: The Importance of Animal Models and What Can Be Learned from Them.

PubMed

Chavatte-Palmer, Pascale; Tarrade, Anne; Rousseau-Ralliard, Delphine

2016-06-14

This review article outlines epidemiologic studies that support the hypothesis that maternal environment (including early nutrition) plays a seminal role in determining the offspring's long-term health and metabolism, known as the concept of Developmental Origins of Health and Diseases (DOHaD). In this context, current concerns are particularly focused on the increased incidence of obesity and diabetes, particularly in youth and women of child-bearing age. We summarize key similarities, differences and limitations of various animal models used to study fetal programming, with a particular focus on placentation, which is critical for translating animal findings to humans. This review will assist researchers and their scientific audience in recognizing the pros and cons of various rodent and non-rodent animal models used to understand mechanisms involved in fetal programming. Knowledge gained will lead to improved translation of proposed interventional therapies before they can be implemented in humans. Although rodents are essential for fundamental exploration of biological processes, other species such as rabbits and other domestic animals offer more tissue-specific physiological (rabbit placenta) or physical (ovine maternal and lamb birth weight) resemblances to humans. We highlight the important maternal, placental, and fetal/neonatal characteristics that contribute to developmentally programmed diseases, specifically in offspring that were affected in utero by undernutrition, overnutrition or maternal diabetes. Selected interventions aimed at prevention are summarized with a specific focus on the 1000 days initiative in humans, and maternal exercise or modification of the n-3/n-6 polyunsaturated fatty acid (PUFA) balance in the diet, which are currently being successfully tested in animal models to correct or reduce adverse prenatal programming. Animal models are essential to understand mechanisms involved in fetal programming and in order to propose interventional therapies before they can be implemented in humans. Non-rodent animals are particularly important and should not be neglected, as they are often more physiologically-appropriate models to mimic the human situation.

Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents.

PubMed

van den Brink, Willem; Emerenciana, Annette; Bellanti, Francesco; Della Pasqua, Oscar; van der Laan, Jan Willem

2017-04-01

Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinear mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes. Copyright © 2017 Elsevier Inc. All rights reserved.

Diet before and during Pregnancy and Offspring Health: The Importance of Animal Models and What Can Be Learned from Them

PubMed Central

Chavatte-Palmer, Pascale; Tarrade, Anne; Rousseau-Ralliard, Delphine

2016-01-01

This review article outlines epidemiologic studies that support the hypothesis that maternal environment (including early nutrition) plays a seminal role in determining the offspring’s long-term health and metabolism, known as the concept of Developmental Origins of Health and Diseases (DOHaD). In this context, current concerns are particularly focused on the increased incidence of obesity and diabetes, particularly in youth and women of child-bearing age. We summarize key similarities, differences and limitations of various animal models used to study fetal programming, with a particular focus on placentation, which is critical for translating animal findings to humans. This review will assist researchers and their scientific audience in recognizing the pros and cons of various rodent and non-rodent animal models used to understand mechanisms involved in fetal programming. Knowledge gained will lead to improved translation of proposed interventional therapies before they can be implemented in humans. Although rodents are essential for fundamental exploration of biological processes, other species such as rabbits and other domestic animals offer more tissue-specific physiological (rabbit placenta) or physical (ovine maternal and lamb birth weight) resemblances to humans. We highlight the important maternal, placental, and fetal/neonatal characteristics that contribute to developmentally programmed diseases, specifically in offspring that were affected in utero by undernutrition, overnutrition or maternal diabetes. Selected interventions aimed at prevention are summarized with a specific focus on the 1000 days initiative in humans, and maternal exercise or modification of the n-3/n-6 polyunsaturated fatty acid (PUFA) balance in the diet, which are currently being successfully tested in animal models to correct or reduce adverse prenatal programming. Animal models are essential to understand mechanisms involved in fetal programming and in order to propose interventional therapies before they can be implemented in humans. Non-rodent animals are particularly important and should not be neglected, as they are often more physiologically-appropriate models to mimic the human situation. PMID:27314367

Estimating hantavirus risk in southern Argentina: a GIS-based approach combining human cases and host distribution.

PubMed

Andreo, Veronica; Neteler, Markus; Rocchini, Duccio; Provensal, Cecilia; Levis, Silvana; Porcasi, Ximena; Rizzoli, Annapaola; Lanfri, Mario; Scavuzzo, Marcelo; Pini, Noemi; Enria, Delia; Polop, Jaime

2014-01-14

We use a Species Distribution Modeling (SDM) approach along with Geographic Information Systems (GIS) techniques to examine the potential distribution of hantavirus pulmonary syndrome (HPS) caused by Andes virus (ANDV) in southern Argentina and, more precisely, define and estimate the area with the highest infection probability for humans, through the combination with the distribution map for the competent rodent host (Oligoryzomys longicaudatus). Sites with confirmed cases of HPS in the period 1995-2009 were mostly concentrated in a narrow strip (~90 km × 900 km) along the Andes range from northern Neuquén to central Chubut province. This area is characterized by high mean annual precipitation (~1,000 mm on average), but dry summers (less than 100 mm), very low percentages of bare soil (~10% on average) and low temperatures in the coldest month (minimum average temperature -1.5 °C), as compared to the HPS-free areas, features that coincide with sub-Antarctic forests and shrublands (especially those dominated by the invasive plant Rosa rubiginosa), where rodent host abundances and ANDV prevalences are known to be the highest. Through the combination of predictive distribution maps of the reservoir host and disease cases, we found that the area with the highest probability for HPS to occur overlaps only 28% with the most suitable habitat for O. longicaudatus. With this approach, we made a step forward in the understanding of the risk factors that need to be considered in the forecasting and mapping of risk at the regional/national scale. We propose the implementation and use of thematic maps, such as the one built here, as a basic tool allowing public health authorities to focus surveillance efforts and normally scarce resources for prevention and control actions in vast areas like southern Argentina.

Characterization of Na+ and Ca2+ Channels in Zebrafish Dorsal Root Ganglion Neurons

PubMed Central

Won, Yu-Jin; Ono, Fumihito; Ikeda, Stephen R.

2012-01-01

Background Dorsal root ganglia (DRG) somata from rodents have provided an excellent model system to study ion channel properties and modulation using electrophysiological investigation. As in other vertebrates, zebrafish (Danio rerio) DRG are organized segmentally and possess peripheral axons that bifurcate into each body segment. However, the electrical properties of zebrafish DRG sensory neurons, as compared with their mammalian counterparts, are relatively unexplored because a preparation suitable for electrophysiological studies has not been available. Methodology/Principal Findings We show enzymatically dissociated DRG neurons from juvenile zebrafish expressing Isl2b-promoter driven EGFP were easily identified with fluorescence microscopy and amenable to conventional whole-cell patch-clamp studies. Two kinetically distinct TTX-sensitive Na+ currents (rapidly- and slowly-inactivating) were discovered. Rapidly-inactivating INa were preferentially expressed in relatively large neurons, while slowly-inactivating INa was more prevalent in smaller DRG neurons. RT-PCR analysis suggests zscn1aa/ab, zscn8aa/ab, zscn4ab and zscn5Laa are possible candidates for these INa components. Voltage-gated Ca2+ currents (ICa) were primarily (87%) comprised of a high-voltage activated component arising from ω-conotoxin GVIA-sensitive CaV2.2 (N-type) Ca2+ channels. A few DRG neurons (8%) displayed a miniscule low-voltage-activated component. ICa in zebrafish DRG neurons were modulated by neurotransmitters via either voltage-dependent or -independent G-protein signaling pathway with large cell-to-cell response variability. Conclusions/Significance Our present results indicate that, as in higher vertebrates, zebrafish DRG neurons are heterogeneous being composed of functionally distinct subpopulations that may correlate with different sensory modalities. These findings provide the first comparison of zebrafish and rodent DRG neuron electrical properties and thus provide a basis for future studies. PMID:22880050

Inhaled delivery of Δ(9)-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology.

PubMed

Nguyen, Jacques D; Aarde, Shawn M; Vandewater, Sophia A; Grant, Yanabel; Stouffer, David G; Parsons, Loren H; Cole, Maury; Taffe, Michael A

2016-10-01

Most human Δ(9)-tetrahydrocannabinol (THC) use is via inhalation, and yet few animal studies of inhalation exposure are available. Popularization of non-combusted methods for the inhalation of psychoactive drugs (Volcano(®), e-cigarettes) further stimulates a need for rodent models of this route of administration. This study was designed to develop and validate a rodent chamber suitable for controlled exposure to vaporized THC in a propylene glycol vehicle, using an e-cigarette delivery system adapted to standard size, sealed rat housing chambers. The in vivo efficacy of inhaled THC was validated using radiotelemetry to assess body temperature and locomotor responses, a tail-flick assay for nociception and plasma analysis to verify exposure levels. Hypothermic responses to inhaled THC in male rats depended on the duration of exposure and the concentration of THC in the vehicle. The temperature nadir was reached after ∼40 min of exposure, was of comparable magnitude (∼3 °Celsius) to that produced by 20 mg/kg THC, i.p. and resolved within 3 h (compared with a 6 h time course following i.p. THC). Female rats were more sensitive to hypothermic effects of 30 min of lower-dose THC inhalation. Male rat tail-flick latency was increased by THC vapor inhalation; this effect was blocked by SR141716 pretreatment. The plasma THC concentration after 30 min of inhalation was similar to that produced by 10 mg/kg THC i.p. This approach is flexible, robust and effective for use in laboratory rats and will be of increasing utility as users continue to adopt "vaping" for the administration of cannabis. Copyright © 2016 Elsevier Ltd. All rights reserved.

High-purity flow sorting of early meiocytes based on DNA analysis of guinea pig spermatogenic cells.

PubMed

Rodríguez-Casuriaga, Rosana; Geisinger, Adriana; Santiñaque, Federico F; López-Carro, Beatriz; Folle, Gustavo A

2011-08-01

Mammalian spermatogenesis is still nowadays poorly understood at the molecular level. Testis cellular heterogeneity is a major drawback for spermatogenic gene expression studies, especially when research is focused on stages that are usually very short and poorly represented at the cellular level such as initial meiotic prophase I (i.e., leptotene [L] and zygotene [Z]). Presumably, genes whose products are involved in critical meiotic events such as alignment, pairing and recombination of homologous chromosomes are expressed during the short stages of early meiotic prophase. Aiming to characterize mammalian early meiotic gene expression, we have found the guinea pig (Cavia porcellus) as an especially attractive model. A detailed analysis of its first spermatogenic wave by flow cytometry (FCM) and optical microscopy showed that guinea pig testes exhibit a higher representation of early meiotic stages compared to other studied rodents, partly because of their longer span, and also as a result of the increased number of cells entering meiosis. Moreover, we have found that adult guinea pig testes exhibit a peculiar 4C DNA content profile, with a bimodal peak for L/Z and P spermatocytes that is absent in other rodents. Besides, we show that this unusual 4C peak allows the separation by FCM of highly pure L/Z spermatocyte populations aside from pachytene ones, even from adult individuals. To our knowledge, this is the first report on an accurate and suitable method for highly pure early meiotic prophase cell isolation from adult mammals, and thus sets an interesting approach for gene expression studies aiming at a deeper understanding of the molecular groundwork underlying male gamete production. Copyright © 2011 International Society for Advancement of Cytometry.

Critical evaluation of colon submucosal microdialysis in awake, mobile rats.

PubMed

Cibicek, Norbert; Ehrmann, Jiri; Proskova, Jitka; Vecera, Rostislav

2018-01-01

Sensors able to record large bowel physiology and biochemistry in situ in awake rodents are lacking. Microdialysis is a mini-invasive technique that may be utilized to continuously deliver or recover low-molecular substances from various tissues. In this experiment we evaluated the feasibility of in vivo microdialysis to monitor extracellular fluid chemistry in the descending colon submucosa of conscious, freely moving rodents. Following surgical implantation of a microdialysis probe, male Wistar rats were housed in metabolic cages where they were analgized and clinically followed for four days with free access to standard diet and water. To assess local microcirculation and probe function, glucose, lactate, glucose-to-lactate ratio and urea clearance were determined in the dialysates from the three postoperative days with focus on the final 24-h period. In an attempt to mitigate the expected tissue inflammatory response, one group of animals had the catheters perfused with 5-aminosalicylic acid-enriched medium with final concentration 1 μmol/L. For verification of probe position and the assessment of the surrounding foreign body reaction, standard histological and immunohistochemical methods were employed. Microdialysis of rat gut is associated with considerable technical challenges that may lead to the loss of probe function and high drop-out rate. In this setting, limited data did not allow to draw any firm conclusion regarding local anti-inflammatory effectiveness of 5-aminosalicylic acid perfusion. Although intestinal microdialysis may be suitable for larger anesthetized animals, low reproducibility of the presented method compromises its routine experimental use in awake and freely moving small-sized rodents.

Development of an Experimental Model of Diabetes Co-Existing with Metabolic Syndrome in Rats.

PubMed

Suman, Rajesh Kumar; Ray Mohanty, Ipseeta; Borde, Manjusha K; Maheshwari, Ujwala; Deshmukh, Y A

2016-01-01

Background. The incidence of metabolic syndrome co-existing with diabetes mellitus is on the rise globally. Objective. The present study was designed to develop a unique animal model that will mimic the pathological features seen in individuals with diabetes and metabolic syndrome, suitable for pharmacological screening of drugs. Materials and Methods. A combination of High-Fat Diet (HFD) and low dose of streptozotocin (STZ) at 30, 35, and 40 mg/kg was used to induce metabolic syndrome in the setting of diabetes mellitus in Wistar rats. Results. The 40 mg/kg STZ produced sustained hyperglycemia and the dose was thus selected for the study to induce diabetes mellitus. Various components of metabolic syndrome such as dyslipidemia {(increased triglyceride, total cholesterol, LDL cholesterol, and decreased HDL cholesterol)}, diabetes mellitus (blood glucose, HbA1c, serum insulin, and C-peptide), and hypertension {systolic blood pressure} were mimicked in the developed model of metabolic syndrome co-existing with diabetes mellitus. In addition to significant cardiac injury, atherogenic index, inflammation (hs-CRP), decline in hepatic and renal function were observed in the HF-DC group when compared to NC group rats. The histopathological assessment confirmed presence of edema, necrosis, and inflammation in heart, pancreas, liver, and kidney of HF-DC group as compared to NC. Conclusion. The present study has developed a unique rodent model of metabolic syndrome, with diabetes as an essential component.

Induced pluripotent stem cells (iPSC)-derived retinal cells in disease modeling and regenerative medicine.

PubMed

Rathod, Reena; Surendran, Harshini; Battu, Rajani; Desai, Jogin; Pal, Rajarshi

2018-02-12

Retinal degenerative disorders are a leading cause of the inherited, irreversible and incurable vision loss. While various rodent model systems have provided crucial information in this direction, lack of disease-relevant tissue availability and species-specific differences have proven to be a major roadblock. Human induced pluripotent stem cells (iPSC) have opened up a whole new avenue of possibilities not just in understanding the disease mechanism but also potential therapeutic approaches towards a cure. In this review, we have summarized recent advances in the methods of deriving retinal cell types from iPSCs which can serve as a renewable source of disease-relevant cell population for basic as well as translational studies. We also provide an overview of the ongoing efforts towards developing a suitable in vitro model for modeling retinal degenerative diseases. This basic understanding in turn has contributed to advances in translational goals such as drug screening and cell-replacement therapies. Furthermore we discuss gene editing approaches for autologous repair of genetic disorders and allogeneic transplantation of stem cell-based retinal derivatives for degenerative disorders with an ultimate goal to restore vision. It is pertinent to note however, that these exciting new developments throw up several challenges that need to be overcome before their full clinical potential can be realized. Copyright © 2018 Elsevier B.V. All rights reserved.

Altered attentional processing in male and female rats in a prenatal valproic acid exposure model of autism spectrum disorder.

PubMed

Anshu, Kumari; Nair, Ajay Kumar; Kumaresan, U D; Kutty, Bindu M; Srinath, Shoba; Laxmi, T Rao

2017-12-01

Attention is foundational to efficient perception and optimal goal driven behavior. Intact attentional processing is crucial for the development of social and communication skills. Deficits in attention are therefore likely contributors to the core pathophysiology of autism spectrum disorder (ASD). Clinical evidence in ASD is suggestive of impairments in attention and its control, but the underlying mechanisms remain elusive. We examined sustained, spatially divided attention in a prenatal valproic acid (VPA) model of ASD using the 5-choice serial reaction time task (5-CSRTT). As compared to controls, male and female VPA rats had progressively lower accuracy and higher omissions with increasing attentional demands during 5-CSRTT training, and showed further performance decrements when subjected to parametric task manipulations. It is noteworthy that although VPA exposure induced attentional deficits in both sexes, there were task parameter specific sex differences. Importantly, we did not find evidence of impulsivity or motivational deficits in VPA rats but we did find reduced social preference, as well as sensorimotor deficits that suggest pre-attentional information processing impairments. Importantly, with fixed rules, graded difficulty levels, and more time, VPA rats could be successfully trained on the attentional task. To the best of our knowledge, this is the first study examining attentional functions in a VPA model. Our work underscores the need for studying both sexes in ASD animal models and validates the use of the VPA model in the quest for mechanistic understanding of aberrant attentional functions and for evaluating suitable therapeutic targets. Autism Res 2017, 10: 1929-1944. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. We studied rats prenatally exposed to valproic acid (VPA), an established rodent model of autism. Both male and female VPA rats had a range of attentional impairments with sex-specific characteristics. Importantly, with fixed rules, graded difficulty levels, and more time, VPA rats could be successfully trained on the attentional task. Our work validates the use of the VPA model in the quest for evaluating suitable therapeutic targets for improving attentional performance. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

High Drinking in the Dark Mice: A genetic model of drinking to intoxication

PubMed Central

Barkley-Levenson, Amanda M.; Crabbe, John C.

2014-01-01

Drinking to intoxication is a critical component of risky drinking behaviors in humans, such as binge drinking. Previous rodent models of alcohol consumption largely failed to demonstrate that animals were patterning drinking in such a way as to experience intoxication. Therefore, few rodent models of binge-like drinking and no specifically genetic models were available to study possible predisposing genes. The High Drinking in the Dark (HDID) selective breeding project was started to help fill this void, with HDID mice selected for reaching high blood alcohol levels in a limited access procedure. HDID mice now represent a genetic model of drinking to intoxication and can be used to help answer questions regarding predisposition toward this trait as well as potential correlated responses. They should also prove useful for the eventual development of better therapeutic strategies. PMID:24360287

Experimental Models of Vaginal Candidiasis and Their Relevance to Human Candidiasis

PubMed Central

Sobel, Jack D.

2016-01-01

Vulvovaginal candidiasis (VVC) is a high-incidence disease seriously affecting the quality of life of women worldwide, particularly in its chronic, recurrent forms (RVVC), and with no definitive cure or preventive measure. Experimental studies in currently used rat and mouse models of vaginal candidiasis have generated a large mass of data on pathogenicity determinants and inflammation and immune responses of potential importance for the control of human pathology. However, reflection is necessary about the relevance of these rodent models to RVVC. Here we examine the chemical, biochemical, and biological factors that determine or contrast the forms of the disease in rodent models and in women and highlight the differences between them. We also appeal for approaches to improve or replace the current models in order to enhance their relevance to human infection. PMID:26883592

Postdispersal seed predation limits the abundance of a long-lived perennial forb (Lithospermum ruderale).

PubMed

Bricker, Mary; Maron, John

2012-03-01

Loss of seeds to consumers is common in plant communities, but the degree to which these losses influence plant abundance or population growth is often unclear. This is particularly the case for postdispersal seed predation by rodents, as most studies of rodent seed predation have focused on the sources of spatiotemporal variation in seed loss but not quantified the population consequences of this loss. In previous work we showed that seed predation by deer mice (Peromyscus maniculatus) substantially reduced seedling recruitment and establishment of Lithospermum ruderale (Boraginaceae), a long-lived perennial forb. To shed light on how rodent seed predation and the near-term effects on plant recruitment might influence longer-term patterns of L. ruderale population growth, we combined experimental results with demographic data in stage-based population models. Model outputs revealed that rodent seed predation had a significant impact on L. ruderale population growth rate (lambda). With the removal of postdispersal seed predation, the projected population growth rates increased between 0.06 and 0.12, depending on site (mean deltalambda across sites = 0.08). Seed predation shifted the projected stable stage distribution of populations from one with a high proportion of young plants to one in which larger adult size classes dominate. Elasticities of vital rates also changed, with germination and growth of seedlings and young plants becoming more important with the removal of seed predation. Simulations varying the magnitude of seed predation pressure while holding other vital rates constant showed that seed predation could lower lambda even if only 40% of available seeds were consumed. These results demonstrate that rodent granivory can be a potent force limiting the abundance of a long-lived perennial forb.

Rat-bites of an epidemic proportion in Peshawar vale; a GIS based approach in risk assessment.

PubMed

Fatima, Syeda Hira; Zaidi, Farrah; Adnan, Muhammad; Ali, Asad; Jamal, Qaiser; Khisroon, Muhammad

2018-03-19

Contemporary studies demonstrate that rodent bites do not occur frequently. However, a huge number of cases were reported from Peshawar vale, Pakistan during 2016. Two species, the local black rat Rattus rattus (Linnaeus, 1758) and the invasive brown rat Rattus norvegicus (Berkenhout, 1769) might be the suspected cause. Several studies indicated the invasion of brown rats into Pakistan presumably via port city of Karachi. In this study, we modeled geospatial distribution of rodent bites for risk assessment in the region. Bite cases reported to tertiary care lady reading hospital were monitored from January 1 to August 31, 2016. Among 1747 cases, statistically informative data (n = 1295) was used for analyses. MaxEnt algorithm was employed for geospatial modeling, taking into account various environmental variables (temperature, precipitation, humidity, and elevation) and anthropogenic factors (human population density, distance from roads, distance from water channels, and land use/land cover). MaxEnt results revealed that urban slums (84.5%) are at highest risk followed by croplands (10.9%) and shrublands (2.7%). Anthropogenic factors affecting incidence of rodent bites included host density (contribution: 34.7), distance from water channels (3.2), land use/land cover (2.8), and distance from roads (2). Most of the cases occurred within a radius of 0.3 km from roads and 5 km from water channels. Rodent bite incidence is currently at its peak in Peshawar vale. Factors significantly affecting rodents' bite activity and their distribution and dispersal include urbanization, distance from roads, and water channels. Further studies are needed to determine the impact of invasion by brown rat on bite incidence.

Lessons From the First Comprehensive Molecular Characterization of Cell Cycle Control in Rodent Insulinoma Cell Lines

PubMed Central

Cozar-Castellano, Irene; Harb, George; Selk, Karen; Takane, Karen; Vasavada, Rupangi; Sicari, Brian; Law, Brian; Zhang, Pili; Scott, Donald K.; Fiaschi-Taesch, Nathalie; Stewart, Andrew F.

2008-01-01

OBJECTIVE—Rodent insulinoma cell lines may serve as a model for designing continuously replicating human β-cell lines and provide clues as to the central cell cycle regulatory molecules in the β-cell. RESEARCH DESIGN AND METHODS—We performed a comprehensive G1/S proteome analysis on the four most widely studied rodent insulinoma cell lines and defined their flow cytometric profiles and growth characteristics. RESULTS—1) Despite their common T-antigen–derived origins, MIN6 and BTC3 cells display markedly different G1/S expression profiles; 2) despite their common radiation origins, RINm5F and INS1 cells display striking differences in cell cycle protein profiles; 3) phosphorylation of pRb is absent in INS1 and RINm5F cells; 4) cyclin D2 is absent in RINm5F and BTC3 cells and therefore apparently dispensable for their proliferation; 5) every cell cycle inhibitor is upregulated, presumably in a futile attempt to halt proliferation; 6) among the G1/S proteome members, seven are pro-proliferation molecules: cyclin-dependent kinase-1, -2, -4, and -6 and cyclins A, E, and D3; and 7) overexpression of the combination of these seven converts arrested proliferation rates in primary rat β-cells to those in insulinoma cells. Unfortunately, this therapeutic overexpression appears to mildly attenuate β-cell differentiation and function. CONCLUSIONS—These studies underscore the importance of characterizing the cell cycle at the protein level in rodent insulinoma cell lines. They also emphasize the hazards of interpreting data from rodent insulinoma cell lines as modeling normal cell cycle progression. Most importantly, they provide seven candidate targets for inducing proliferation in human β-cells. PMID:18650366

Identifying Rodent Resting-State Brain Networks with Independent Component Analysis

PubMed Central

Bajic, Dusica; Craig, Michael M.; Mongerson, Chandler R. L.; Borsook, David; Becerra, Lino

2017-01-01

Rodent models have opened the door to a better understanding of the neurobiology of brain disorders and increased our ability to evaluate novel treatments. Resting-state functional magnetic resonance imaging (rs-fMRI) allows for in vivo exploration of large-scale brain networks with high spatial resolution. Its application in rodents affords researchers a powerful translational tool to directly assess/explore the effects of various pharmacological, lesion, and/or disease states on known neural circuits within highly controlled settings. Integration of animal and human research at the molecular-, systems-, and behavioral-levels using diverse neuroimaging techniques empowers more robust interrogations of abnormal/ pathological processes, critical for evolving our understanding of neuroscience. We present a comprehensive protocol to evaluate resting-state brain networks using Independent Component Analysis (ICA) in rodent model. Specifically, we begin with a brief review of the physiological basis for rs-fMRI technique and overview of rs-fMRI studies in rodents to date, following which we provide a robust step-by-step approach for rs-fMRI investigation including data collection, computational preprocessing, and brain network analysis. Pipelines are interwoven with underlying theory behind each step and summarized methodological considerations, such as alternative methods available and current consensus in the literature for optimal results. The presented protocol is designed in such a way that investigators without previous knowledge in the field can implement the analysis and obtain viable results that reliably detect significant differences in functional connectivity between experimental groups. Our goal is to empower researchers to implement rs-fMRI in their respective fields by incorporating technical considerations to date into a workable methodological framework. PMID:29311770

A review of the proposed role of neutrophils in rodent amebic liver abscess models

PubMed Central

Campos-Rodríguez, Rafael; Gutiérrez-Meza, Manuel; Jarillo-Luna, Rosa Adriana; Drago-Serrano, María Elisa; Abarca-Rojano, Edgar; Ventura-Juárez, Javier; Cárdenas-Jaramillo, Luz María; Pacheco-Yepez, Judith

2016-01-01

Host invasion by Entamoeba histolytica, the pathogenic agent of amebiasis, can lead to the development of amebic liver abscess (ALA). Due to the difficulty of exploring host and amebic factors involved in the pathogenesis of ALA in humans, most studies have been conducted with animal models (e.g., mice, gerbils, and hamsters). Histopathological findings reveal that the chronic phase of ALA in humans corresponds to lytic or liquefactive necrosis, whereas in rodent models there is granulomatous inflammation. However, the use of animal models has provided important information on molecules and mechanisms of the host/parasite interaction. Hence, the present review discusses the possible role of neutrophils in the effector immune response in ALA in rodents. Properly activated neutrophils are probably successful in eliminating amebas through oxidative and non-oxidative mechanisms, including neutrophil degranulation, the generation of free radicals (O2−, H2O2, HOCl) and peroxynitrite, the activation of NADPH-oxidase and myeloperoxidase (MPO) enzymes, and the formation of neutrophil extracellular traps (NETs). On the other hand, if amebas are not eliminated in the early stages of infection, they trigger a prolonged and exaggerated inflammatory response that apparently causes ALAs. Genetic differences in animals and humans are likely to be key to a successful host immune response. PMID:26880421

Transmission and adaptation of chronic wasting disease to hamsters and transgenic mice: evidence for strains.

PubMed

Raymond, Gregory J; Raymond, Lynne D; Meade-White, Kimberly D; Hughson, Andrew G; Favara, Cynthia; Gardner, Donald; Williams, Elizabeth S; Miller, Michael W; Race, Richard E; Caughey, Byron

2007-04-01

In vitro screening using the cell-free prion protein conversion system indicated that certain rodents may be susceptible to chronic wasting disease (CWD). Therefore, CWD isolates from mule deer, white-tailed deer, and elk were inoculated intracerebrally into various rodent species to assess the rodents' susceptibility and to develop new rodent models of CWD. The species inoculated were Syrian golden, Djungarian, Chinese, Siberian, and Armenian hamsters, transgenic mice expressing the Syrian golden hamster prion protein, and RML Swiss and C57BL10 wild-type mice. The transgenic mice and the Syrian golden, Chinese, Siberian, and Armenian hamsters had limited susceptibility to certain of the CWD inocula, as evidenced by incomplete attack rates and long incubation periods. For serial passages of CWD isolates in Syrian golden hamsters, incubation periods rapidly stabilized, with isolates having either short (85 to 89 days) or long (408 to 544 days) mean incubation periods and distinct neuropathological patterns. In contrast, wild-type mouse strains and Djungarian hamsters were not susceptible to CWD. These results show that CWD can be transmitted and adapted to some species of rodents and suggest that the cervid-derived CWD inocula may have contained or diverged into at least two distinct transmissible spongiform encephalopathy strains.

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

PubMed Central

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

Impact of parity on ewe vaginal mechanical properties relative to the nonhuman primate and rodent.

PubMed

Knight, Katrina M; Moalli, Pamela A; Nolfi, Alexis; Palcsey, Stacy; Barone, William R; Abramowitch, Steven D

2016-08-01

Parity is the leading risk factor for the development of pelvic organ prolapse. To assess the impact of pregnancy and delivery on vaginal tissue, researchers commonly use nonhuman primate (NHP) and rodent models. The purpose of this study was to evaluate the ewe as an alternative model by investigating the impact of parity on the ewe vaginal mechanical properties and collagen structure. Mechanical properties of 15 nulliparous and parous ewe vaginas were determined via uniaxial tensile tests. Collagen content was determined by hydroxyproline assay and collagen fiber thickness was analyzed using picrosirius red staining. Outcome measures were compared using Independent samples t or Mann-Whitney U tests. ANOVA (Gabriel's pairwise post-hoc test) or the Welch Alternative for the F-ratio (Games Howell post-hoc test) was used to compare data with previously published NHP and rodent data. Vaginal tissue from the nulliparous ewe had a higher tangent modulus and tensile strength compared with the parous ewe (p < 0.025). The parous ewe vagina elongated 42 % more than the nulliparous ewe vagina (p = 0.015). No significant differences were observed in collagen structure among ewe vaginas. The tangent modulus of the nulliparous ewe vagina was not different from that of the NHP or rodent (p = 0.290). Additionally, the tangent moduli of the parous ewe and NHP vaginas did not differ (p = 0.773). Parity has a negative impact on the mechanical properties of the ewe vagina, as also observed in the NHP. The ewe may serve as an alternative model for studying parity and ultimately prolapse development.

Comparison between Surrogate Indexes of Insulin Sensitivity/Resistance and Hyperinsulinemic Euglycemic Glucose Clamps in Rhesus Monkeys

PubMed Central

Lee, Ho-Won; Muniyappa, Ranganath; Yan, Xu; Yue, Lilly Q.; Linden, Ellen H.; Chen, Hui; Hansen, Barbara C.

2011-01-01

The euglycemic glucose clamp is the reference method for assessing insulin sensitivity in humans and animals. However, clamps are ill-suited for large studies because of extensive requirements for cost, time, labor, and technical expertise. Simple surrogate indexes of insulin sensitivity/resistance including quantitative insulin-sensitivity check index (QUICKI) and homeostasis model assessment (HOMA) have been developed and validated in humans. However, validation studies of QUICKI and HOMA in both rats and mice suggest that differences in metabolic physiology between rodents and humans limit their value in rodents. Rhesus monkeys are a species more similar to humans than rodents. Therefore, in the present study, we evaluated data from 199 glucose clamp studies obtained from a large cohort of 86 monkeys with a broad range of insulin sensitivity. Data were used to evaluate simple surrogate indexes of insulin sensitivity/resistance (QUICKI, HOMA, Log HOMA, 1/HOMA, and 1/Fasting insulin) with respect to linear regression, predictive accuracy using a calibration model, and diagnostic performance using receiver operating characteristic. Most surrogates had modest linear correlations with SIClamp (r ≈ 0.4–0.64) with comparable correlation coefficients. Predictive accuracy determined by calibration model analysis demonstrated better predictive accuracy of QUICKI than HOMA and Log HOMA. Receiver operating characteristic analysis showed equivalent sensitivity and specificity of most surrogate indexes to detect insulin resistance. Thus, unlike in rodents but similar to humans, surrogate indexes of insulin sensitivity/resistance including QUICKI and log HOMA may be reasonable to use in large studies of rhesus monkeys where it may be impractical to conduct glucose clamp studies. PMID:21209021

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

NASA Astrophysics Data System (ADS)

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.

Spatial memory tasks in rodents: what do they model?

PubMed

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.

Molecular Hydrogen as an Emerging Therapeutic Medical Gas for Neurodegenerative and Other Diseases

PubMed Central

Ohno, Kinji; Ito, Mikako; Ichihara, Masatoshi; Ito, Masafumi

2012-01-01

Effects of molecular hydrogen on various diseases have been documented for 63 disease models and human diseases in the past four and a half years. Most studies have been performed on rodents including two models of Parkinson's disease and three models of Alzheimer's disease. Prominent effects are observed especially in oxidative stress-mediated diseases including neonatal cerebral hypoxia; Parkinson's disease; ischemia/reperfusion of spinal cord, heart, lung, liver, kidney, and intestine; transplantation of lung, heart, kidney, and intestine. Six human diseases have been studied to date: diabetes mellitus type 2, metabolic syndrome, hemodialysis, inflammatory and mitochondrial myopathies, brain stem infarction, and radiation-induced adverse effects. Two enigmas, however, remain to be solved. First, no dose-response effect is observed. Rodents and humans are able to take a small amount of hydrogen by drinking hydrogen-rich water, but marked effects are observed. Second, intestinal bacteria in humans and rodents produce a large amount of hydrogen, but an addition of a small amount of hydrogen exhibits marked effects. Further studies are required to elucidate molecular bases of prominent hydrogen effects and to determine the optimal frequency, amount, and method of hydrogen administration for each human disease. PMID:22720117

Unique inhibitory cascade pattern of molars in canids contributing to their potential to evolutionary plasticity of diet

PubMed Central

Asahara, Masakazu

2013-01-01

Developmental origins that guide the evolution of dental morphology and dental formulae are fundamental subjects in mammalian evolution. In a previous study, a developmental model termed the inhibitory cascade model was established. This model could explain variations in relative molar sizes and loss of the lower third molars, which sometimes reflect diet, in murine rodents and other mammals. Here, I investigated the pattern of relative molar sizes (inhibitory cascade pattern) in canids, a taxon exhibiting a wide range of dietary habits. I found that interspecific variation in canid molars suggests a unique inhibitory cascade pattern that differs from that in murine rodents and other previously reported mammals, and that this variation reflects dietary habits. This unique variability in molars was also observed in individual variation in canid species. According to these observations, canid species have greater variability in the relative sizes of first molars (carnassials), which are functionally important for dietary adaptation in the Carnivora. In conclusion, an inhibitory cascade that differs from that in murine rodents and other mammals may have contributed to diverse dietary patterns and to their parallel evolution in canids. PMID:23467478

Considerations for the Optimization of Induced White Matter Injury Preclinical Models

PubMed Central

Ahmad, Abdullah Shafique; Satriotomo, Irawan; Fazal, Jawad; Nadeau, Stephen E.; Doré, Sylvain

2015-01-01

White matter (WM) injury in relation to acute neurologic conditions, especially stroke, has remained obscure until recently. Current advances in imaging technologies in the field of stroke have confirmed that WM injury plays an important role in the prognosis of stroke and suggest that WM protection is essential for functional recovery and post-stroke rehabilitation. However, due to the lack of a reproducible animal model of WM injury, the pathophysiology and mechanisms of this injury are not well studied. Moreover, producing selective WM injury in animals, especially in rodents, has proven to be challenging. Problems associated with inducing selective WM ischemic injury in the rodent derive from differences in the architecture of the brain, most particularly, the ratio of WM to gray matter in rodents compared to humans, the agents used to induce the injury, and the location of the injury. Aging, gender differences, and comorbidities further add to this complexity. This review provides a brief account of the techniques commonly used to induce general WM injury in animal models (stroke and non-stroke related) and highlights relevance, optimization issues, and translational potentials associated with this particular form of injury. PMID:26322013

The hindlimb unloading rat model: literature overview, technique update and comparison with space flight data

NASA Technical Reports Server (NTRS)

Morey-Holton, Emily; Globus, Ruth K.; Kaplansky, Alexander; Durnova, Galina

2005-01-01

The hindlimb unloading rodent model is used extensively to study the response of many physiological systems to certain aspects of space flight, as well as to disuse and recovery from disuse for Earth benefits. This chapter describes the evolution of hindlimb unloading, and is divided into three sections. The first section examines the characteristics of 1064 articles using or reviewing the hindlimb unloading model, published between 1976 and April 1, 2004. The characteristics include number of publications, journals, countries, major physiological systems, method modifications, species, gender, genetic strains and ages of rodents, experiment duration, and countermeasures. The second section provides a comparison of results between space flown and hindlimb unloading animals from the 14-day Cosmos 2044 mission. The final section describes modifications to hindlimb unloading required by different experimental paradigms and a method to protect the tail harness for long duration studies. Hindlimb unloading in rodents has enabled improved understanding of the responses of the musculoskeletal, cardiovascular, immune, renal, neural, metabolic, and reproductive systems to unloading and/or to reloading on Earth with implications for both long-duration human space flight and disuse on Earth.

Therapeutic targeting of oxygen-sensing prolyl hydroxylases abrogates ATF4-dependent neuronal death and improves outcomes after brain hemorrhage in several rodent models

PubMed Central

Karuppagounder, Saravanan S.; Alim, Ishraq; Khim, Soah J.; Bourassa, Megan W.; Sleiman, Sama F.; John, Roseleen; Thinnes, Cyrille C.; Yeh, Tzu-Lan; Demetriades, Marina; Neitemeier, Sandra; Cruz, Dana; Gazaryan, Irina; Killilea, David W.; Morgenstern, Lewis; Xi, Guohua; Keep, Richard F.; Schallert, Timothy; Tappero, Ryan V.; Zhong, Jian; Cho, Sunghee; Maxfield, Frederick R.; Holman, Theodore R.; Culmsee, Carsten; Fong, Guo-Hua; Su, Yijing; Ming, Guo-li; Song, Hongjun; Cave, John W.; Schofield, Christopher J.; Colbourne, Frederick; Coppola, Giovanni; Ratan, Rajiv R.

2017-01-01

Disability or death due to intracerebral hemorrhage (ICH) is attributed to blood lysis, liberation of iron, and consequent oxidative stress. Iron chelators bind to free iron and prevent neuronal death induced by oxidative stress and disability due to ICH, but the mechanisms for this effect remain unclear. We show that the hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) family of iron-dependent, oxygen-sensing enzymes are effectors of iron chelation. Molecular reduction of the three HIF-PHD enzyme isoforms in the mouse striatum improved functional recovery after ICH. A low-molecular-weight hydroxyquinoline inhibitor of the HIF-PHD enzymes, adaptaquin, reduced neuronal death and behavioral deficits after ICH in several rodent models without affecting total iron or zinc distribution in the brain. Unexpectedly, protection from oxidative death in vitro or from ICH in vivo by adaptaquin was associated with suppression of activity of the prodeath factor ATF4 rather than activation of an HIF-dependent prosurvival pathway. Together, these findings demonstrate that brain-specific inactivation of the HIF-PHD metalloenzymes with the blood-brain barrier-permeable inhibitor adaptaquin can improve functional outcomes after ICH in several rodent models. PMID:26936506

Development of Novel Combinatorial Treatment to Prevent Chemotherapeutic Resistance and Enhance Efficacy of Riluzole in a Rodent Model of SCI

DTIC Science & Technology

2016-10-01

site as well as in the cervical and lumbar cords out to at least 10 months post-injury. While our rodent study was ongoing, a multi-center clinical...lead to a preservation of motor function and an attenuation in long-term pathologies like neuropathic pain in rats following an acute therapeutic...chemotherapeutic resistance, mass spectrometry, riluzole, licofelone, neuropathic pain , locomotor, bioavailability 11 University of Mississippi

Anatomy and histology of the lower urinary tract.

PubMed

Pradidarcheep, Wisuit; Wallner, Christian; Dabhoiwala, Noshir F; Lamers, Wouter H

2011-01-01

The function of the lower urinary tract is basically storage of urine in the bladder and the at-will periodic evacuation of the stored urine. Urinary incontinence is one of the most common lower urinary tract disorders in adults, but especially in the elderly female. The urethra, its sphincters, and the pelvic floor are key structures in the achievement of continence, but their basic anatomy is little known and, to some extent, still incompletely understood. Because questions with respect to continence arise from human morbidity, but are often investigated in rodent animal models, we present findings in human and rodent anatomy and histology. Differences between males and females in the role that the pelvic floor plays in the maintenance of continence are described. Furthermore, we briefly describe the embryologic origin of ureters, bladder, and urethra, because the developmental origin of structures such as the vesicoureteral junction, the bladder trigone, and the penile urethra are often invoked to explain (clinical) observations. As the human pelvic floor has acquired features in evolution that are typical for a species with bipedal movement, we also compare the pelvic floor of humans with that of rodents to better understand the rodent (or any other quadruped, for that matter) as an experimental model species. The general conclusion is that the "Bauplan" is well conserved, even though its common features are sometimes difficult to discern.

Wernicke-Korsakoff Syndrome

MedlinePlus

... Coordinating Committees CounterACT Rigor & Transparency Scientific Resources Animal Models Cell/Tissue/DNA Clinical and Translational Resources Gene ... modulation of certain nerve cells in a rodent model of amnesia produced by by thiamine deficiency. The ...

A Physiologically-based Model for Methylmercury Uptake and Accumulation in Female American Kestrels

EPA Science Inventory

A physiologically-based model was developed to describe the uptake, distribution, and elimination of methylmercury in female American Kestrels (Falco sparverius). The model was adapted from established models for methylmercury in rodents. Features unique to the model include meth...

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

PubMed

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.

Modeling the Disease Course of Zaire ebolavirus Infection in the Outbred Guinea Pig.

PubMed

Cross, Robert W; Fenton, Karla A; Geisbert, Joan B; Mire, Chad E; Geisbert, Thomas W

2015-10-01

Rodent models that accurately reflect human filovirus infection are needed as early screens for medical countermeasures. Prior work in rodents with the Zaire species of Ebola virus (ZEBOV) primarily used inbred mice and guinea pigs to model disease. However, these inbred species do not show some of the important features of primate ZEBOV infection, most notably, coagulation abnormalities. Thirty-six outbred guinea pigs were infected with guinea pig-adapted ZEBOV and examined sequentially over an 8-day period to investigate the pathologic events that lead to death. Features of disease in ZEBOV-infected outbred guinea pigs were largely consistent with disease in humans and nonhuman primates and included early infection of macrophages and dendritiform cells, apoptosis of bystander lymphocytes, and increases in levels of proinflammatory cytokines. Most importantly, dysregulation of circulating levels of fibrinogen, protein C activity, and antifibrinolytic proteins and deposition of fibrin in tissues demonstrated both biochemical and microscopic evidence of disseminated intravascular coagulation. These findings suggest that the outbred guinea pig model recapitulates ZEBOV infection of primates better than inbred rodent models, is useful for dissecting key events in the pathogenesis of ZEBOV, and is useful for evaluating candidate interventions prior to assessment in primates. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

An improved method for the isolation of rat alveolar type II lung cells: Use in the Comet assay to determine DNA damage induced by cigarette smoke.

PubMed

Dalrymple, Annette; Ordoñez, Patricia; Thorne, David; Dillon, Debbie; Meredith, Clive

2015-06-01

Smoking is a cause of serious diseases, including lung cancer, emphysema, chronic bronchitis and heart disease. DNA damage is thought to be one of the mechanisms by which cigarette smoke (CS) initiates disease in the lung. Indeed, CS induced DNA damage can be measured in vitro and in vivo. The potential of the Comet assay to measure DNA damage in isolated rat lung alveolar type II epithelial cells (AEC II) was explored as a means to include a genotoxicity end-point in rodent sub-chronic inhalation studies. In this study, published AEC II isolation methods were improved to yield viable cells suitable for use in the Comet assay. The improved method reduced the level of basal DNA damage and DNA repair in isolated AEC II. CS induced DNA damage could also be quantified in isolated cells following a single or 5 days CS exposure. In conclusion, the Comet assay has the potential to determine CS or other aerosol induced DNA damage in AEC II isolated from rodents used in sub-chronic inhalation studies. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Fabrication of an inexpensive, implantable cooling device for reversible brain deactivation in animals ranging from rodents to primates

PubMed Central

Cooke, Dylan F.; Goldring, Adam B.; Yamayoshi, Itsukyo; Tsourkas, Phillippos; Recanzone, Gregg H.; Tiriac, Alex; Pan, Tingrui; Simon, Scott I.

2012-01-01

We have developed a compact and lightweight microfluidic cooling device to reversibly deactivate one or more areas of the neocortex to examine its functional macrocircuitry as well as behavioral and cortical plasticity. The device, which we term the “cooling chip,” consists of thin silicone tubing (through which chilled ethanol is circulated) embedded in mechanically compliant polydimethylsiloxane (PDMS). PDMS is tailored to compact device dimensions (as small as 21 mm3) that precisely accommodate the geometry of the targeted cortical area. The biocompatible design makes it suitable for both acute preparations and chronic implantation for long-term behavioral studies. The cooling chip accommodates an in-cortex microthermocouple measuring local cortical temperature. A microelectrode may be used to record simultaneous neural responses at the same location. Cortex temperature is controlled by computer regulation of the coolant flow, which can achieve a localized cortical temperature drop from 37 to 20°C in less than 3 min and maintain target temperature to within ±0.3°C indefinitely. Here we describe cooling chip fabrication and performance in mediating cessation of neural signaling in acute preparations of rodents, ferrets, and primates. PMID:22402651

An improved human anxiety process biomarker: characterization of frequency band, personality and pharmacology

PubMed Central

Shadli, S M; Glue, P; McIntosh, J; McNaughton, N

2015-01-01

Anxiety disorders are among the most common mental illness in the western world with a major impact on disability. But their diagnosis has lacked objective biomarkers. We previously demonstrated a human anxiety process biomarker, goal-conflict-specific electroencephalography (EEG) rhythmicity (GCSR) in the stop-signal task (SST). Here we have developed and characterized an improved test appropriate for clinical group testing. We modified the SST to produce balanced numbers of trials in clearly separated stop-signal delay groups. As previously, right frontal (F8) GCSR was extracted as the difference in EEG log Fourier power between matching stop and go trials (that is, stop-signal-specific power) of a quadratic contrast of the three delay values (that is, power when stopping and going are in balanced conflict compared with the average of when stopping or going is greater). Separate experiments assessed drug sensitivity (n=34) and personality relations (n=59). GCSR in this new SST was reduced by three chemically distinct anxiolytic drugs (administered double-blind): buspirone (10 mg), triazolam (0.25 mg) and pregabalin (75 mg); had a frequency range (4–12 Hz) consistent with rodent model data; and positively correlated significantly with neuroticism and nonsignificantly with trait anxiety scores. GCSR, measured in our new form of the SST, should be suitable as a biomarker for one specific anxiety process in the testing of clinical groups and novel drugs and in the development of measures suitable for individual diagnosis. PMID:26670284

Scaling law in free walking of mice in circular open fields of various diameters.

PubMed

Shoji, Hiroto

2016-03-01

Open-field tests are routinely used to study locomotor activity in rodents. I studied the effects of apparatus size on rodent locomotor activity, specifically with respect to how resting and walking periods are interwoven. I explored the open-field behavior of mice utilizing circular open fields of various diameters. When the diameter of the test apparatus was greater than 75 cm, the durations of the resting and moving periods of free walking behavior obeyed bounded power-law distribution functions. I found that the properties of the scaling exponents and model selection became similar for test apparatus diameters greater than 75 cm. These results can provide a guide for the selection of the size of the test apparatus for use in the study of the open-field behavior of rodents.

Effects of sex and locality on the abundance of lice on the wild rodent Oligoryzomys nigripes.

PubMed

Fernandes, Fernanda Rodrigues; Cruz, Leonardo Dominici; Linhares, Arício Xavier

2012-10-01

Various factors can affect the parasite distribution on a host. In this study, the influence of sex, body size, and locality of a rodent host, Oligoryzomys nigripes, on lice abundance was investigated. A generalized linear model indicated that the sex and locality of O. nigripes significantly contributed to the variation in lice abundance on the host. The male bias of lice parasitizing the rodent host O. nigripes may be associated with intersexual differences in physiology and behavior, while locality differences in lice abundance may be associated with differences in host density and diversity between the two localities sampled. Studies of host-parasite associations improve the understanding of the ecology of infectious diseases, as well as the evolution of these host-parasite interactions.

ANIMAL MODELS OF COGNITIVE DEVELOPMENT IN NEUROTOXICITY

EPA Science Inventory

The thesis of this chapter has been that spatial delayed alternation versus position discrimination learning can serve as a valuable rodent model of cognitive development in neurotoxicology. his model captures dual process conceptualizations of memory in human neuropsychology and...

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

PubMed

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 the FLC population, there is consensus about the essential role of gonadotrophins in testosterone production. Like the FLC population, adult Leydig cells (ALC) in rodents arise from stem cells, which have their origin in the fetal testis. In contrast, in primates the ALC population is thought to originate from FLC, which undergo several cycles of regression and redifferentiation before giving rise to the mature ALC population, as well as from differentiation of stem cells/precursor cells. Despite this difference in origin, both in primates and rodents the formation of the mature and functionally active ALC population is critically dependent on the pituitary gonadotrophin, LH. From studies on rodents considerable knowledge has emerged on factors that are involved besides LH in the regulation of this developmental process. Whether the same factors also play a role in the development of the mature primate LC population awaits further investigation. Distinct populations of LC develop along the life span of males, including fetal, neonatal (primates) and ALC. Despite differences in the LC lineages of rodents and primates, the end product is a mature population of LC with the main function to provide androgens necessary for the maintenance of spermatogenesis and extra-gonadal androgen actions. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Computer simulation analysis of normal and abnormal development of the mammalian diaphragm

PubMed Central

Fisher, Jason C; Bodenstein, Lawrence

2006-01-01

Background Congenital diaphragmatic hernia (CDH) is a birth defect with significant morbidity and mortality. Knowledge of diaphragm morphogenesis and the aberrations leading to CDH is limited. Although classical embryologists described the diaphragm as arising from the septum transversum, pleuroperitoneal folds (PPF), esophageal mesentery and body wall, animal studies suggest that the PPF is the major, if not sole, contributor to the muscular diaphragm. Recently, a posterior defect in the PPF has been identified when the teratogen nitrofen is used to induce CDH in fetal rodents. We describe use of a cell-based computer modeling system (Nudge++™) to study diaphragm morphogenesis. Methods and results Key diaphragmatic structures were digitized from transverse serial sections of paraffin-embedded mouse embryos at embryonic days 11.5 and 13. Structure boundaries and simulated cells were combined in the Nudge++™ software. Model cells were assigned putative behavioral programs, and these programs were progressively modified to produce a diaphragm consistent with the observed anatomy in rodents. Homology between our model and recent anatomical observations occurred under the following simulation conditions: (1) cell mitoses are restricted to the edge of growing tissue; (2) cells near the chest wall remain mitotically active; (3) mitotically active non-edge cells migrate toward the chest wall; and (4) movement direction depends on clonal differentiation between anterior and posterior PPF cells. Conclusion With the PPF as the sole source of mitotic cells, an early defect in the PPF evolves into a posteromedial diaphragm defect, similar to that of the rodent nitrofen CDH model. A posterolateral defect, as occurs in human CDH, would be more readily recreated by invoking other cellular contributions. Our results suggest that recent reports of PPF-dominated diaphragm morphogenesis in the rodent may not be strictly applicable to man. The ability to recreate a CDH defect using a combination of experimental data and testable hypotheses gives impetus to simulation modeling as an adjunct to experimental analysis of diaphragm morphogenesis. PMID:16483386

Computer simulation analysis of normal and abnormal development of the mammalian diaphragm.

PubMed

Fisher, Jason C; Bodenstein, Lawrence

2006-02-17

Congenital diaphragmatic hernia (CDH) is a birth defect with significant morbidity and mortality. Knowledge of diaphragm morphogenesis and the aberrations leading to CDH is limited. Although classical embryologists described the diaphragm as arising from the septum transversum, pleuroperitoneal folds (PPF), esophageal mesentery and body wall, animal studies suggest that the PPF is the major, if not sole, contributor to the muscular diaphragm. Recently, a posterior defect in the PPF has been identified when the teratogen nitrofen is used to induce CDH in fetal rodents. We describe use of a cell-based computer modeling system (Nudge++) to study diaphragm morphogenesis. Key diaphragmatic structures were digitized from transverse serial sections of paraffin-embedded mouse embryos at embryonic days 11.5 and 13. Structure boundaries and simulated cells were combined in the Nudge++ software. Model cells were assigned putative behavioral programs, and these programs were progressively modified to produce a diaphragm consistent with the observed anatomy in rodents. Homology between our model and recent anatomical observations occurred under the following simulation conditions: (1) cell mitoses are restricted to the edge of growing tissue; (2) cells near the chest wall remain mitotically active; (3) mitotically active non-edge cells migrate toward the chest wall; and (4) movement direction depends on clonal differentiation between anterior and posterior PPF cells. With the PPF as the sole source of mitotic cells, an early defect in the PPF evolves into a posteromedial diaphragm defect, similar to that of the rodent nitrofen CDH model. A posterolateral defect, as occurs in human CDH, would be more readily recreated by invoking other cellular contributions. Our results suggest that recent reports of PPF-dominated diaphragm morphogenesis in the rodent may not be strictly applicable to man. The ability to recreate a CDH defect using a combination of experimental data and testable hypotheses gives impetus to simulation modeling as an adjunct to experimental analysis of diaphragm morphogenesis.

Exercise offers anxiolytic potential: A role for stress and brain noradrenergic-galaninergic mechanisms

PubMed Central

Sciolino, Natale R.; Holmes, Philip V.

2016-01-01

Although physical activity reduces anxiety in humans, the neural basis for this response is unclear. Rodent models are essential to understand the mechanisms that underlie the benefits of exercise. However, it is controversial whether exercise exerts anxiolytic-like potential in rodents. Evidence is reviewed to evaluate the effects of wheel running, an experimental mode of exercise in rodents, on behavior in tests of anxiety and on norepinephrine and galanin systems in neural circuits that regulate stress. Stress is proposed to account for mixed behavioral findings in this literature. Indeed, running promotes an adaptive response to stress and alters anxiety-like behaviors in a manner dependent on stress. Running amplifies galanin expression in noradrenergic locus coeruleus (LC) and suppresses stress-induced activity of the LC and norepinephrine output in LC-target regions. Thus, enhanced galanin-mediated suppression of brain norepinephrine in runners is supported by current literature as a mechanism that may contribute to the stress-protective effects of exercise. These data support the use of rodents to study the emotional and neurobiological consequences of exercise. PMID:22771334

Efficacy of Selective PDE4D Negative Allosteric Modulators in the Object Retrieval Task in Female Cynomolgus Monkeys (Macaca fascicularis)

PubMed Central

Sutcliffe, Jane S.; Beaumont, Vahri; Watson, James M.; Chew, Chang Sing; Beconi, Maria; Hutcheson, Daniel M.; Dominguez, Celia; Munoz-Sanjuan, Ignacio

2014-01-01

Cyclic adenosine monophosphate (cAMP) signalling plays an important role in synaptic plasticity and information processing in the hippocampal and basal ganglia systems. The augmentation of cAMP signalling through the selective inhibition of phosphodiesterases represents a viable strategy to treat disorders associated with dysfunction of these circuits. The phosphodiesterase (PDE) type 4 inhibitor rolipram has shown significant pro-cognitive effects in neurological disease models, both in rodents and primates. However, competitive non-isoform selective PDE4 inhibitors have a low therapeutic index which has stalled their clinical development. Here, we demonstrate the pro-cognitive effects of selective negative allosteric modulators (NAMs) of PDE4D, D159687 and D159797 in female Cynomolgous macaques, in the object retrieval detour task. The efficacy displayed by these NAMs in a primate cognitive task which engages the corticostriatal circuitry, together with their suitable pharmacokinetic properties and safety profiles, suggests that clinical development of these allosteric modulators should be considered for the treatment of a variety of brain disorders associated with cognitive decline. PMID:25050979

Developmental origins of cardiovascular disease: Impact of early life stress in humans and rodents.

PubMed

Murphy, M O; Cohn, D M; Loria, A S

2017-03-01

The Developmental Origins of Health and Disease (DOHaD) hypothesizes that environmental insults during childhood programs the individual to develop chronic disease in adulthood. Emerging epidemiological data strongly supports that early life stress (ELS) given by the exposure to adverse childhood experiences is regarded as an independent risk factor capable of predicting future risk of cardiovascular disease. Experimental animal models utilizing chronic behavioral stress during postnatal life, specifically maternal separation (MatSep) provides a suitable tool to elucidate molecular mechanisms by which ELS increases the risk to develop cardiovascular disease, including hypertension. The purpose of this review is to highlight current epidemiological studies linking ELS to the development of cardiovascular disease and to discuss the potential molecular mechanisms identified from animal studies. Overall, this review reveals the need for future investigations to further clarify the molecular mechanisms of ELS in order to develop more personalized therapeutics to mitigate the long-term consequences of chronic behavioral stress including cardiovascular and heart disease in adulthood. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mass spectrometric analysis of sulfur mustard-induced biomolecular adducts: Are DNA adducts suitable biomarkers of exposure?

PubMed

Zubel, Tabea; Bürkle, Alexander; Mangerich, Aswin

2018-09-01

The bi-functional chemical warfare agent sulfur mustard (SM), whose release in asymmetric conflicts or terrorist attacks represents a realistic threat, induces several kinds of biomolecular adducts, including highly toxic DNA adducts. Isotope dilution liquid chromatographic tandem mass spectrometry (ID-LC-MS/MS) is considered the gold standard for highly accurate, precise, specific and sensitive quantification of DNA adducts in general. Recently, a number of LC-MS/MS approaches have been established to analyze SM-induced protein and DNA adducts in cell culture and rodent animal models. As DNA adducts are mechanism-based biomarkers for SM exposure, results from such studies provide a deeper understanding of the etiology of SM-induced pathologies, especially of long-term effects such as cancer formation. As a result, medical treatment of SM-exposed individuals might be improved. Yet, despite the progress that has been made during the last years, there is still a need for advanced methods of ID-LC-MS/MS for the detection and quantitation of SM adducts. Copyright © 2017 Elsevier B.V. All rights reserved.

Prediction of thyroid C-cell carcinogenicity after chronic administration of GLP1-R agonists in rodents

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

Brink, Willem van den; Emerenciana, Annette

Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinearmore » mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2 years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes. - Highlights: • An integrative PKPD model is applied to study GLP-1r agonist carcinogenicity. • C-cell carcinogenicity is impacted by both pharmacokinetics and pharmacodynamics. • The relation of GLP-1r stimulation and C-cell hyperplasia appears drug-independent. • Understanding carcinogenic risk needs a pharmacological basis.« less

New Development in NASA's Rodent Research Hardware for Conducting Long Duration Biomedical and Basic Research in Space

NASA Technical Reports Server (NTRS)

Shirazi-Fard, Y.; Choi, S.; Harris, C.; Gong, C.; Beegle, J. E.; Stube, K. C.; Martin, K. J.; Nevitt, R. G.; Globus, R. G.

2017-01-01

Animal models, particularly rodents, are the foundation of pre-clinical research to understand human diseases and evaluate new therapeutics, and play a key role in advancing biomedical discoveries both on Earth and in space. The National Research Councils Decadal survey emphasized the importance of expanding NASAs life sciences research to perform long duration, rodent experiments on the International Space Station (ISS). To accomplish this objective, flight hardware, operations, and science capabilities were developed at NASA Ames Research Center (ARC) to enhance science return for both commercial (CASIS) and government-sponsored rodent research. The Rodent Research program at NASA ARC has pioneered a new research capability on the International Space Station and has progressed toward translating research to the ISS utilizing commercial rockets, collaborating with academia and science industry, while training crewmembers to assist in performing research on orbit. Throughout phases of these missions, our practices, hardware and operations have evolved from tested to developed standards, and we are able to modify and customize our procedure and operations for mission specific requirements. The Rodent Research Habitat is capable of providing a living environment for animals on ISS according to standard animal welfare requirements. Using the cameras in the Habitat, the Rodent Research team has the ability to perform daily health checks on animals, and further analyze the collected videos for behavioral studies. A recent development of the Rodent Research hardware is inclusion of enrichment, to provide the animals the ability to rest and huddle. The Enrichment Hut is designed carefully for adult mice (up to 35 week old) within animal welfare, engineering, and operations constraints. The Hut is made out of the same stainless steel mesh as the cage interior, it has an ingress and an egress to allow animals move freely, and a hinge door to allow crewmembers remove the animals easily. The Rodent Research team has also developed Live Animal Return (LAR) capability, which will be implemented during Rodent Research-5 mission for the first time. The animals will be transported from the Habitat to a Transporter, which will return on the Dragon capsule and splashes down in the Pacific Ocean. Once SpaceX retrieves the Dragon, all powered payloads will be transferred to a SeaVan and transferred to the Long Beach pier. The NASA team then receives the transporter and delivers to a PI-designated laboratory within 120 mile radius of Long Beach. This is a significant improvement allowing researchers to examine animals within 72 hrs. of reentry or to conduct recovery experiments. Together, the hardware improvements and experience that the Rodent Research team has gained working with principal investigators and ISS crew to conduct complex experiments on orbit are expanding capabilities for long duration rodent research on the ISS to achieve both basic science and biomedical objectives.

Estimating sources of Valley Fever pathogen propagation in southern Arizona: A remote sensing approach

NASA Astrophysics Data System (ADS)

Pianalto, Frederick S.

Coccidioidomycosis (Valley Fever) is an environmentally-mediated respiratory disease caused by the inhalation of airborne spores from the fungi Coccidioides spp. The fungi reside in arid and semi-arid soils of the Americas. The disease has increased epidemically in Arizona and other areas within the last two decades. Despite this increase, the ecology of the fungi remains obscure, and environmental antecedents of the disease are largely unstudied. Two sources of soil disturbance, hypothesized to affect soil ecology and initiate spore dissemination, are investigated. Nocturnal desert rodents interact substantially with the soil substrate. Rodents are hypothesized to act as a reservoir of coccidioidomycosis, a mediator of soil properties, and a disseminator of fungal spores. Rodent distributions are poorly mapped for the study area. We build automated multi-linear regression models and decision tree models for ten rodent species using rodent trapping data from the Organ Pipe Cactus National Monument (ORPI) in southwest Arizona with a combination of surface temperature, a vegetation index and its texture, and a suite of topographic rasters. Surface temperature, derived from Landsat TM thermal images, is the most widely selected predictive variable in both automated methods. Construction-related soil disturbance (e.g. road construction, trenching, land stripping, and earthmoving) is a significant source of fugitive dust, which decreases air quality and may carry soil pathogens. Annual differencing of Landsat Thematic Mapper (TM) mid-infrared images is used to create change images, and thresholded change areas are associated with coordinates of local dust inspections. The output metric identifies source areas of soil disturbance, and it estimates the annual amount of dust-producing surface area for eastern Pima County spanning 1994 through 2009. Spatially explicit construction-related soil disturbance and rodent abundance data are compared with coccidioidomycosis incidence data using rank order correlation and regression methods. Construction-related soil disturbance correlates strongly with annual county-wide incidence. It also correlates with Tucson periphery incidence aggregated to zip codes. Abundance values for the desert pocket mouse (Chaetodipus penicillatus), derived from a soil-adjusted vegetation index, aspect (northing) and thermal radiance, correlate with total study period incidence aggregated to zip code.

Control of Domestic Rats & Mice, Training Guide--Rodent Control Series.

ERIC Educational Resources Information Center

Bjornson, Bayard F.; And Others

As one booklet in a series on rodent control, this training guide has been developed to assist administrators, rodent-control operators, and others responsible for rodent-control operations in the training of employees in this field. Topics covered include rodents and human welfare, description and habits of domestic rats and mice, rodent-borne…

Optimal decision-making in mammals: insights from a robot study of rodent texture discrimination

PubMed Central

Lepora, Nathan F.; Fox, Charles W.; Evans, Mathew H.; Diamond, Mathew E.; Gurney, Kevin; Prescott, Tony J.

2012-01-01

Texture perception is studied here in a physical model of the rat whisker system consisting of a robot equipped with a biomimetic vibrissal sensor. Investigations of whisker motion in rodents have led to several explanations for texture discrimination, such as resonance or stick-slips. Meanwhile, electrophysiological studies of decision-making in monkeys have suggested a neural mechanism of evidence accumulation to threshold for competing percepts, described by a probabilistic model of Bayesian sequential analysis. For our robot whisker data, we find that variable reaction-time decision-making with sequential analysis performs better than the fixed response-time maximum-likelihood estimation. These probabilistic classifiers also use whatever available features of the whisker signals aid the discrimination, giving improved performance over a single-feature strategy, such as matching the peak power spectra of whisker vibrations. These results cast new light on how the various proposals for texture discrimination in rodents depend on the whisker contact mechanics and suggest the possibility of a common account of decision-making across mammalian species. PMID:22279155

Rodents and climate: A new model for estimating past temperatures [rapid communication

NASA Astrophysics Data System (ADS)

Legendre, Serge; Montuire, Sophie; Maridet, Olivier; Escarguel, Gilles

2005-06-01

Based on the high correlation between species richness in sigmodontine rodents and temperatures, we propose a new model in order to quantify past climates. Because of the close phylogenetic relationship and the tooth morphological similarity between extant New World cricetids (Sigmodontinae) and fossil European cricetids (Cricetinae s.l.), extant New World sigmodontines are taken as analogues for Old World fossil cricetines. Sigmodontine species richness has been compiled for 282 extant local faunas from North, Central and South America, with corresponding climatic data (temperatures and precipitations). There is almost no correlation between areas covered by local faunas (ranging from 1 km 2 up to 46,000 km 2) and numbers of sigmodontine species in localities ( R2 = 0.027). Number of sigmodontine species in local faunas and mean annual daily temperatures are highly correlated ( R2 = 0.88). The relationships of species richness and precipitation is low ( R2 = 0.19 for mean annual precipitation). The method is exemplified for Old World cricetines using well documented Miocene rodent faunas located in the Lyon area (France MN4-5 to MN10).

Brain Stimulation Reward Supports More Consistent and Accurate Rodent Decision-Making than Food Reward.

PubMed

McMurray, Matthew S; Conway, Sineadh M; Roitman, Jamie D

2017-01-01

Animal models of decision-making rely on an animal's motivation to decide and its ability to detect differences among various alternatives. Food reinforcement, although commonly used, is associated with problematic confounds, especially satiety. Here, we examined the use of brain stimulation reward (BSR) as an alternative reinforcer in rodent models of decision-making and compared it with the effectiveness of sugar pellets. The discriminability of various BSR frequencies was compared to differing numbers of sugar pellets in separate free-choice tasks. We found that BSR was more discriminable and motivated greater task engagement and more consistent preference for the larger reward. We then investigated whether rats prefer BSR of varying frequencies over sugar pellets. We found that animals showed either a clear preference for sugar reward or no preference between reward modalities, depending on the frequency of the BSR alternative and the size of the sugar reward. Overall, these results suggest that BSR is an effective reinforcer in rodent decision-making tasks, removing food-related confounds and resulting in more accurate, consistent, and reliable metrics of choice.

Prevention of chemotherapy-induced alopecia in rodent models

PubMed Central

Jimenez, Joaquin J.; Roberts, Stephen M.; Mejia, Jessica; Mauro, Lucia M.; Munson, John W.; Elgart, George W.; Connelly, Elizabeth Alvarez; Chen, Qingbin; Zou, Jiangying; Goldenberg, Carlos

2008-01-01

Alopecia (hair loss) is experienced by thousands of cancer patients every year. Substantial-to-severe alopecia is induced by anthracyclines (e.g., adriamycin), taxanes (e.g., taxol), alkylating compounds (e.g., cyclophosphamide), and the topisomerase inhibitor etoposide, agents that are widely used in the treatment of leukemias and breast, lung, ovarian, and bladder cancers. Currently, no treatment appears to be generally effective in reliably preventing this secondary effect of chemotherapy. We observed in experiments using different rodent models that localized administration of heat or subcutaneous/intradermal injection of geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin induced a stress protein response in hair follicles and effectively prevented alopecia from adriamycin, cyclophosphamide, taxol, and etoposide. Model tumor therapy experiments support the presumption that such localized hair-saving treatment does not negatively affect chemotherapy efficacy. PMID:18347939

A comparison of the biological properties of small molecular weight agonists and antagonists of CD200:CD200R interactions.

PubMed

Gorczynski, Reg; Boudakov, Ivo; Khatri, Ismat

2008-11-01

Our laboratory and others have documented in some detail the immunological consequences which follow from interaction of the ubiquitously expressed molecule CD200 with its receptor(s) CD200R (expressed predominantly on cells of myeloid and lymphoid origin). In particular, there is evidence that these interactions lead to immunosuppressive signals which modulate graft rejection responses; decrease the manifestations of arthritis in rodent models; diminish mast cell mediator release in models of allergic disease; and favour the growth of tumors in both mice and humans. The development of small molecular weight agonists (and/or antagonists) of these interactions would thus likely have significant clinical importance. The data reported herein characterizes several such molecules in a number of rodent models.

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

PubMed

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.

Borrelia afzelii ospC genotype diversity in Ixodes ricinus questing ticks and ticks from rodents in two Lyme borreliosis endemic areas: contribution of co-feeding ticks.

PubMed

Pérez, David; Kneubühler, Yvan; Rais, Olivier; Jouda, Fatima; Gern, Lise

2011-09-01

In Europe, the Lyme borreliosis (LB) agents like Borrelia burgdorferi sensu stricto (ss), B. afzelii, and B. garinii are maintained in nature by enzoonotic transmission cycles between vertebrate hosts and Ixodes ricinus ticks. The outer surface protein C is a highly antigenic protein expressed by spirochaetes during transmission from ticks to mammals as well as during dissemination in the vertebrate hosts. Previous studies based on analysis of ospC gene sequences have led to the classification of ospC genotypes into ospC groups. The aim of this study was to analyse and compare ospC group distribution among isolates of the rodent-associated genospecies, B. afzelii, at 3 levels (questing ticks, ticks feeding on rodents, and xenodiagnostic ticks). Isolates were obtained during a study carried out in 2 LB endemic areas located on the Swiss Plateau [Portes-Rouges (PR) and Staatswald (SW)], where rodents were differently infested by co-feeding ticks (Pérez et al., unpublished data). Overall, we identified 10 different ospC groups with different distributions among isolates from questing ticks, ticks that detached from rodents, and xenodiagnostic ticks at the 2 sites. We observed a higher ospC diversity among isolates from ticks that fed on rodents at SW, and mixed infections with 2 ospC groups were also more frequent among isolates from ticks that fed on rodents at SW (n=18) than at PR (n=1). At both sites, B. afzelii isolates obtained from larvae that were feeding on the rodents simultaneously with nymphs displayed a higher diversity of ospC groups (mean number of ospC groups: 2.25 for PR and 1.75 for SW) than isolates from larvae feeding without nymphs (mean number of ospC groups: 1.17 for PR and 1 for SW). We suggest that co-feeding transmission of Borrelia, previously described in laboratory models, contributes in nature in promoting and maintaining ospC diversity within local tick populations. Copyright © 2011 Elsevier GmbH. All rights reserved.

Modeling zoonotic cutaneous leishmaniasis incidence in central Tunisia from 2009-2015: Forecasting models using climate variables as predictors

PubMed Central

Bellali, Hedia; Ben-Alaya, Nissaf; Saez, Marc; Malouche, Dhafer; Chahed, Mohamed Kouni

2017-01-01

Transmission of zoonotic cutaneous leishmaniasis (ZCL) depends on the presence, density and distribution of Leishmania major rodent reservoir and the development of these rodents is known to have a significant dependence on environmental and climate factors. ZCL in Tunisia is one of the most common forms of leishmaniasis. The aim of this paper was to build a regression model of ZCL cases to identify the relationship between ZCL occurrence and possible risk factors, and to develop a predicting model for ZCL's control and prevention purposes. Monthly reported ZCL cases, environmental and bioclimatic data were collected over 6 years (2009–2015). Three rural areas in the governorate of Sidi Bouzid were selected as the study area. Cross-correlation analysis was used to identify the relevant lagged effects of possible risk factors, associated with ZCL cases. Non-parametric modeling techniques known as generalized additive model (GAM) and generalized additive mixed models (GAMM) were applied in this work. These techniques have the ability to approximate the relationship between the predictors (inputs) and the response variable (output), and express the relationship mathematically. The goodness-of-fit of the constructed model was determined by Generalized cross-validation (GCV) score and residual test. There were a total of 1019 notified ZCL cases from July 2009 to June 2015. The results showed seasonal distribution of reported ZCL cases from August to January. The model highlighted that rodent density, average temperature, cumulative rainfall and average relative humidity, with different time lags, all play role in sustaining and increasing the ZCL incidence. The GAMM model could be applied to predict the occurrence of ZCL in central Tunisia and could help for the establishment of an early warning system to control and prevent ZCL in central Tunisia. PMID:28841642

Modeling zoonotic cutaneous leishmaniasis incidence in central Tunisia from 2009-2015: Forecasting models using climate variables as predictors.

PubMed

Talmoudi, Khouloud; Bellali, Hedia; Ben-Alaya, Nissaf; Saez, Marc; Malouche, Dhafer; Chahed, Mohamed Kouni

2017-08-01

Transmission of zoonotic cutaneous leishmaniasis (ZCL) depends on the presence, density and distribution of Leishmania major rodent reservoir and the development of these rodents is known to have a significant dependence on environmental and climate factors. ZCL in Tunisia is one of the most common forms of leishmaniasis. The aim of this paper was to build a regression model of ZCL cases to identify the relationship between ZCL occurrence and possible risk factors, and to develop a predicting model for ZCL's control and prevention purposes. Monthly reported ZCL cases, environmental and bioclimatic data were collected over 6 years (2009-2015). Three rural areas in the governorate of Sidi Bouzid were selected as the study area. Cross-correlation analysis was used to identify the relevant lagged effects of possible risk factors, associated with ZCL cases. Non-parametric modeling techniques known as generalized additive model (GAM) and generalized additive mixed models (GAMM) were applied in this work. These techniques have the ability to approximate the relationship between the predictors (inputs) and the response variable (output), and express the relationship mathematically. The goodness-of-fit of the constructed model was determined by Generalized cross-validation (GCV) score and residual test. There were a total of 1019 notified ZCL cases from July 2009 to June 2015. The results showed seasonal distribution of reported ZCL cases from August to January. The model highlighted that rodent density, average temperature, cumulative rainfall and average relative humidity, with different time lags, all play role in sustaining and increasing the ZCL incidence. The GAMM model could be applied to predict the occurrence of ZCL in central Tunisia and could help for the establishment of an early warning system to control and prevent ZCL in central Tunisia.

Rodent consumption in Khon Kaen Province, Thailand.

PubMed

Suwannarong, Kanokwan; Chapman, Robert S

2014-09-01

Rodents are important reservoirs of rodent-borne infections worldwide, including Southeast Asia and Northeast Thailand (Isaan), where rodent consumption may be a source of rodent-borne diseases. The behavior of consuming rodents is related to a population's traditions, knowledge, cultural, and household contexts, among other factors. This cross-sectional survey was conducted in Khon Kaen Province, Thailand during November-December 2011. It aimed to elicit information about rodent consumption among residents of this province, and to identify factors associated with rodent consumption there. Multiple logistic regression analysis indicated that male gender, large family size, and use of rainwater as the main source of drinking water were positively associated with reported rodent consumption in this province, while having proper knowledge/attitudes towards animal-borne disease was negatively associated. These results provide evidence-base information for further studies, such as participatory ac- tion research, to further explore how people interact with rodents in different contexts. Further research is also needed to characterize risk of zoonotic diseases in relation to rodent consumption.

Approximate analytical modeling of leptospirosis infection

NASA Astrophysics Data System (ADS)

Ismail, Nur Atikah; Azmi, Amirah; Yusof, Fauzi Mohamed; Ismail, Ahmad Izani

2017-11-01

Leptospirosis is an infectious disease carried by rodents which can cause death in humans. The disease spreads directly through contact with feces, urine or through bites of infected rodents and indirectly via water contaminated with urine and droppings from them. Significant increase in the number of leptospirosis cases in Malaysia caused by the recent severe floods were recorded during heavy rainfall season. Therefore, to understand the dynamics of leptospirosis infection, a mathematical model based on fractional differential equations have been developed and analyzed. In this paper an approximate analytical method, the multi-step Laplace Adomian decomposition method, has been used to conduct numerical simulations so as to gain insight on the spread of leptospirosis infection.

Traffic-related air pollution and brain development.

PubMed

Woodward, Nicholas; Finch, Caleb E; Morgan, Todd E

Automotive traffic-related air pollution (TRP) imposes an increasing health burden with global urbanization. Gestational and early child exposure to urban TRP is associated with higher risk of autism spectrum disorders and schizophrenia, as well as low birth weight. While cardio-respiratory effects from exposure are well documented, cognitive effects are only recently becoming widely recognized. This review discusses effects of TRP on brain and cognition in human and animal studies. The mechanisms underlying these epidemiological associations are studied with rodent models of pre- and neonatal exposure to TRP, which show persisting inflammatory changes and altered adult behaviors and cognition. Some behavioral and inflammatory changes show male bias. Rodent models may identify dietary and other interventions for neuroprotection to TRP.

Rodent Auditory Perception: Critical Band Limitations and Plasticity

PubMed Central

King, Julia; Insanally, Michele; Jin, Menghan; Martins, Ana Raquel O.; D'amour, James A.; Froemke, Robert C.

2015-01-01

What do animals hear? While it remains challenging to adequately assess sensory perception in animal models, it is important to determine perceptual abilities in model systems to understand how physiological processes and plasticity relate to perception, learning, and cognition. Here we discuss hearing in rodents, reviewing previous and recent behavioral experiments querying acoustic perception in rats and mice, and examining the relation between behavioral data and electrophysiological recordings from the central auditory system. We focus on measurements of critical bands, which are psychoacoustic phenomena that seem to have a neural basis in the functional organization of the cochlea and the inferior colliculus. We then discuss how behavioral training, brain stimulation, and neuropathology impact auditory processing and perception. PMID:25827498

The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis.

PubMed

Williamson, James D; Sadofsky, Laura R; Hart, Simon P

2015-03-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. In this review, we compare the pathogenesis and histological features of human IPF and bleomycin-induced pulmonary fibrosis (BPF) induced in rodents by intratracheal delivery. We discuss the current understanding of IPF and BPF disease development, from the contribution of alveolar epithelial cells and inflammation to the role of fibroblasts and cytokines, and draw conclusions about what we have learned from the intratracheal bleomycin model of lung fibrosis.

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

PubMed

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.

Screening of nanoparticulate delivery systems for the photodetection of cancer in a simple and cost-effective model.

PubMed

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.

Rodent model choice has major impact on variability of standard preclinical readouts associated with diabetes and obesity research

PubMed Central

Jensen, Victoria S; Porsgaard, Trine; Lykkesfeldt, Jens; Hvid, Henning

2016-01-01

Laboratory rodents are available as either genetically defined inbred strains or genetically undefined outbred stocks. As outbred rodents are generally thought to display a higher level of phenotypic variation compared to inbred strains, it has been argued that experimental studies should preferentially be performed by using inbred rodents. However, very few studies with adequate sample sizes have in fact compared phenotypic variation between inbred strains and outbred stocks of rodents and moreover, these studies have not reached consistent conclusions. The aim of the present study was to compare the phenotypic variation in commonly used experimental readouts within obesity and diabetes research, for four of the most frequently used mouse strains: inbred C57BL/6 and BALB/c and outbred NMRI and CD-1 mice. The variation for all readouts was examined by calculating the coefficient of variation (CV), i.e., the relative variation, including a 95% confidence interval for the CV. We observed that for the majority of the selected readouts, inbred and outbred mice showed comparable phenotypic variation. The observed variation appeared highly influenced by strain choice and type of readout, which suggests that these collectively would serve as more predictive of the phenotypic variation than the more general classification of mice as inbred or outbred based on genetic heterogeneity. PMID:27648148

Impact of parity on ewe vaginal mechanical properties relative to the nonhuman primate and rodent

PubMed Central

Knight, Katrina M.; Moalli, Pamela A.; Nolfi, Alexis; Palcsey, Stacy; Barone, William R.

2016-01-01

Introduction and hypothesis Parity is the leading risk factor for the development of pelvic organ prolapse. To assess the impact of pregnancy and delivery on vaginal tissue, researchers commonly use nonhuman primate (NHP) and rodent models. The purpose of this study was to evaluate the ewe as an alternative model by investigating the impact of parity on the ewe vaginal mechanical properties and collagen structure. Methods Mechanical properties of 15 nulliparous and parous ewe vaginas were determined via uniaxial tensile tests. Collagen content was determined by hydroxyproline assay and collagen fiber thickness was analyzed using picrosirius red staining. Outcome measures were compared using Independent samples t or Mann–Whitney U tests. ANOVA (Gabriel’s pairwise post-hoc test) or the Welch Alternative for the F-ratio (Games Howell post-hoc test) was used to compare data with previously published NHP and rodent data. Results Vaginal tissue from the nulliparous ewe had a higher tangent modulus and tensile strength compared with the parous ewe (p < 0.025). The parous ewe vagina elongated 42 % more than the nulliparous ewe vagina (p = 0.015). No significant differences were observed in collagen structure among ewe vaginas. The tangent modulus of the nulliparous ewe vagina was not different from that of the NHP or rodent (p = 0.290). Additionally, the tangent moduli of the parous ewe and NHP vaginas did not differ (p = 0.773). Conclusions Parity has a negative impact on the mechanical properties of the ewe vagina, as also observed in the NHP. The ewe may serve as an alternative model for studying parity and ultimately prolapse development. PMID:26872644

Testing episodic memory in animals: a new approach.

PubMed

Griffiths, D P; Clayton, N S

2001-08-01

Episodic memory involves the encoding and storage of memories concerned with unique personal experiences and their subsequent recall, and it has long been the subject of intensive investigation in humans. According to Tulving's classical definition, episodic memory "receives and stores information about temporally dated episodes or events and temporal-spatial relations among these events." Thus, episodic memory provides information about the 'what' and 'when' of events ('temporally dated experiences') and about 'where' they happened ('temporal-spatial relations'). The storage and subsequent recall of this episodic information was thought to be beyond the memory capabilities of nonhuman animals. Although there are many laboratory procedures for investigating memory for discrete past episodes, until recently there were no previous studies that fully satisfied the criteria of Tulving's definition: they can all be explained in much simpler terms than episodic memory. However, current studies of memory for cache sites in food-storing jays provide an ethologically valid model for testing episodic-like memory in animals, thereby bridging the gap between human and animal studies memory. There is now a pressing need to adapt these experimental tests of episodic memory for other animals. Given the potential power of transgenic and knock-out procedures for investigating the genetic and molecular bases of learning and memory in laboratory rodents, not to mention the wealth of knowledge about the neuroanatomy and neurophysiology of the rodent hippocampus (a brain area heavily implicated in episodic memory), an obvious next step is to develop a rodent model of episodic-like memory based on the food-storing bird paradigm. The development of a rodent model system could make an important contribution to our understanding of the neural, molecular, and behavioral mechanisms of mammalian episodic memory.

Effects of Cage Type and NASA Rodent Food Bar in Male Sprague-Dawley Rats

NASA Technical Reports Server (NTRS)

Lau, Angela; Ramirez, J.; Pruitt, S.; Melson, E.; Zirkle-Yoshida, M.; Girten, B.; Apseloff, G.

2001-01-01

Early prototype caging for the rodent Advanced Animal Habitat (P-AAH) for the International Space Station (ISS) is currently being tested. In this five week study, effects of the wire-bottom P-AAH cages and specialized NASA rodent food bars (FB) were compared to standard vivarium cages (VIV) with corn-cob, litter-filled bottoms, and standard Purina rat chow (CH). Ninety-six male Sprague-Dawley rats were divided into four treatment groups (24 rats/treatment): Group 1) VIV+CH, Group 2) P-AAH+CH, Group 3) VIV+FB, and Group 4) P-AAH+FB. Each VIV and P-AAH cage housed three and six rats, respectively. After five weeks of treatment rats were weighed, euthanized, and blood samples were collected. Weights of liver (LIV), kidney (KID), brain (BRN), epididymal fat (EPI), and perirenal fat (PERI) were also measured. Statistical analysis to compare differences between groups was performed by standard analysis of variance procedures (ANOVA) with a significance level of pLO.05. Results indicated P-AAH housed rats had significantly lower body weights (BW), LIV weights, and LIV/BW than VIV housed rats. FB fed rats had significantly lower blood urea nitrogen (BUN) levels and LIV/BW than CH fed rats. In addition, FB fed rats had significantly higher cholesterol (CHOL) levels, EPI/BW, PERI/BW, and total fat (EPI+PERI)/BW than CH fed rats. The P-AAH+FB group had significantly lower EPI, BRN, and total fat than VIV+FB rats. VIV+FB rats had significantly higher BRN, EPI, PERI, and total fat than VIV+CH rats. Triglycerides (TG), KID, KID/BW, and BRN/BW were not significantly different among treatment groups. These findings provide valuable information regarding cage design and food bar suitability for long-term use on the ISS.

Quantitative Structure--Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure

EPA Science Inventory

Background: Few Quantitative Structure-Activity Relationship (QSAR) studies have successfully modeled large, diverse rodent toxicity endpoints. Objective: In this study, a combinatorial QSAR approach has been employed for the creation of robust and predictive models of acute toxi...

Risk estimates for CO exposure in man based on behavioral and physiological responses in rodents

NASA Technical Reports Server (NTRS)

Gross, M. K.

1983-01-01

An examination of animal response to CO is studied along with potential models for extrapolating animal test data to humans. The best models for extrapolating data were found to be the Probit and Weibull models.

Lassa fever or lassa hemorrhagic fever risk to humans from rodent-borne zoonoses.

PubMed

El-Bahnasawy, Mamdouh M; Megahed, Laila Abdel-Mawla; Abdalla Saleh, Hala Ahmed; Morsy, Tosson A

2015-04-01

Viral hemorrhagic fevers (VHFs) typically manifest as rapidly progressing acute febrile syndromes with profound hemorrhagic manifestations and very high fatality rates. Lassa fever, an acute hemorrhagic fever characterized by fever, muscle aches, sore throat, nausea, vomiting, diarrhea and chest and abdominal pain. Rodents are important reservoirs of rodent-borne zoonosis worldwide. Transmission rodents to humans occur by aerosol spread, either from the genus Mastomys rodents' excreta (multimammate rat) or through the close contact with infected patients (nosocomial infection). Other rodents of the genera Rattus, Mus, Lemniscomys, and Praomys are incriminated rodents hosts. Now one may ask do the rodents' ectoparasites play a role in Lassa virus zoonotic transmission. This paper summarized the update knowledge on LHV; hopping it might be useful to the clinicians, nursing staff, laboratories' personals as well as those concerned zoonoses from rodents and rodent control.

Oxidative Injury and Iron Redistribution Are Pathological Hallmarks of Marmoset Experimental Autoimmune Encephalomyelitis.

PubMed

Dunham, Jordon; Bauer, Jan; Campbell, Graham R; Mahad, Don J; van Driel, Nikki; van der Pol, Susanne M A; 't Hart, Bert A; Lassmann, Hans; Laman, Jon D; van Horssen, Jack; Kap, Yolanda S

2017-06-01

Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as redistribution of iron are hallmarks of the MS-like pathology in the EAE model in the common marmoset. Active lesions in the marmoset EAE brain display increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p22phox, p47phox, and gp91phox) and inducible nitric oxide synthase immunoreactivity within lesions with active inflammation and demyelination, coinciding with enhanced expression of mitochondrial heat-shock protein 70 and superoxide dismutase 1 and 2. The EAE lesion-associated liberation of iron (due to loss of iron-containing myelin) was associated with altered expression of the iron metabolic markers FtH1, lactoferrin, hephaestin, and ceruloplasmin. The enhanced expression of oxidative damage markers in inflammatory lesions indicates that the enhanced antioxidant enzyme expression could not counteract reactive oxygen and nitrogen species-induced cellular damage, as is also observed in MS brains. This study demonstrates that oxidative injury and aberrant iron distribution are prominent pathological hallmarks of marmoset EAE thus making this model suitable for therapeutic intervention studies aimed at reducing oxidative stress and associated iron dysmetabolism. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

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

PubMed

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 in order to accurately reconstruct an environmental signature when these taxa are found in the fossil record.

Surfaces and spaces: troubleshooting the study of dietary niche space overlap between North American stem primates and rodents

NASA Astrophysics Data System (ADS)

Prufrock, Kristen A.; López-Torres, Sergi; Silcox, Mary T.; Boyer, Doug M.

2016-06-01

Dental topographic metrics provide quantitative, biologically meaningful data on the three-dimensional (3D) form of teeth. In this study, three dental topographic metrics (Dirichlet normal energy (DNE), relief index (RFI), and orientation patch count rotated (OPCR)) are used to evaluate the presence of dietary niche overlap between North American plesiadapoid primates (Plesiadapidae, Carpolestidae, and Saxonellidae) and early rodents. Calculation of these metrics requires researchers to modify the 3D surface models of the teeth by cropping them to a region of interest and/or orienting them. The current study therefore also examines the error introduced by cropping and orientation, and evaluates the contribution of these metrics to the niche overlap hypothesis. Our results indicate that cropping creates significantly more variation in RFI than DNE. Furthermore, orientation is an even larger source of variation in the calculation of RFI than cropping. Orientation does not strongly influence OPCR values. However, none of these sources of error are significant enough to undermine the extent to which these metrics can speak to the niche overlap hypothesis. The DNE and RFI results suggest that carpolestids and saxonellids had very different molar morphologies from early rodents, and thus these groups were not adapted to consume the same resources. Some plesiadapids show similar levels of occlusal curvature, relief, and complexity to early rodents. The plesiadapid Chiromyoides, which has distinctively low cusps and weak shearing crest development, has molars that are the most rodent-like of all taxa compared. This suggests that Chiromyoides had a dietary niche that overlapped with early rodents and would have been the most likely to be competing over food resources. Results from the plesiadapoid-rodent dental topographic analysis highlight the utility of DNE for detecting more fine-scaled differences in occlusal surface morphology than OPCR, whereas RFI provided valuable data on the degree to which teeth were high crowned.

Are Synonymous Sites in Primates and Rodents Functionally Constrained?

PubMed

Price, Nicholas; Graur, Dan

2016-01-01

It has been claimed that synonymous sites in mammals are under selective constraint. Furthermore, in many studies the selective constraint at such sites in primates was claimed to be more stringent than that in rodents. Given the larger effective population sizes in rodents than in primates, the theoretical expectation is that selection in rodents would be more effective than that in primates. To resolve this contradiction between expectations and observations, we used processed pseudogenes as a model for strict neutral evolution, and estimated selective constraint on synonymous sites using the rate of substitution at pseudosynonymous and pseudononsynonymous sites in pseudogenes as the neutral expectation. After controlling for the effects of GC content, our results were similar to those from previous studies, i.e., synonymous sites in primates exhibited evidence for higher selective constraint that those in rodents. Specifically, our results indicated that in primates up to 24% of synonymous sites could be under purifying selection, while in rodents synonymous sites evolved neutrally. To further control for shifts in GC content, we estimated selective constraint at fourfold degenerate sites using a maximum parsimony approach. This allowed us to estimate selective constraint using mutational patterns that cause a shift in GC content (GT ↔ TG, CT ↔ TC, GA ↔ AG, and CA ↔ AC) and ones that do not (AT ↔ TA and CG ↔ GC). Using this approach, we found that synonymous sites evolve neutrally in both primates and rodents. Apparent deviations from neutrality were caused by a higher rate of C → A and C → T mutations in pseudogenes. Such differences are most likely caused by the shift in GC content experienced by pseudogenes. We conclude that previous estimates according to which 20-40% of synonymous sites in primates were under selective constraint were most likely artifacts of the biased pattern of mutation.

A Systematic Review of Fetal Genes as Biomarkers of Cardiac Hypertrophy in Rodent Models of Diabetes

PubMed Central

2014-01-01

Pathological cardiac hypertrophy activates a suite of genes called the fetal gene program (FGP). Pathological hypertrophy occurs in diabetic cardiomyopathy (DCM); therefore, the FGP is widely used as a biomarker of DCM in animal studies. However, it is unknown whether the FGP is a consistent marker of hypertrophy in rodent models of diabetes. Therefore, we analyzed this relationship in 94 systematically selected studies. Results showed that diabetes induced with cytotoxic glucose analogs such as streptozotocin was associated with decreased cardiac weight, but genetic or diet-induced models of diabetes were significantly more likely to show cardiac hypertrophy (P<0.05). Animal strain, sex, age, and duration of diabetes did not moderate this effect. There were no correlations between the heart weight:body weight index and mRNA or protein levels of the fetal genes α-myosin heavy chain (α-MHC) or β-MHC, sarco/endoplasmic reticulum Ca2+-ATPase, atrial natriuretic peptide (ANP), or brain natriuretic peptide. The only correlates of non-indexed heart weight were the protein levels of α-MHC (Spearman's ρ = 1, P<0.05) and ANP (ρ = −0.73, P<0.05). These results indicate that most commonly measured genes in the FGP are confounded by diabetogenic methods, and are not associated with cardiac hypertrophy in rodent models of diabetes. PMID:24663494

Population-level consequences of antipredator behavior: a metaphysiological model based on the functional ecology of the leaf-eared mouse.

PubMed

Ramos-Jiliberto, Rodrigo; González-Olivares, Eduardo; Bozinovic, Francisco

2002-08-01

We present a predator-prey metaphysiological model, based on the available behavioral and physiological information of the sigmodontine rodent Phyllotis darwini. The model is focused on the population-level consequences of the antipredator behavior, performed by the rodent population, which is assumed to be an inducible response of predation avoidance. The decrease in vulnerability is explicitly considered to have two associated costs: a decreasing foraging success and an increasing metabolic loss. The model analysis was carried out on a reduced form of the system by means of numerical and analytical tools. We evaluated the stability properties of equilibrium points in the phase plane, and carried out bifurcation analyses of rodent equilibrium density under varying conditions of three relevant parameters. The bifurcation parameters chosen represent predator avoidance effectiveness (A), foraging cost of antipredator behavior (C(1)'), and activity-metabolism cost (C(4)'). Our analysis suggests that the trade-offs involved in antipredator behavior plays a fundamental role in the stability properties of the system. Under conditions of high foraging cost, stability decreases as antipredator effectiveness increases. Under the complementary scenario (not considering the highest foraging costs), the equilibria are either stable when both costs are low, or unstable when both costs are higher, independent of antipredator effectiveness. No evidence of stabilizing effects of antipredator behavior was found. Copyright 2002 Elsevier Science (USA).

Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

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

Woolbright, Benjamin L.; Dorko, Kenneth; Antoine, Daniel J.

Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with,more » or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury compared to rodents. • Primary human hepatocytes largely undergo necrosis in response to BA toxicity. • Cholestatic liver injury in vivo is predominantly necrotic with minor apoptosis. • Rodent models of bile acid toxicity may not recapitulate the injury in man.« less

Rodent reservoirs of future zoonotic diseases

PubMed Central

Han, Barbara A.; Schmidt, John Paul; Bowden, Sarah E.; Drake, John M.

2015-01-01

The increasing frequency of zoonotic disease events underscores a need to develop forecasting tools toward a more preemptive approach to outbreak investigation. We apply machine learning to data describing the traits and zoonotic pathogen diversity of the most speciose group of mammals, the rodents, which also comprise a disproportionate number of zoonotic disease reservoirs. Our models predict reservoir status in this group with over 90% accuracy, identifying species with high probabilities of harboring undiscovered zoonotic pathogens based on trait profiles that may serve as rules of thumb to distinguish reservoirs from nonreservoir species. Key predictors of zoonotic reservoirs include biogeographical properties, such as range size, as well as intrinsic host traits associated with lifetime reproductive output. Predicted hotspots of novel rodent reservoir diversity occur in the Middle East and Central Asia and the Midwestern United States. PMID:26038558

Improved inhalation technology for setting safe exposure levels for workplace chemicals

NASA Technical Reports Server (NTRS)

Stuart, Bruce O.

1993-01-01

Threshold Limit Values recommended as allowable air concentrations of a chemical in the workplace are often based upon a no-observable-effect-level (NOEL) determined by experimental inhalation studies using rodents. A 'safe level' for human exposure must then be estimated by the use of generalized safety factors in attempts to extrapolate from experimental rodents to man. The recent development of chemical-specific physiologically-based toxicokinetics makes use of measured physiological, biochemical, and metabolic parameters to construct a validated model that is able to 'scale-up' rodent response data to predict the behavior of the chemical in man. This procedure is made possible by recent advances in personal computer software and the emergence of appropriate biological data, and provides an analytical tool for much more reliable risk evaluation and airborne chemical exposure level setting for humans.

A domestic porcine model for studying the effects of radiation on head and neck cancers.

PubMed

Arnold, Christoph R; Kloss, Frank; Singh, Sarvpreet; Vasiljevic, Danijela; Stigler, Robert; Auberger, Thomas; Wenzel, Volker; Klima, Günter; Lukas, Peter; Lepperdinger, Günter; Gassner, Robert

2017-05-01

Radiation therapy (RT) of the head and neck region is often accompanied by serious side effects. Research in this area is needed to improve treatment outcomes and ameliorate therapy tolerance. Laboratory rodents are barely matching today's clinical standards in RT research. Yet domestic swine (Sus scrofa domestica) have previously proved suitable for various advanced tests in clinical research and training. We therefore investigated whether S. scrofa domestica is also appropriate for irradiation of the mandible. A common scheme for irradiation treatment of S. scrofa domestica mandibles in a split-mouth design was acquired by applying computed tomography (CT) scanning under sedation. Basing on close anatomic resemblance, a standard treatment plan comprising 2 opposed irradiation fields could be accomplished. RT was carried out in a clinical environment with 2 × 9 Gy. The resulting operating procedure facilitated complication-free sedation, transport, positioning, CT scanning, and effective irradiation. Based on common standards applied for RT in humans, domestic pigs can be employed to progress RT clinical research. Due to their human-like anatomy, physiology, size, and weight, the swine model is expedient for advancing experimental RT of the head and neck area. Copyright © 2016 Elsevier Inc. All rights reserved.

Automated Gait Analysis Through Hues and Areas (AGATHA): a method to characterize the spatiotemporal pattern of rat gait

PubMed Central

Kloefkorn, Heidi E.; Pettengill, Travis R.; Turner, Sara M. F.; Streeter, Kristi A.; Gonzalez-Rothi, Elisa J.; Fuller, David D.; Allen, Kyle D.

2016-01-01

While rodent gait analysis can quantify the behavioral consequences of disease, significant methodological differences exist between analysis platforms and little validation has been performed to understand or mitigate these sources of variance. By providing the algorithms used to quantify gait, open-source gait analysis software can be validated and used to explore methodological differences. Our group is introducing, for the first time, a fully-automated, open-source method for the characterization of rodent spatiotemporal gait patterns, termed Automated Gait Analysis Through Hues and Areas (AGATHA). This study describes how AGATHA identifies gait events, validates AGATHA relative to manual digitization methods, and utilizes AGATHA to detect gait compensations in orthopaedic and spinal cord injury models. To validate AGATHA against manual digitization, results from videos of rodent gait, recorded at 1000 frames per second (fps), were compared. To assess one common source of variance (the effects of video frame rate), these 1000 fps videos were re-sampled to mimic several lower fps and compared again. While spatial variables were indistinguishable between AGATHA and manual digitization, low video frame rates resulted in temporal errors for both methods. At frame rates over 125 fps, AGATHA achieved a comparable accuracy and precision to manual digitization for all gait variables. Moreover, AGATHA detected unique gait changes in each injury model. These data demonstrate AGATHA is an accurate and precise platform for the analysis of rodent spatiotemporal gait patterns. PMID:27554674

A New Variational Method for Bias Correction and Its Applications to Rodent Brain Extraction.

PubMed

Chang, Huibin; Huang, Weimin; Wu, Chunlin; Huang, Su; Guan, Cuntai; Sekar, Sakthivel; Bhakoo, Kishore Kumar; Duan, Yuping

2017-03-01

Brain extraction is an important preprocessing step for further analysis of brain MR images. Significant intensity inhomogeneity can be observed in rodent brain images due to the high-field MRI technique. Unlike most existing brain extraction methods that require bias corrected MRI, we present a high-order and L 0 regularized variational model for bias correction and brain extraction. The model is composed of a data fitting term, a piecewise constant regularization and a smooth regularization, which is constructed on a 3-D formulation for medical images with anisotropic voxel sizes. We propose an efficient multi-resolution algorithm for fast computation. At each resolution layer, we solve an alternating direction scheme, all subproblems of which have the closed-form solutions. The method is tested on three T2 weighted acquisition configurations comprising a total of 50 rodent brain volumes, which are with the acquisition field strengths of 4.7 Tesla, 9.4 Tesla and 17.6 Tesla, respectively. On one hand, we compare the results of bias correction with N3 and N4 in terms of the coefficient of variations on 20 different tissues of rodent brain. On the other hand, the results of brain extraction are compared against manually segmented gold standards, BET, BSE and 3-D PCNN based on a number of metrics. With the high accuracy and efficiency, our proposed method can facilitate automatic processing of large-scale brain studies.

Automated Gait Analysis Through Hues and Areas (AGATHA): A Method to Characterize the Spatiotemporal Pattern of Rat Gait.

PubMed

Kloefkorn, Heidi E; Pettengill, Travis R; Turner, Sara M F; Streeter, Kristi A; Gonzalez-Rothi, Elisa J; Fuller, David D; Allen, Kyle D

2017-03-01

While rodent gait analysis can quantify the behavioral consequences of disease, significant methodological differences exist between analysis platforms and little validation has been performed to understand or mitigate these sources of variance. By providing the algorithms used to quantify gait, open-source gait analysis software can be validated and used to explore methodological differences. Our group is introducing, for the first time, a fully-automated, open-source method for the characterization of rodent spatiotemporal gait patterns, termed Automated Gait Analysis Through Hues and Areas (AGATHA). This study describes how AGATHA identifies gait events, validates AGATHA relative to manual digitization methods, and utilizes AGATHA to detect gait compensations in orthopaedic and spinal cord injury models. To validate AGATHA against manual digitization, results from videos of rodent gait, recorded at 1000 frames per second (fps), were compared. To assess one common source of variance (the effects of video frame rate), these 1000 fps videos were re-sampled to mimic several lower fps and compared again. While spatial variables were indistinguishable between AGATHA and manual digitization, low video frame rates resulted in temporal errors for both methods. At frame rates over 125 fps, AGATHA achieved a comparable accuracy and precision to manual digitization for all gait variables. Moreover, AGATHA detected unique gait changes in each injury model. These data demonstrate AGATHA is an accurate and precise platform for the analysis of rodent spatiotemporal gait patterns.

Pathobiology and management of laboratory rodents administered CDC category A agents.

PubMed

He, Yongqun; Rush, Howard G; Liepman, Rachel S; Xiang, Zuoshuang; Colby, Lesley A

2007-02-01

The Centers for Disease Control and Prevention Category A infectious agents include Bacillus anthracis (anthrax), Clostridium botulinum toxin (botulism), Yersinia pestis (plague), variola major virus (smallpox), Francisella tularensis (tularemia), and the filoviruses and arenaviruses that induce viral hemorrhagic fevers. These agents are regarded as having the greatest potential for adverse impact on public health and therefore are a focus of renewed attention in infectious disease research. Frequently rodent models are used to study the pathobiology of these agents. Although much is known regarding naturally occurring infections in humans, less is documented on the sources of exposures and potential risks of infection to researchers and animal care personnel after the administration of these hazardous substances to laboratory animals. Failure to appropriately manage the animals can result both in the creation of workplace hazards if human exposures occur and in disruption of the research if unintended animal exposures occur. Here we review representative Category A agents, with a focus on comparing the biologic effects in naturally infected humans and rodent models and on considerations specific to the management of infected rodent subjects. The information reviewed for each agent has been curated manually and stored in a unique Internet-based database system called HazARD (Hazards in Animal Research Database, http://helab.bioinformatics.med.umich.edu/hazard/) that is designed to assist researchers, administrators, safety officials, Institutional Biosafety Committees, and veterinary personnel seeking information on the management of risks associated with animal studies involving hazardous substances.

A revised model of ex-vivo reduction of hexavalent chromium in human and rodent gastric juices

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

Schlosser, Paul M., E-mail: schlosser.paul@epa.gov; Sasso, Alan F.

Chronic oral exposure to hexavalent chromium (Cr-VI) in drinking water has been shown to induce tumors in the mouse gastrointestinal (GI) tract and rat oral cavity. The same is not true for trivalent chromium (Cr-III). Thus reduction of Cr-VI to Cr-III in gastric juices is considered a protective mechanism, and it has been suggested that the difference between the rate of reduction among mice, rats, and humans could explain or predict differences in sensitivity to Cr-VI. We evaluated previously published models of gastric reduction and believe that they do not fully describe the data on reduction as a function ofmore » Cr-VI concentration, time, and (in humans) pH. The previous models are parsimonious in assuming only a single reducing agent in rodents and describing pH-dependence using a simple function. We present a revised model that assumes three pools of reducing agents in rats and mice with pH-dependence based on known speciation chemistry. While the revised model uses more fitted parameters than the original model, they are adequately identifiable given the available data, and the fit of the revised model to the full range of data is shown to be significantly improved. Hence the revised model should provide better predictions of Cr-VI reduction when integrated into a corresponding PBPK model. - Highlights: • Hexavalent chromium (Cr-VI) reduction in gastric juices is a key detoxifying step. • pH-dependent Cr-VI reduction rates are explained using known chemical speciation. • Reduction in rodents appears to involve multiple pools of electron donors. • Reduction appears to continue after 60 min, although more slowly than initial rates.« less

Spatial clustering of Borrelia burgdorferi sensu lato within populations of Allen's chipmunks and dusky-footed woodrats in northwestern California

PubMed Central

Brown, Richard N.; Fedorova, Natalia; Girard, Yvette A.; Higley, Mark; Clueit, Bernadette; Lane, Robert S.

2018-01-01

The ecology of Lyme borreliosis is complex in northwestern California, with several potential reservoir hosts, tick vectors, and genospecies of Borrelia burgdorferi sensu lato. The primary objective of this study was to determine the fine-scale spatial distribution of different genospecies in four rodent species, the California ground squirrel (Otospermophilus beecheyi), northern flying squirrel (Glaucomys sabrinus), dusky-footed woodrat (Neotoma fuscipes), and Allen’s chipmunk (Neotamias senex). Rodents were live-trapped between June 2004 and May 2005 at the Hoopa Valley Tribal Reservation (HVTR) in Humboldt County, California. Ear-punch biopsies obtained from each rodent were tested by polymerase chain reaction (PCR) and sequencing analysis. The programs ArcGIS and SaTScan were used to examine the spatial distribution of genospecies. Multinomial log-linear models were used to model habitat and host-specific characteristics and their effect on the presence of each borrelial genospecies. The Akaike information criterion (AICc) was used to compare models and determine model fit. Borrelia burgdorferi sensu stricto was primarily associated with chipmunks and B. bissettiae largely with woodrats. The top model included the variables “host species”, “month”, and “elevation” (weight = 0.84). Spatial clustering of B. bissettiae was detected in the northwestern section of the HVTR, whereas B. burgdorferi sensu stricto was clustered in the southeastern section. We conclude that the spatial distribution of these borreliae are driven at least in part by host species, time-of-year, and elevation. PMID:29634745

Spatial clustering of Borrelia burgdorferi sensu lato within populations of Allen's chipmunks and dusky-footed woodrats in northwestern California.

PubMed

Hacker, Gregory M; Brown, Richard N; Fedorova, Natalia; Girard, Yvette A; Higley, Mark; Clueit, Bernadette; Lane, Robert S

2018-01-01

The ecology of Lyme borreliosis is complex in northwestern California, with several potential reservoir hosts, tick vectors, and genospecies of Borrelia burgdorferi sensu lato. The primary objective of this study was to determine the fine-scale spatial distribution of different genospecies in four rodent species, the California ground squirrel (Otospermophilus beecheyi), northern flying squirrel (Glaucomys sabrinus), dusky-footed woodrat (Neotoma fuscipes), and Allen's chipmunk (Neotamias senex). Rodents were live-trapped between June 2004 and May 2005 at the Hoopa Valley Tribal Reservation (HVTR) in Humboldt County, California. Ear-punch biopsies obtained from each rodent were tested by polymerase chain reaction (PCR) and sequencing analysis. The programs ArcGIS and SaTScan were used to examine the spatial distribution of genospecies. Multinomial log-linear models were used to model habitat and host-specific characteristics and their effect on the presence of each borrelial genospecies. The Akaike information criterion (AICc) was used to compare models and determine model fit. Borrelia burgdorferi sensu stricto was primarily associated with chipmunks and B. bissettiae largely with woodrats. The top model included the variables "host species", "month", and "elevation" (weight = 0.84). Spatial clustering of B. bissettiae was detected in the northwestern section of the HVTR, whereas B. burgdorferi sensu stricto was clustered in the southeastern section. We conclude that the spatial distribution of these borreliae are driven at least in part by host species, time-of-year, and elevation.

Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides

PubMed Central

WILCOX, CHRISTOPHER S.; PEARLMAN, ADAM

2009-01-01

Nitroxides can undergo one- or two-electron reduction reactions to hydroxylamines or oxammonium cations, respectively, which themselves are interconvertible, thereby providing redox metabolic actions. 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) is the most extensively studied nitroxide. It is a cell membrane-permeable amphilite that dismutates superoxide catalytically, facilitates hydrogen peroxide metabolism by catalase-like actions, and limits formation of toxic hydroxyl radicals produced by Fenton reactions. It is broadly effective in detoxifying these reactive oxygen species in cell and animal studies. When administered intravenously to hypertensive rodent models, tempol caused rapid and reversible dose-dependent reductions in blood pressure in 22 of 26 studies. This was accompanied by vasodilation, increased nitric oxide activity, reduced sympathetic nervous system activity at central and peripheral sites, and enhanced potassium channel conductance in blood vessels and neurons. When administered orally or by infusion over days or weeks to hypertensive rodent models, it reduced blood pressure in 59 of 68 studies. This was accompanied by correction of salt sensitivity and endothelial dysfunction and reduced agonist-evoked oxidative stress and contractility of blood vessels, reduced renal vascular resistance, and increased renal tissue oxygen tension. Thus, tempol is broadly effective in reducing blood pressure, whether given by acute intravenous injection or by prolonged administration, in a wide range of rodent models of hypertension. PMID:19112152

Mammary gland neoplasia in long-term rodent studies.

PubMed Central

Russo, I H; Russo, J

1996-01-01

Breast cancer, the most frequent spontaneous malignancy diagnosed in women in the western world, is continuously increasing in incidence in industrialized nations. Although breast cancer develops in women as the result of a combination of external and endogenous factors such as exposure to ionizing radiation, diet, socioeconomic status, and endocrinologic, familial, or genetic factors, no specific etiologic agent(s) or the mechanisms responsible of the disease has been identified as yet. Thus, experimental models that exhibit the same complex interactions are needed for testing various mechanisms and for assessing the carcinogenic potential of given chemicals. Rodent mammary carcinomas represent such a model to a great extent because, in these species, mammary cancer is a multistep complex process that can be induced by either chemicals, radiation, viruses, or genetic factors. Long-term studies in rodent models have been particularly useful for dissecting the initiation, promotion, and progression steps of carcinogenesis. The susceptibility of the rodent mammary gland to develop neoplasms has made this organ a unique target for testing the carcinogenic potential of specific genotoxic chemicals and environmental agents. Mammary tumors induced by indirect- or direct-acting carcinogens such as 7, 12-dimethlbenz(a)anthracene or N-methyl-N-nitrosourea are, in general, hormone dependent adenocarcinomas whose incidence, number of tumors per animal, tumor latency, and tumor type are influenced by the age, reproductive history, and endocarinologic milieu of the host at the time of carcinogen exposure. Rodent models are informative in the absence of human data. They have provided valuable information on the dose and route of administration to be used and optimal host conditions for eliciting maximal tumorigenic response. Studies of the influence of normal gland development on the pathogenesis of chemically induced mammary carcinomas have clarified the role of differentiation in cancer initiation. Comparative studies with the development of the human breast and the pathogenesis of breast cancer have contributed to validate rodent-to-human extrapolations. However, it has not been definitively established what type of information is necessary for human risk assessment, whether currently toxicity testing methodologies are sufficient for fulfilling those needs, or whether treatment-induced tumorigenic responses in rodents are predictive of potential human risk. An alternative to the traditional bioassays are mechanism-based toxicology and molecular and cellular approaches, combined with comparative in vitro systems. These approaches might allow the rapid screen of chemicals for setting priorities for further studies to determine the dose-response relationship for chemical effects at low doses, to assess effects other than mutagenesis and/or tumorigenesis, or to establish qualitative and quantitative relationships of biomarkers to toxic effects. Until there is enough information on the predictive value of mechanism-based toxicology for risk assessment, this approach should be used in conjunction with and validated by the traditional in vivo long-term bioassays. Images Figure 1. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6. Figure 7. A Figure 7. B Figure 8. A Figure 8. B Figure 9. Figure 10. Figure 11. Figure 12. Figure 13. Figure 14. Figure 15. Figure 16. Figure 17. Figure 18. Figure 19. Figure 20. Figure 21. Figure 22. Figure 23. Figure 24. Figure 25. Figure 26. PMID:8899375

A MATHEMATICAL MODEL FOR THE ANDROGENIC REGULATION OF THE PROSTATE IN INTACT AND CASTRATE ADULT MALE RATS

EPA Science Inventory

An abstract that provides understanding for a mathematical model by Barton and Anderson, for the dynamics of androgenic synthesis, transport, metabolism, and regulation of the rodent ventral prostate.

Acute Stress Decreases but Chronic Stress Increases Myocardial Sensitivity to Ischemic Injury in Rodents

PubMed Central

Eisenmann, Eric D.; Rorabaugh, Boyd R.; Zoladz, Phillip R.

2016-01-01

Cardiovascular disease (CVD) is the largest cause of mortality worldwide, and stress is a significant contributor to the development of CVD. The relationship between acute and chronic stress and CVD is well evidenced. Acute stress can lead to arrhythmias and ischemic injury. However, recent evidence in rodent models suggests that acute stress can decrease sensitivity to myocardial ischemia–reperfusion injury (IRI). Conversely, chronic stress is arrhythmogenic and increases sensitivity to myocardial IRI. Few studies have examined the impact of validated animal models of stress-related psychological disorders on the ischemic heart. This review examines the work that has been completed using rat models to study the effects of stress on myocardial sensitivity to ischemic injury. Utilization of animal models of stress-related psychological disorders is critical in the prevention and treatment of cardiovascular disorders in patients experiencing stress-related psychiatric conditions. PMID:27199778

Acute Stress Decreases but Chronic Stress Increases Myocardial Sensitivity to Ischemic Injury in Rodents.

PubMed

Eisenmann, Eric D; Rorabaugh, Boyd R; Zoladz, Phillip R

2016-01-01

Cardiovascular disease (CVD) is the largest cause of mortality worldwide, and stress is a significant contributor to the development of CVD. The relationship between acute and chronic stress and CVD is well evidenced. Acute stress can lead to arrhythmias and ischemic injury. However, recent evidence in rodent models suggests that acute stress can decrease sensitivity to myocardial ischemia-reperfusion injury (IRI). Conversely, chronic stress is arrhythmogenic and increases sensitivity to myocardial IRI. Few studies have examined the impact of validated animal models of stress-related psychological disorders on the ischemic heart. This review examines the work that has been completed using rat models to study the effects of stress on myocardial sensitivity to ischemic injury. Utilization of animal models of stress-related psychological disorders is critical in the prevention and treatment of cardiovascular disorders in patients experiencing stress-related psychiatric conditions.

Schizophrenia and Depression Co-Morbidity: What We have Learned from Animal Models

PubMed Central

Samsom, James N.; Wong, Albert H. C.

2015-01-01

Patients with schizophrenia are at an increased risk for the development of depression. Overlap in the symptoms and genetic risk factors between the two disorders suggests a common etiological mechanism may underlie the presentation of comorbid depression in schizophrenia. Understanding these shared mechanisms will be important in informing the development of new treatments. Rodent models are powerful tools for understanding gene function as it relates to behavior. Examining rodent models relevant to both schizophrenia and depression reveals a number of common mechanisms. Current models which demonstrate endophenotypes of both schizophrenia and depression are reviewed here, including models of CUB and SUSHI multiple domains 1, PDZ and LIM domain 5, glutamate Delta 1 receptor, diabetic db/db mice, neuropeptide Y, disrupted in schizophrenia 1, and its interacting partners, reelin, maternal immune activation, and social isolation. Neurotransmission, brain connectivity, the immune system, the environment, and metabolism emerge as potential common mechanisms linking these models and potentially explaining comorbid depression in schizophrenia. PMID:25762938

Rodents and Risk in the Mekong Delta of Vietnam: Seroprevalence of Selected Zoonotic Viruses in Rodents and Humans

PubMed Central

Van Cuong, Nguyen; Carrique-Mas, Juan; Vo Be, Hien; An, Nguyen Ngoc; Tue, Ngo Tri; Anh, Nguyet Lam; Anh, Pham Hong; Phuc, Nguyen The; Baker, Stephen; Voutilainen, Liina; Jääskeläinen, Anne; Huhtamo, Eili; Utriainen, Mira; Sironen, Tarja; Vaheri, Antti; Henttonen, Heikki; Vapalahti, Olli; Chaval, Yannick

2015-01-01

Abstract In the Mekong Delta in southern Vietnam, rats are commonly traded in wet markets and sold live for food consumption. We investigated seroprevalence to selected groups of rodent-borne viruses among human populations with high levels of animal exposure and among co-located rodent populations. The indirect fluorescence antibody test (IFAT) was used to determine seropositivity to representative reference strains of hantaviruses (Dobrava virus [DOBV], Seoul virus [SEOV]), cowpox virus, arenaviruses (lymphocytic choriomeningitis virus [LCMV]), flaviviruses (tick-borne encephalitis virus [TBEV]), and rodent parechoviruses (Ljungan virus), using sera from 245 humans living in Dong Thap Province and 275 rodents representing the five common rodent species sold in wet markets and present in peridomestic and farm settings. Combined seropositivity to DOBV and SEOV among the rodents and humans was 6.9% (19/275) and 3.7% (9/245), respectively; 1.1% (3/275) and 4.5% (11/245) to cowpox virus; 5.4% (15/275) and 47.3% (116/245) for TBEV; and exposure to Ljungan virus was 18.8% (46/245) in humans, but 0% in rodents. Very little seroreactivity was observed to LCMV in either rodents (1/275, 0.4%) or humans (2/245, 0.8%). Molecular screening of rodent liver tissues using consensus primers for flaviviruses did not yield any amplicons, whereas molecular screening of rodent lung tissues for hantavirus yielded one hantavirus sequence (SEOV). In summary, these results indicate low to moderate levels of endemic hantavirus circulation, possible circulation of a flavivirus in rodent reservoirs, and the first available data on human exposures to parechoviruses in Vietnam. Although the current evidence suggests only limited exposure of humans to known rodent-borne diseases, further research is warranted to assess public health implications of the rodent trade. PMID:25629782

Animal models for Ebola and Marburg virus infections

PubMed Central

Nakayama, Eri; Saijo, Masayuki

2013-01-01

Ebola and Marburg hemorrhagic fevers (EHF and MHF) are caused by the Filoviridae family, Ebolavirus and Marburgvirus (ebolavirus and marburgvirus), respectively. These severe diseases have high mortality rates in humans. Although EHF and MHF are endemic to sub-Saharan Africa. A novel filovirus, Lloviu virus, which is genetically distinct from ebolavirus and marburgvirus, was recently discovered in Spain where filoviral hemorrhagic fever had never been reported. The virulence of this virus has not been determined. Ebolavirus and marburgvirus are classified as biosafety level-4 (BSL-4) pathogens and Category A agents, for which the US government requires preparedness in case of bioterrorism. Therefore, preventive measures against these viral hemorrhagic fevers should be prepared, not only in disease-endemic regions, but also in disease-free countries. Diagnostics, vaccines, and therapeutics need to be developed, and therefore the establishment of animal models for EHF and MHF is invaluable. Several animal models have been developed for EHF and MHF using non-human primates (NHPs) and rodents, which are crucial to understand pathophysiology and to develop diagnostics, vaccines, and therapeutics. Rhesus and cynomolgus macaques are representative models of filovirus infection as they exhibit remarkably similar symptoms to those observed in humans. However, the NHP models have practical and ethical problems that limit their experimental use. Furthermore, there are no inbred and genetically manipulated strains of NHP. Rodent models such as mouse, guinea pig, and hamster, have also been developed. However, these rodent models require adaptation of the virus to produce lethal disease and do not mirror all symptoms of human filovirus infection. This review article provides an outline of the clinical features of EHF and MHF in animals, including humans, and discusses how the animal models have been developed to study pathophysiology, vaccines, and therapeutics. PMID:24046765

Animal models for Ebola and Marburg virus infections.

PubMed

Nakayama, Eri; Saijo, Masayuki

2013-09-05

Ebola and Marburg hemorrhagic fevers (EHF and MHF) are caused by the Filoviridae family, Ebolavirus and Marburgvirus (ebolavirus and marburgvirus), respectively. These severe diseases have high mortality rates in humans. Although EHF and MHF are endemic to sub-Saharan Africa. A novel filovirus, Lloviu virus, which is genetically distinct from ebolavirus and marburgvirus, was recently discovered in Spain where filoviral hemorrhagic fever had never been reported. The virulence of this virus has not been determined. Ebolavirus and marburgvirus are classified as biosafety level-4 (BSL-4) pathogens and Category A agents, for which the US government requires preparedness in case of bioterrorism. Therefore, preventive measures against these viral hemorrhagic fevers should be prepared, not only in disease-endemic regions, but also in disease-free countries. Diagnostics, vaccines, and therapeutics need to be developed, and therefore the establishment of animal models for EHF and MHF is invaluable. Several animal models have been developed for EHF and MHF using non-human primates (NHPs) and rodents, which are crucial to understand pathophysiology and to develop diagnostics, vaccines, and therapeutics. Rhesus and cynomolgus macaques are representative models of filovirus infection as they exhibit remarkably similar symptoms to those observed in humans. However, the NHP models have practical and ethical problems that limit their experimental use. Furthermore, there are no inbred and genetically manipulated strains of NHP. Rodent models such as mouse, guinea pig, and hamster, have also been developed. However, these rodent models require adaptation of the virus to produce lethal disease and do not mirror all symptoms of human filovirus infection. This review article provides an outline of the clinical features of EHF and MHF in animals, including humans, and discusses how the animal models have been developed to study pathophysiology, vaccines, and therapeutics.

Nutritional programming of gastrointestinal tract development. Is the pig a good model for man?

PubMed

Guilloteau, Paul; Zabielski, Romuald; Hammon, Harald M; Metges, Cornelia C

2010-06-01

The consequences of early-life nutritional programming in man and other mammalian species have been studied chiefly at the metabolic level. Very few studies, if any, have been performed in the gastrointestinal tract (GIT) as the target organ, but extensive GIT studies are needed since the GIT plays a key role in nutrient supply and has an impact on functions of the entire organism. The possible deleterious effects of nutritional programming at the metabolic level were discovered following epidemiological studies in human subjects, and confirmed in animal models. Investigating the impact of programming on GIT structure and function would need appropriate animal models due to ethical restrictions in the use of human subjects. The aim of the present review is to discuss the use of pigs as an animal model as a compromise between ethically acceptable animal studies and the requirement of data which can be interpolated to the human situation. In nutritional programming studies, rodents are the most frequently used model for man, but GIT development and digestive function in rodents are considerably different from those in man. In that aspect, the pig GIT is much closer to the human than that of rodents. The swine species is closely comparable with man in many nutritional and digestive aspects, and thus provides ample opportunity to be used in investigations on the consequences of nutritional programming for the GIT. In particular, the 'sow-piglets' dyad could be a useful tool to simulate the 'human mother-infant' dyad in studies which examine short-, middle- and long-term effects and is suggested as the reference model.

Intracranial glioblastoma models in preclinical neuro-oncology: neuropathological characterization and tumor progression

PubMed Central

Candolfi, Marianela; Curtin, James F.; Stephen Nichols, W.; Muhammad, AKM. G.; King, Gwendalyn D.; Elizabeth Pluhar, G.; McNiel, Elizabeth A.; Ohlfest, John R.; Freese, Andrew B.; Moore, Peter F.; Lerner, Jonathan; Lowenstein, Pedro R.

2008-01-01

Although rodent glioblastoma (GBM) models have been used for over 30 years, the extent to which they recapitulate the characteristics encountered in human GBMs remains controversial. We studied the histopathological features of dog GBM and human xenograft GBM models in immune-deficient mice (U251 and U87 GBM in nude Balb/c), and syngeneic GBMs in immune-competent rodents (GL26 cells in C57BL/6 mice, CNS-1 cells in Lewis rats). All GBMs studied exhibited neovascularization, pleomorphism, vimentin immunoreactivity, and infiltration of T-cells and macrophages. All the tumors showed necrosis and hemorrhages, except the U87 human xenograft, in which the most salient feature was its profuse neovascularization. The tumors differed in the expression of astrocytic intermediate filaments: human and dog GBMs, as well as U251 xenografts expressed glial fibrillary acidic protein (GFAP) and vimentin, while the U87 xenograft and the syngeneic rodent GBMs were GFAP− and vimentin+. Also, only dog GBMs exhibited endothelial proliferation, a key feature that was absent in the murine models. In all spontaneous and implanted GBMs we found histopathological features compatible with tumor invasion into the non-neoplastic brain parenchyma. Our data indicate that murine models of GBM appear to recapitulate several of the human GBM histopathological features and, considering their reproducibility and availability, they constitute a valuable in vivo system for preclinical studies. Importantly, our results indicate that dog GBM emerges as an attractive animal model for testing novel therapies in a spontaneous tumor in the context of a larger brain. PMID:17874037

The utility of animal models to evaluate novel anti-obesity agents

PubMed Central

Vickers, Steven P; Jackson, Helen C; Cheetham, Sharon C

2011-01-01

The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models used in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long-term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.g. insulin) are evident. In addition, behavioural models such as the behavioural satiety sequence can be used to confirm that a drug treatment has a selective effect on food intake. Typically, animal models have excellent predictive validity whereby drug-induced weight loss in rodents subsequently translates to weight loss in man. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events. While the utility of rodent models in predicting clinical weight loss is detailed, the review also discusses whether animals can be used to predict adverse events such as those seen with recent anti-obesity drugs in the clinic. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21265828

Concise review: Patient-derived olfactory stem cells: new models for brain diseases.

PubMed

Mackay-Sim, Alan

2012-11-01

Traditional models of brain diseases have had limited success in driving candidate drugs into successful clinical translation. This has resulted in large international pharmaceutical companies moving out of neuroscience research. Cells are not brains, obviously, but new patient-derived stem models have the potential to elucidate cell biological aspects of brain diseases that are not present in worm, fly, or rodent models, the work horses of disease investigations and drug discovery. Neural stem cells are present in the olfactory mucosa, the organ of smell in the nose. Patient-derived olfactory mucosa has demonstrated disease-associated differences in a variety of brain diseases and recently olfactory mucosa stem cells have been generated from patients with schizophrenia, Parkinson's disease, and familial dysautonomia. By comparison with cells from healthy controls, patient-derived olfactory mucosa stem cells show disease-specific alterations in gene expression and cell functions including: a shorter cell cycle and faster proliferation in schizophrenia, oxidative stress in Parkinson's disease, and altered cell migration in familial dysautonomia. Olfactory stem cell cultures thus reveal patient-control differences, even in complex genetic diseases such as schizophrenia and Parkinson's disease, indicating that multiple genes of small effect can converge on shared cell signaling pathways to present as a disease-specific cellular phenotype. Olfactory mucosa stem cells can be maintained in homogeneous cultures that allow robust and repeatable multiwell assays suitable for screening libraries of drug candidate molecules. Copyright © 2012 AlphaMed Press.

Urban resident attitudes toward rodents, rodent control products, and environmental effects

EPA Science Inventory

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...

Rodent models of insomnia: a review of experimental procedures that induce sleep disturbances.

PubMed

Revel, Florent G; Gottowik, Juergen; Gatti, Sylvia; Wettstein, Joseph G; Moreau, Jean-Luc

2009-06-01

Insomnia, the most common sleep disorder, is characterized by persistent difficulty in falling or staying asleep despite adequate opportunity to sleep, leading to daytime fatigue and mental dysfunction. As sleep is a sophisticated physiological process generated by a network of neuronal systems that cannot be reproduced in-vitro, pre-clinical development of hypnotic drugs requires in-vivo investigations. Accordingly, this review critically evaluates current and putative rodent models of insomnia which could be used to screen novel hypnotics. Only few valid insomnia models are currently available, although many experimental conditions lead to disturbance of physiological sleep. We categorized these conditions as a function of the procedure used to induce perturbation of sleep, and we discuss their respective advantages and pitfalls with respect to validity, feasibility and translational value to human research.

The Role of Estrogens in Pancreatic Islet Physiopathology.

PubMed

Mauvais-Jarvis, Franck; Le May, Cedric; Tiano, Joseph P; Liu, Suhuan; Kilic-Berkmen, Gamze; Kim, Jun Ho

2017-01-01

In rodent models of insulin-deficient diabetes, 17β-estradiol (E2) protects pancreatic insulin-producing β-cells against oxidative stress, amyloid polypeptide toxicity, gluco-lipotoxicity, and apoptosis. Three estrogen receptors (ERs)-ERα, ERβ, and the G protein-coupled ER (GPER)-have been identified in rodent and human β-cells. This chapter describes recent advances in our understanding of the role of ERs in islet β-cell function, nutrient homeostasis, survival from pro-apoptotic stimuli, and proliferation. We discuss why and how ERs represent potential therapeutic targets for the maintenance of functional β-cell mass.

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

PubMed

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.

Using Modelling to Disentangle the Relative Contributions of Zoonotic and Anthroponotic Transmission: The Case of Lassa Fever

PubMed Central

Lo Iacono, Giovanni; Cunningham, Andrew A.; Fichet-Calvet, Elisabeth; Garry, Robert F.; Grant, Donald S.; Khan, Sheik Humarr; Leach, Melissa; Moses, Lina M.; Schieffelin, John S.; Shaffer, Jeffrey G.; Webb, Colleen T.; Wood, James L. N.

2015-01-01

Background Zoonotic infections, which transmit from animals to humans, form the majority of new human pathogens. Following zoonotic transmission, the pathogen may already have, or may acquire, the ability to transmit from human to human. With infections such as Lassa fever (LF), an often fatal, rodent-borne, hemorrhagic fever common in areas of West Africa, rodent-to-rodent, rodent-to-human, human-to-human and even human-to-rodent transmission patterns are possible. Indeed, large hospital-related outbreaks have been reported. Estimating the proportion of transmission due to human-to-human routes and related patterns (e.g. existence of super-spreaders), in these scenarios is challenging, but essential for planned interventions. Methodology/Principal Findings Here, we make use of an innovative modeling approach to analyze data from published outbreaks and the number of LF hospitalized patients to Kenema Government Hospital in Sierra Leone to estimate the likely contribution of human-to-human transmission. The analyses show that almost of the cases at KGH are secondary cases arising from human-to-human transmission. However, we found much of this transmission is associated with a disproportionally large impact of a few individuals (‘super-spreaders’), as we found only of human cases result in an effective reproduction number (i.e. the average number of secondary cases per infectious case) , with a maximum value up to . Conclusions/Significance This work explains the discrepancy between the sizes of reported LF outbreaks and a clinical perception that human-to-human transmission is low. Future assessment of risks of LF and infection control guidelines should take into account the potentially large impact of super-spreaders in human-to-human transmission. Our work highlights several neglected topics in LF research, the occurrence and nature of super-spreading events and aspects of social behavior in transmission and detection. PMID:25569707

Using modelling to disentangle the relative contributions of zoonotic and anthroponotic transmission: the case of lassa fever.

PubMed

Lo Iacono, Giovanni; Cunningham, Andrew A; Fichet-Calvet, Elisabeth; Garry, Robert F; Grant, Donald S; Khan, Sheik Humarr; Leach, Melissa; Moses, Lina M; Schieffelin, John S; Shaffer, Jeffrey G; Webb, Colleen T; Wood, James L N

2015-01-01

Zoonotic infections, which transmit from animals to humans, form the majority of new human pathogens. Following zoonotic transmission, the pathogen may already have, or may acquire, the ability to transmit from human to human. With infections such as Lassa fever (LF), an often fatal, rodent-borne, hemorrhagic fever common in areas of West Africa, rodent-to-rodent, rodent-to-human, human-to-human and even human-to-rodent transmission patterns are possible. Indeed, large hospital-related outbreaks have been reported. Estimating the proportion of transmission due to human-to-human routes and related patterns (e.g. existence of super-spreaders), in these scenarios is challenging, but essential for planned interventions. Here, we make use of an innovative modeling approach to analyze data from published outbreaks and the number of LF hospitalized patients to Kenema Government Hospital in Sierra Leone to estimate the likely contribution of human-to-human transmission. The analyses show that almost [Formula: see text] of the cases at KGH are secondary cases arising from human-to-human transmission. However, we found much of this transmission is associated with a disproportionally large impact of a few individuals ('super-spreaders'), as we found only [Formula: see text] of human cases result in an effective reproduction number (i.e. the average number of secondary cases per infectious case) [Formula: see text], with a maximum value up to [Formula: see text]. This work explains the discrepancy between the sizes of reported LF outbreaks and a clinical perception that human-to-human transmission is low. Future assessment of risks of LF and infection control guidelines should take into account the potentially large impact of super-spreaders in human-to-human transmission. Our work highlights several neglected topics in LF research, the occurrence and nature of super-spreading events and aspects of social behavior in transmission and detection.

Animal reservoir, natural and socioeconomic variations and the transmission of hemorrhagic fever with renal syndrome in Chenzhou, China, 2006-2010.

PubMed

Xiao, Hong; Tian, Huai-Yu; Gao, Li-Dong; Liu, Hai-Ning; Duan, Liang-Song; Basta, Nicole; Cazelles, Bernard; Li, Xiu-Jun; Lin, Xiao-Ling; Wu, Hong-Wei; Chen, Bi-Yun; Yang, Hui-Suo; Xu, Bing; Grenfell, Bryan

2014-01-01

China has the highest incidence of hemorrhagic fever with renal syndrome (HFRS) worldwide. Reported cases account for 90% of the total number of global cases. By 2010, approximately 1.4 million HFRS cases had been reported in China. This study aimed to explore the effect of the rodent reservoir, and natural and socioeconomic variables, on the transmission pattern of HFRS. Data on monthly HFRS cases were collected from 2006 to 2010. Dynamic rodent monitoring data, normalized difference vegetation index (NDVI) data, climate data, and socioeconomic data were also obtained. Principal component analysis was performed, and the time-lag relationships between the extracted principal components and HFRS cases were analyzed. Polynomial distributed lag (PDL) models were used to fit and forecast HFRS transmission. Four principal components were extracted. Component 1 (F1) represented rodent density, the NDVI, and monthly average temperature. Component 2 (F2) represented monthly average rainfall and monthly average relative humidity. Component 3 (F3) represented rodent density and monthly average relative humidity. The last component (F4) represented gross domestic product and the urbanization rate. F2, F3, and F4 were significantly correlated, with the monthly HFRS incidence with lags of 4 months (r = -0.289, P<0.05), 5 months (r = -0.523, P<0.001), and 0 months (r = -0.376, P<0.01), respectively. F1 was correlated with the monthly HFRS incidence, with a lag of 4 months (r = 0.179, P = 0.192). Multivariate PDL modeling revealed that the four principal components were significantly associated with the transmission of HFRS. The monthly trend in HFRS cases was significantly associated with the local rodent reservoir, climatic factors, the NDVI, and socioeconomic conditions present during the previous months. The findings of this study may facilitate the development of early warning systems for the control and prevention of HFRS and similar diseases.

Dye-enhanced visualization of rat whiskers for behavioral studies.

PubMed

Rigosa, Jacopo; Lucantonio, Alessandro; Noselli, Giovanni; Fassihi, Arash; Zorzin, Erik; Manzino, Fabrizio; Pulecchi, Francesca; Diamond, Mathew E

2017-06-14

Visualization and tracking of the facial whiskers is required in an increasing number of rodent studies. Although many approaches have been employed, only high-speed videography has proven adequate for measuring whisker motion and deformation during interaction with an object. However, whisker visualization and tracking is challenging for multiple reasons, primary among them the low contrast of the whisker against its background. Here, we demonstrate a fluorescent dye method suitable for visualization of one or more rat whiskers. The process makes the dyed whisker(s) easily visible against a dark background. The coloring does not influence the behavioral performance of rats trained on a vibrissal vibrotactile discrimination task, nor does it affect the whiskers' mechanical properties.

Clinical and pathological manifestations of cardiovascular disease in rat models: the influence of acute ozone exposure

EPA Science Inventory

This paper shows that rat models of cardiovascular diseases have differential degrees of underlying pathologies at a young age. Rodent models of cardiovascular diseases (CVD) and metabolic disorders are used for examining susceptibility variations to environmental exposures. How...

Leveraging Small Aquarium Fishes to Advance Understanding of Environmentally Influenced Human Disorders and Diseases

EPA Science Inventory

Small aquarium fishes provide a model organism that recapitulates the development, physiology and specific disease processes present in humans without the many limitations of rodent-based models currently in use. Fish models offer advantages in cost, rapid life-cycles, and extern...

More than two decades of Apc modeling in rodents

PubMed Central

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

Setting the main circadian clock of a diurnal mammal by hypocaloric feeding

PubMed Central

Mendoza, Jorge; Gourmelen, Sylviane; Dumont, Stephanie; Sage-Ciocca, Dominique; Pévet, Paul; Challet, Etienne

2012-01-01

Caloric restriction attenuates the onset of a number of pathologies related to ageing. In mammals, circadian rhythms, controlled by the hypothalamic suprachiasmatic (SCN) clock, are altered with ageing. Although light is the main synchronizer for the clock, a daily hypocaloric feeding (HF) may also modulate the SCN activity in nocturnal rodents. Here we report that a HF also affects behavioural, physiological and molecular circadian rhythms of the diurnal rodent Arvicanthis ansorgei. Under constant darkness HF, but not normocaloric feeding (NF), entrains circadian behaviour. Under a light–dark cycle, HF at midnight led to phase delays of the rhythms of locomotor activity and plasma corticosterone. Furthermore, Per2 and vasopressin gene oscillations in the SCN were phase delayed in HF Arvicanthis compared with animals fed ad libitum. Moreover, light-induced expression of Per genes in the SCN was modified in HF Arvicanthis, despite a non-significant effect on light-induced behavioural phase delays. Together, our data show that HF affects the circadian system of the diurnal rodent Arvicanthis ansorgei differentially from nocturnal rodents. The Arvicanthis model has relevance for the potential use of HF to manipulate circadian rhythms in diurnal species including humans. PMID:22570380

Ultrasonic vocalisation emitted by infant rodents: a tool for assessment of neurobehavioural development.

PubMed

Branchi, I; Santucci, D; Alleva, E

2001-11-01

Ultrasonic vocalisations (USVs) emitted by altricial rodent pups are whistle-like sounds with frequencies between 30 and 90 kHz. These signals play an important communicative role in mother-offspring interaction since they elicit in the dam a prompt response concerning caregiving behaviours. Both physical and social parameters modulate the USV emission in the infant rodent. Recently, a more detailed analysis of the ultrasonic vocalisation pattern, considering the spectrographic structure of sounds has allowed a deeper investigation of this behaviour. In order to investigate neurobehavioural development, the analysis of USVs presents several advantages, mainly: (i) USVs are one of the few responses produced by very young mice that can be quantitatively analysed and elicited by quantifiable stimuli; (ii) USV production follows a clear ontogenetic profile from birth to PND 14-15, thus allowing longitudinal neurobehavioural analysis during very early postnatal ontogeny. The study of this ethologically-ecologically relevant behaviour represent a valid model to evaluate possible alterations in the neurobehavioural development of perinatally treated or genetically modified infant rodents. Furthermore, the role played by several receptor agonists and antagonists in modulating USV rate makes this measure particularly important when investigating the effects of anxiogenic and anxiolytic compounds, and emotional behaviour in general.

Behavioral and physiological consequences of enrichment loss in rats

PubMed Central

Smith, Brittany L.; Lyons, Carey E; Correa, Fernanda Guilhaume; Benoit, Stephen C.; Myers, Brent; Solomon, Matia B.; Herman, James P.

2017-01-01

Significant loss produces the highest degree of stress and compromised well-being in humans. Current rodent models of stress involve the application of physically or psychologically aversive stimuli, but do not address the concept of loss. We developed a rodent model for significant loss, involving removal of long-term access to a rewarding enriched environment. Our results indicate that removal from environmental enrichment produces a profound behavioral and physiological phenotype with depression-like qualities, including helplessness behavior, hypothalamo-pituitary-adrenocortical axis dysregulation and overeating. Importantly, this enrichment removal phenotype was prevented by antidepressant treatment. Furthermore, the effects of enrichment removal do not occur following relief from chronic stress and are not duplicated by loss of exercise or social contact. PMID:28012292

Hantavirus Immunology of Rodent Reservoirs: Current Status and Future Directions

PubMed Central

Schountz, Tony; Prescott, Joseph

2014-01-01

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. PMID:24638205

Hantavirus immunology of rodent reservoirs: current status and future directions.

PubMed

Schountz, Tony; Prescott, Joseph

2014-03-14

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.

Antitumor Efficacy Testing in Rodents

PubMed Central

2008-01-01

The preclinical research and human clinical trials necessary for developing anticancer therapeutics are costly. One contributor to these costs is preclinical rodent efficacy studies, which, in addition to the costs associated with conducting them, often guide the selection of agents for clinical development. If inappropriate or inaccurate recommendations are made on the basis of these preclinical studies, then additional costs are incurred. In this commentary, I discuss the issues associated with preclinical rodent efficacy studies. These include the identification of proper preclinical efficacy models, the selection of appropriate experimental endpoints, and the correct statistical evaluation of the resulting data. I also describe important experimental design considerations, such as selecting the drug vehicle, optimizing the therapeutic treatment plan, properly powering the experiment by defining appropriate numbers of replicates in each treatment arm, and proper randomization. Improved preclinical selection criteria can aid in reducing unnecessary human studies, thus reducing the overall costs of anticancer drug development. PMID:18957675

Dendrimer-driven neurotrophin expression differs in temporal patterns between rodent and human stem cells.

PubMed

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.

Perceptual Decision Making in Rodents, Monkeys, and Humans.

PubMed

Hanks, Timothy D; Summerfield, Christopher

2017-01-04

Perceptual decision making is the process by which animals detect, discriminate, and categorize information from the senses. Over the past two decades, understanding how perceptual decisions are made has become a central theme in the neurosciences. Exceptional progress has been made by recording from single neurons in the cortex of the macaque monkey and using computational models from mathematical psychology to relate these neural data to behavior. More recently, however, the range of available techniques and paradigms has dramatically broadened, and researchers have begun to harness new approaches to explore how rodents and humans make perceptual decisions. The results have illustrated some striking convergences with findings from the monkey, but also raised new questions and provided new theoretical insights. In this review, we summarize key findings, and highlight open challenges, for understanding perceptual decision making in rodents, monkeys, and humans. Copyright © 2017 Elsevier Inc. All rights reserved.

Environmental variability and the transmission of haemorrhagic fever with renal syndrome in Changsha, People's Republic of China.

PubMed

Xiao, H; Gao, L D; Li, X J; Lin, X L; Dai, X Y; Zhu, P J; Chen, B Y; Zhang, X X; Zhao, J; Tian, H Y

2013-09-01

The transmission of haemorrhagic fever with renal syndrome (HFRS) is influenced by climatic, reservoir and environmental variables. The epidemiology of the disease was studied over a 6-year period in Changsha. Variables relating to climate, environment, rodent host distribution and disease occurrence were collected monthly and analysed using a time-series adjusted Poisson regression model. It was found that the density of the rodent host and multivariate El Niño Southern Oscillation index had the greatest effect on the transmission of HFRS with lags of 2–6 months. However, a number of climatic and environmental factors played important roles in affecting the density and transmission potential of the rodent host population. It was concluded that the measurement of a number of these variables could be used in disease surveillance to give useful advance warning of potential disease epidemics.

Rodent wearable ultrasound system for wireless neural recording.

PubMed

Piech, David K; Kay, Joshua E; Boser, Bernhard E; Maharbiz, Michel M

2017-07-01

Advances in minimally-invasive, distributed biological interface nodes enable possibilities for networks of sensors and actuators to connect the brain with external devices. The recent development of the neural dust sensor mote has shown that utilizing ultrasound backscatter communication enables untethered sub-mm neural recording devices. These implanted sensor motes require a wearable external ultrasound interrogation device to enable in-vivo, freely-behaving neural interface experiments. However, minimizing the complexity and size of the implanted sensors shifts the power and processing burden to the external interrogator. In this paper, we present an ultrasound backscatter interrogator that supports real-time backscatter processing in a rodent-wearable, completely wireless device. We demonstrate a generic digital encoding scheme which is intended for transmitting neural information. The system integrates a front-end ultrasonic interface ASIC with off-the-shelf components to enable a highly compact ultrasound interrogation device intended for rodent neural interface experiments but applicable to other model systems.

The touchscreen operant platform for testing learning and memory in rats and mice

PubMed Central

Horner, Alexa E.; Heath, Christopher J.; Hvoslef-Eide, Martha; Kent, Brianne A.; Kim, Chi Hun; Nilsson, Simon R. O.; Alsiö, Johan; Oomen, Charlotte A.; Holmes, Andrew; Saksida, Lisa M.; Bussey, Timothy J.

2014-01-01

Summary An increasingly popular method of assessing cognitive functions in rodents is the automated touchscreen platform, on which a number of different cognitive tests can be run in a manner very similar to touchscreen methods currently used to test human subjects. This methodology is low stress (using appetitive, rather than aversive reinforcement), has high translational potential, and lends itself to a high degree of standardisation and throughput. Applications include the study of cognition in rodent models of psychiatric and neurodegenerative diseases (e.g., Alzheimer’s disease, schizophrenia, Huntington’s disease, frontotemporal dementia), and characterisation of the role of select brain regions, neurotransmitter systems and genes in rodents. This protocol describes how to perform four touchscreen assays of learning and memory: Visual Discrimination, Object-Location Paired-Associates Learning, Visuomotor Conditional Learning and Autoshaping. It is accompanied by two further protocols using the touchscreen platform to assess executive function, working memory and pattern separation. PMID:24051959

Zoonoses of rabbits and rodents.

PubMed

Hill, William Allen; Brown, Julie Paige

2011-09-01

Millions of households in the US own rabbits or rodents, including hamsters, guinea pigs, and gerbils. Activities such as hunting and camping also involve human interactions with wild rabbits and rodents. In many environments, feral rabbits and rodents live in close proximity to humans, domesticated animals, and other wildlife. Education of rodent and rabbit owners and individuals with occupational or recreational exposures to these species is paramount to reduce the prevalence of zoonoses associated with rabbit and rodent exposure.

Lassa serology in natural populations of rodents and horizontal transmission.

PubMed

Fichet-Calvet, Elisabeth; Becker-Ziaja, Beate; Koivogui, Lamine; Günther, Stephan

2014-09-01

Lassa virus causes hemorrhagic fever in West Africa. Previously, we demonstrated by PCR screening that only the multimammate mouse, Mastomys natalensis, hosts Lassa virus in Guinea. In the present study, we used the same specimen collection from 17 villages in Coastal, Upper, and Forest Guinea to investigate the Lassa virus serology in the rodent population. The aim was to determine the dynamics of antibody development in M. natalensis and to detect potential spillover infections in other rodent species. Immunoglobulin G (IgG) antibody screening was performed using the indirect immunofluorescence assay with the Guinean Lassa virus strain Bantou 289 as antigen. The overall seroprevalence was 8% (129/1551) with the following rodents testing positive: 109 M. natalensis, seven Mastomys erythroleucus, four Lemniscomys striatus, four Praomys daltoni, three Mus minutoides, and two Praomys rostratus. Nearly all of them (122/129) originated from Bantou, Tanganya, and Gbetaya, where Lassa virus is highly endemic in M. natalensis. The antibody seroprevalence in M. natalensis from this high-endemic area (27%; 108/396) depended on the village, habitat, host age, and host abundance. A main positive factor was age; the maximum seroprevalence reached 50% in older animals. Our data fit with a model implicating that most M. natalensis rodents become horizontally infected, clear the virus within a period significantly shorter than their life span, and develop antibodies. In addition, the detection of antibodies in other species trapped in the habitats of M. natalensis suggests spillover infections.

Rodent models in Down syndrome research: impact and future opportunities

PubMed Central

2017-01-01

ABSTRACT Down syndrome is caused by trisomy of chromosome 21. To date, a multiplicity of mouse models with Down-syndrome-related features has been developed to understand this complex human chromosomal disorder. These mouse models have been important for determining genotype-phenotype relationships and identification of dosage-sensitive genes involved in the pathophysiology of the condition, and in exploring the impact of the additional chromosome on the whole genome. Mouse models of Down syndrome have also been used to test therapeutic strategies. Here, we provide an overview of research in the last 15 years dedicated to the development and application of rodent models for Down syndrome. We also speculate on possible and probable future directions of research in this fast-moving field. As our understanding of the syndrome improves and genome engineering technologies evolve, it is necessary to coordinate efforts to make all Down syndrome models available to the community, to test therapeutics in models that replicate the whole trisomy and design new animal models to promote further discovery of potential therapeutic targets. PMID:28993310

Rodent models in Down syndrome research: impact and future opportunities.

PubMed

Herault, Yann; Delabar, Jean M; Fisher, Elizabeth M C; Tybulewicz, Victor L J; Yu, Eugene; Brault, Veronique

2017-10-01

Down syndrome is caused by trisomy of chromosome 21. To date, a multiplicity of mouse models with Down-syndrome-related features has been developed to understand this complex human chromosomal disorder. These mouse models have been important for determining genotype-phenotype relationships and identification of dosage-sensitive genes involved in the pathophysiology of the condition, and in exploring the impact of the additional chromosome on the whole genome. Mouse models of Down syndrome have also been used to test therapeutic strategies. Here, we provide an overview of research in the last 15 years dedicated to the development and application of rodent models for Down syndrome. We also speculate on possible and probable future directions of research in this fast-moving field. As our understanding of the syndrome improves and genome engineering technologies evolve, it is necessary to coordinate efforts to make all Down syndrome models available to the community, to test therapeutics in models that replicate the whole trisomy and design new animal models to promote further discovery of potential therapeutic targets. © 2017. Published by The Company of Biologists Ltd.

Relevance of Rodent Models of Depression in Clinical Practice: Can We Overcome the Obstacles in Translational Neuropsychiatry?

PubMed

Söderlund, Johan; Lindskog, Maria

2018-04-23

The diagnosis of a mental disorder generally depends on clinical observations and phenomenological symptoms reported by the patient. The definition of a given diagnosis is criteria based and relies on the ability to accurately interpret subjective symptoms and complex behavior. This type of diagnosis comprises a challenge to translate to reliable animal models, and these translational uncertainties hamper the development of new treatments. In this review, we will discuss how depressive-like behavior can be induced in rodents, and the relationship between these models and depression in humans. Specifically, we suggest similarities between triggers of depressive-like behavior in animal models and human conditions known to increase the risk of depression, for example exhaustion and bullying. Although we acknowledge the potential problems in comparing animal findings to human conditions, such comparisons are useful for understanding the complexity of depression, and we highlight the need to develop clinical diagnoses and animal models in parallel to overcome translational uncertainties.

Intrinsic neurophysiological properties of hilar ectopic and normotopic dentate granule cells in human temporal lobe epilepsy and a rat model.

PubMed

Althaus, A L; Sagher, O; Parent, J M; Murphy, G G

2015-02-15

Hilar ectopic dentate granule cells (DGCs) are a salient feature of aberrant plasticity in human temporal lobe epilepsy (TLE) and most rodent models of the disease. Recent evidence from rodent TLE models suggests that hilar ectopic DGCs contribute to hyperexcitability within the epileptic hippocampal network. Here we investigate the intrinsic excitability of DGCs from humans with TLE and the rat pilocarpine TLE model with the objective of comparing the neurophysiology of hilar ectopic DGCs to their normotopic counterparts in the granule cell layer (GCL). We recorded from 36 GCL and 7 hilar DGCs from human TLE tissue. Compared with GCL DGCs, hilar DGCs in patient tissue exhibited lower action potential (AP) firing rates, more depolarized AP threshold, and differed in single AP waveform, consistent with an overall decrease in excitability. To evaluate the intrinsic neurophysiology of hilar ectopic DGCs, we made recordings from retrovirus-birthdated, adult-born DGCs 2-4 mo after pilocarpine-induced status epilepticus or sham treatment in rats. Hilar DGCs from epileptic rats exhibited higher AP firing rates than normotopic DGCs from epileptic or control animals. They also displayed more depolarized resting membrane potential and wider AP waveforms, indicating an overall increase in excitability. The contrasting findings between disease and disease model may reflect differences between the late-stage disease tissue available from human surgical specimens and the earlier disease stage examined in the rat TLE model. These data represent the first neurophysiological characterization of ectopic DGCs from human hippocampus and prospectively birthdated ectopic DGCs in a rodent TLE model. Copyright © 2015 the American Physiological Society.

Pulmonary Complications Resulting from Genetic Cardiovascular Disease in Two Rat Models

EPA Science Inventory

Underlying cardiovascular disease (CVD) has been considered a risk factor for exacerbation of air pollution health effects. Therefore, rodent models of CVD are increasingly used to examine mechanisms of variation in susceptibility. Pulmonary complications and altered iron homeost...

THE SPONTANEOUSLY HYPERTENSIVE RAT: AN EXPERIMENTAL MODEL OF SULFUR DIOXIDE-INDUCED AIRWAYS DISEASE

EPA Science Inventory

Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction, inflammation and mucus hypersecretion; features that capture bronchitis, emphysema and often asthma. However, current rodent models do not reflect this human disease. Because genetically predisp...

The Effects of Fortetropin Supplementation on Body Composition, Strength, and Power in Humans and Mechanism of Action in a Rodent Model.

PubMed

Sharp, Matthew H; Lowery, Ryan P; Mobley, C Brooks; Fox, Carlton D; de Souza, Eduardo O; Shields, Kevin A; Healy, James C; Arick, Ned Q; Thompson, Richard M; Roberts, Michael D; Wilson, Jacob M

2016-01-01

The purpose of this study was to investigate the effects of Fortetropin on skeletal muscle growth and strength in resistance-trained individuals and to investigate the anabolic and catabolic signaling effects using human and rodent models. In the rodent model, male Wistar rats (250 g) were gavage fed with either 1.2 ml of tap water control (CTL) or 0.26 g Fortetropin for 8 days. Then rats participated in a unilateral plantarflexion exercise bout. Nonexercised and exercised limbs were harvested at 180 minutes following and analyzed for gene and protein expression relative to mammalian target of rapamycin (mTOR) and ubiquitin signaling. For the human model, 45 (of whom 37 completed the study), resistance-trained college-aged males were divided equally into 3 groups receiving a placebo macronutrient matched control, 6.6 or 19.8 g of Fortetropin supplementation during 12 weeks of resistance training. Lean mass, muscle thickness, and lower and upper body strength were measured before and after 12 weeks of training. The human study results indicated a Group × Time effect (p ≤ 0.05) for lean mass in which the 6.6 g (+1.7 kg) and 19.8 g (+1.68 kg) but not placebo (+0.6 kg) groups increased lean mass. Similarly, there was a Group × Time effect for muscle thickness (p ≤ 0.05), which increased in the experimental groups only. All groups increased equally in bench press and leg press strength. In the rodent model, a main effect for exercise (p ≤ 0.05) in which the control plus exercise but not Fortetropin plus exercise increased both ubiquitin monomer protein expression and polyubiquitination. mTOR signaling was elevated to a greater extent in the Fortetropin exercising conditions as indicated by greater phosphorylation status of 4EBP1, rp6, and p70S6K for both exercising conditions. Fortetropin supplementation increases lean body mass (LBM) and decreases markers of protein breakdown while simultaneously increasing mTOR signaling.

Automated registration of tail bleeding in rats.

PubMed

Johansen, Peter B; Henriksen, Lars; Andresen, Per R; Lauritzen, Brian; Jensen, Kåre L; Juhl, Trine N; Tranholm, Mikael

2008-05-01

An automated system for registration of tail bleeding in rats using a camera and a user-designed PC-based software program has been developed. The live and processed images are displayed on the screen and are exported together with a text file for later statistical processing of the data allowing calculation of e.g. number of bleeding episodes, bleeding times and bleeding areas. Proof-of-principle was achieved when the camera captured the blood stream after infusion of rat whole blood into saline. Suitability was assessed by recording of bleeding profiles in heparin-treated rats, demonstrating that the system was able to capture on/off bleedings and that the data transfer and analysis were conducted successfully. Then, bleeding profiles were visually recorded by two independent observers simultaneously with the automated recordings after tail transection in untreated rats. Linear relationships were found in the number of bleedings, demonstrating, however, a statistically significant difference in the recording of bleeding episodes between observers. Also, the bleeding time was longer for visual compared to automated recording. No correlation was found between blood loss and bleeding time in untreated rats, but in heparinized rats a correlation was suggested. Finally, the blood loss correlated with the automated recording of bleeding area. In conclusion, the automated system has proven suitable for replacing visual recordings of tail bleedings in rats. Inter-observer differences can be eliminated, monotonous repetitive work avoided, and a higher through-put of animals in less time achieved. The automated system will lead to an increased understanding of the nature of bleeding following tail transection in different rodent models.

Unilateral brain hypothermia as a method to examine efficacy and mechanisms of neuroprotection against global ischemia.

PubMed

Silasi, Gergely; Colbourne, Frederick

2011-01-01

Hypothermia, especially applied during ischemia, is the gold-standard neuroprotectant. When delayed, cooling must often be maintained for a day or more to achieve robust, permanent protection. Most animal and clinical studies use whole-body cooling-an arduous technique that can cause systemic complications. Brain-selective cooling may avoid such problems. Thus, in this rat study, we used a method that cools one hemisphere without affecting the contralateral side or the body. Localized brain hypothermia was achieved by flushing cold water through a metal tube attached to the rats' skull. First, in anesthetized rats we measured temperature in the cooled and contralateral hemisphere to demonstrate selective unilateral cooling. Subsequent telemetry recordings in awake rats confirmed that brain cooling did not cause systemic hypothermia during prolonged treatment. Additionally, we subjected rats to transient global ischemia and after recovering from anesthesia they remained at normothermia or had their right hemisphere cooled for 2 days (∼32°C-33°C). Hypothermia significantly lessened CA1 injury and microglia activation on the right side at 1 and 4 week survival times. Near-complete injury and a strong microglia response occurred in the left (normothermic) hippocampus as occurred in both hippocampi of the untreated group. Thus, this focal cooling method is suitable for evaluating the efficacy and mechanisms of hypothermic neuroprotection in global ischemia models. This method also has advantages over many current systemic cooling protocols in rodents, namely: (1) lower cost, (2) simplicity, (3) safety and suitability for long-term cooling, and (4) an internal control-the normothermic hemisphere.

Screening and Characterization of Spontaneous Porcine Congenital Heart Defects for Gene Identification and Models of Human Disease

USDA-ARS?s Scientific Manuscript database

Background: Rodent models of human congenital birth defects have been instrumental for gene discovery and investigation of mechanisms of disease. However, these models are limited by their small size making practiced intervention or detailed anatomic evaluation difficult. Swine have similar anato...

Exposure to chronic variable social stress during adolescence alters affect-related behaviors and adrenocortical activity in adult male and female inbred mice.

PubMed

Caruso, Michael J; Kamens, Helen M; Cavigelli, Sonia A

2017-09-01

Rodent models provide valuable insight into mechanisms that underlie vulnerability to adverse effects of early-life challenges. Few studies have evaluated sex differences in anxiogenic or depressogenic effects of adolescent social stress in a rodent model. Furthermore, adolescent stress studies often use genetically heterogeneous outbred rodents which can lead to variable results. The current study evaluated the effects of adolescent social stress in male and female inbred (BALB/cJ) mice. Adolescent mice were exposed to repeat cycles of alternating social isolation and social novelty for 4 weeks. Adolescent social stress increased anxiety-related behaviors in both sexes and depression-related behavior in females. Locomotion/exploratory behavior was also decreased in both sexes by stress. Previously stressed adult mice produced less basal fecal corticosteroids than controls. Overall, the novel protocol induced sex-specific changes in anxiety- and depression-related behaviors and corticoid production in inbred mice. The chronic variable social stress protocol used here may be beneficial to systematically investigate sex-specific neurobiological mechanisms underlying adolescent stress vulnerability where genetic background can be controlled. © 2017 Wiley Periodicals, Inc.

Genotoxic evaluation of pirfenidone using erythrocyte rodent micronucleus assay.

PubMed

Alcántar-Díaz, Blanca E; Gómez-Meda, Belinda C; Zúñiga-González, Guillermo M; Zamora-Perez, Ana L; González-Cuevas, Jaime; Alvarez-Rodríguez, Bertha A; Sánchez-Parada, María Guadalupe; García-Bañuelos, Jesús J; Armendáriz-Borunda, Juan

2012-08-01

Pirfenidone is a non-steroidal antifibrotic compound that has been proposed in clinical protocols and experimental studies as a pharmacological treatment for fibroproliferative diseases. The objective of this study was to determine the genotoxicity or cytotoxicity of three doses of pirfenidone using the micronuclei test in peripheral blood erythrocytes of rodent models. Pirfenidone was administered orally to Balb-C mice for 3 days, and also was administered topically to hairless Sprague Dawley rats during the final stage of gestation. Mice were sampled every 24 h over the course of 6 days; pregnant rats were sampled every 24 h during the last 6 days of gestation, and pups were sampled at birth. Blood smears were analyzed and the frequencies of micronucleated erythrocytes (MNEs), micronucleated polychromatic erythrocytes (MNPCEs), and the proportion of polychromatic erythrocytes (PCEs), were recorded in samples from mice, pregnant rats and rat neonates. Increases in MN frequencies (p<0.03) were noted only in the positive control groups. No genotoxic effects or decreased PCE values were observed neither in newborn rats transplacentally exposed to pirfenidone, or in two adult rodent models when pirfenidone was administered orally or topically. Copyright © 2012 Elsevier Ltd. All rights reserved.

Amyloid β Enhances Typical Rodent Behavior While It Impairs Contextual Memory Consolidation.

PubMed

Salgado-Puga, Karla; Prado-Alcalá, Roberto A; Peña-Ortega, Fernando

2015-01-01

Alzheimer's disease (AD) is associated with an early hippocampal dysfunction, which is likely induced by an increase in soluble amyloid beta peptide (Aβ). This hippocampal failure contributes to the initial memory deficits observed both in patients and in AD animal models and possibly to the deterioration in activities of daily living (ADL). One typical rodent behavior that has been proposed as a hippocampus-dependent assessment model of ADL in mice and rats is burrowing. Despite the fact that AD transgenic mice show some evidence of reduced burrowing, it has not been yet determined whether or not Aβ can affect this typical rodent behavior and whether this alteration correlates with the well-known Aβ-induced memory impairment. Thus, the purpose of this study was to test whether or not Aβ affects burrowing while inducing hippocampus-dependent memory impairment. Surprisingly, our results show that intrahippocampal application of Aβ increases burrowing while inducing memory impairment. We consider that this Aβ-induced increase in burrowing might be associated with a mild anxiety state, which was revealed by increased freezing behavior in the open field, and conclude that Aβ-induced hippocampal dysfunction is reflected in the impairment of ADL and memory, through mechanisms yet to be determined.

Consumption of Substances of Abuse during Pregnancy Increases Consumption in Offspring: Possible Underlying Mechanisms

PubMed Central

Poon, Kinning; Leibowitz, Sarah F.

2016-01-01

Correlative human observational studies on substances of abuse have been highly dependent on the use of rodent models to determine the neuronal and molecular mechanisms that control behavioral outcomes. This is particularly true for gestational exposure to non-illicit substances of abuse, such as excessive dietary fat, ethanol, and nicotine, which are commonly consumed in our society. Exposure to these substances during the prenatal period has been shown in offspring to increase their intake of these substances, induce other behavioral changes, and affect neurochemical systems in several brain areas that are known to control behavior. More importantly, emerging studies are linking the function of the immune system to these neurochemicals and ingestion of these abused substances. This review article will summarize the prenatal rodent models used to study developmental changes in offspring caused by prenatal exposure to dietary fat, ethanol, or nicotine. We will discuss the various techniques used for the administration of these substances into rodents and summarize the published outcomes induced by prenatal exposure to these substances. Finally, this review will cover some of the recent evidence for the role of immune factors in causing these behavioral and neuronal changes. PMID:27148536

Sub-processes of motor learning revealed by a robotic manipulandum for rodents.

PubMed

Lambercy, O; Schubring-Giese, M; Vigaru, B; Gassert, R; Luft, A R; Hosp, J A

2015-02-01

Rodent models are widely used to investigate neural changes in response to motor learning. Usually, the behavioral readout of motor learning tasks used for this purpose is restricted to a binary measure of performance (i.e. "successful" movement vs. "failure"). Thus, the assignability of research in rodents to concepts gained in human research - implying diverse internal models that constitute motor learning - is still limited. To solve this problem, we recently introduced a three-degree-of-freedom robotic platform designed for rats (the ETH-Pattus) that combines an accurate behavioral readout (in the form of kinematics) with the possibility to invasively assess learning related changes within the brain (e.g. by performing immunohistochemistry or electrophysiology in acute slice preparations). Here, we validate this platform as a tool to study motor learning by establishing two forelimb-reaching paradigms that differ in degree of skill. Both conditions can be precisely differentiated in terms of their temporal pattern and performance levels. Based on behavioral data, we hypothesize the presence of several sub-processes contributing to motor learning. These share close similarities with concepts gained in humans or primates. Copyright © 2014 Elsevier B.V. All rights reserved.

Measuring Changes in Tactile Sensitivity in the Hind Paw of Mice Using an Electronic von Frey Apparatus

PubMed Central

Martinov, Tijana; Mack, Madison; Sykes, Akilah; Chatterjea, Devavani

2013-01-01

Measuring inflammation-induced changes in thresholds of hind paw withdrawal from mechanical pressure is a useful technique to assess changes in pain perception in rodents. Withdrawal thresholds can be measured first at baseline and then following drug, venom, injury, allergen, or otherwise evoked inflammation by applying an accurate force on very specific areas of the skin. An electronic von Frey apparatus allows precise assessment of mouse hind paw withdrawal thresholds that are not limited by the available filament sizes in contrast to classical von Frey measurements. The ease and rapidity of measurements allow for incorporation of assessment of tactile sensitivity outcomes in diverse models of rapid-onset inflammatory and neuropathic pain as multiple measurements can be taken within a short time period. Experimental measurements for individual rodent subjects can be internally controlled against individual baseline responses and exclusion criteria easily established to standardize baseline responses within and across experimental groups. Thus, measurements using an electronic von Frey apparatus represent a useful modification of the well-established classical von Frey filament-based assays for rodent mechanical allodynia that may also be applied to other nonhuman mammalian models. PMID:24378519

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

PubMed

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.

Tularemia and plague survey in rodents in an earthquake zone in southeastern Iran

PubMed Central

Gyuranecz, Miklós

2015-01-01

OBJECTIVES: Earthquakes are one the most common natural disasters that lead to increased mortality and morbidity from transmissible diseases, partially because the rodents displaced by an earthquake can lead to an increased rate of disease transmission. The aim of this study was to evaluate the prevalence of plague and tularemia in rodents in the earthquake zones in southeastern Iran. METHODS: In April 2013, a research team was dispatched to explore the possible presence of diseases in rodents displaced by a recent earthquake magnitude 7.7 around the cities of Khash and Saravan in Sistan and Baluchestan Province. Rodents were trapped near and in the earthquake zone, in a location where an outbreak of tularemia was reported in 2007. Rodent serums were tested for a serological survey using an enzyme-linked immunosorbent assay. RESULTS: In the 13 areas that were studied, nine rodents were caught over a total of 200 trap-days. Forty-eight fleas and 10 ticks were obtained from the rodents. The ticks were from the Hyalomma genus and the fleas were from the Xenopsylla genus. All the trapped rodents were Tatera indica. Serological results were negative for plague, but the serum agglutination test was positive for tularemia in one of the rodents. Tatera indica has never been previously documented to be involved in the transmission of tularemia. CONCLUSIONS: No evidence of the plague cycle was found in the rodents of the area, but evidence was found of tularemia infection in rodents, as demonstrated by a positive serological test for tularemia in one rodent. PMID:26602769

The role of rodents in the ecology of Ixodes ricinus and associated pathogens in Central and Eastern Europe.

PubMed

Mihalca, Andrei D; Sándor, Attila D

2013-01-01

Rodents comprise more species than any other mammal order. Most rodents are considered keystone species in their ecological communities, hence the survival of many other species in the ecosystem depend on them. From medical point of view, this is particularly important for rodent-dependent pathogens. In the particular case of tick-borne diseases, rodents are important as hosts for vector ticks and as reservoir hosts (Lyme borreliosis, human granulocytic anaplasmosis, Crimean-Congo hemorrhagic fever, Tick-borne relapsing fevers, tick-borne rickettsioses, babesiosis). Community and population ecology of rodents was shown to be correlated with disease ecology in the case of many tick-borne diseases. In Eastern Europe, several adult hard-tick species use rodents as their principal hosts: Ixodes apronophorus, I. crenulatus, I. laguri, I. redikorzevi, I. trianguliceps. However, the majority of ticks feeding on rodents are immature stages of ticks which as adults are parasitic on larger mammals. Larvae and nymphs of Ixodes ricinus, the most abundant and medically important tick from Europe, are commonly found on rodents. This is particularly important, as many rodents are synanthropic and, together with other micromammals and birds are often the only available natural hosts for ticks in urban environments. This work reviews the correlated ecology of rodents and I. ricinus.

A Field Study of Plague and Tularemia in Rodents, Western Iran.

PubMed

Mostafavi, Ehsan; Shahraki, Abdolrazagh Hashemi; Japoni-Nejad, Alireza; Esmaeili, Saber; Darvish, Jamshid; Sedaghat, Mohammad Mehdi; Mohammadi, Ali; Mohammadi, Zeinolabedin; Mahmoudi, Ahmad; Pourhossein, Behzad; Ghasemi, Ahmad; Gyuranecz, Miklós; Carniel, Elisabeth

2017-04-01

Kurdistan Province in Iran is a historical focus for plague and tularemia. This study aimed at assessing the current status of these two foci by studying their rodent reservoirs. Rodents were trapped and their ectoparasites were collected. The genus and species of both rodents and ectoparasites were determined. Serological analyses of rodent blood samples were done by enzyme-linked immunosorbent assay for plague and by standard tube agglutination assay for tularemia. Rodent spleen samples were subjected to bacterial culture, microscopic examination, and real-time PCR to search for active plague or tularemia infection. During this study, 245 rodents were trapped, of which the most abundant genera were Apodemus (40%), Mus (24.49%), and Meriones (12.65%). One hundred fifty-three fleas, 37 mites, and 54 ticks were collected on these rodents. The results of all direct and indirect tests were negative for plague. Serological tests were positive for tularemia in 4.8% of trapped rodents. This study is the first report on the presence of tularemia infection in rodents in Western Iran. Since Meriones persicus is a known reservoir for plague and tularemia, and this rodent carried plague and tularemia vectors in Marivan and Sanandaj districts, there is a real potential for the occurrence of these two diseases in this region.

Cancer Chemoprevention with Korean Angelica: Active Compounds, Pharmacokinetics, and Human Translational Considerations

PubMed Central

Lü, Junxuan; Zhang, Jinhui; Li, Li; Jiang, Cheng; Xing, Chengguo

2015-01-01

Angelica gigas Nakai (AGN) is a major medicinal herb used in Korea and several other Asian countries. Traditionally, its dried root has been used to treat anemia, pain, infection and articular rheumatism, most often through boiling in water to prepare the dosage forms. AGN extract or AGN-containing herbal mixtures are sold in the US and globally as dietary supplements for pain killing, memory enhancement and post-menopausal symptom relief. Decursin (D) and its isomer decursinol angelate (DA) are the major chemicals in the alcoholic extracts of the root of AGN. The anti-cancer activity of AGN alcoholic extract has been established in a number of animal cancer models, including a transgenic model of prostate carcinogenesis. Cell culture structure-activity studies have uncovered distinct cellular and molecular effects of D and DA vs. their pyranocoumarin core decursinol (DOH) with respect to cancer cells and those associated with their microenvironment. Pharmacokinetic (PK) study by us and others in rodent models indicated that DOH is the major and rapid in vivo first-pass liver metabolite of D and DA. Cognizant of metabolic differences among rodents and humans, we carried out a first-in-human PK study of D/DA to inform the translational relevance of efficacy and mechanism studies with rodent models. The combined use of vigorous animal tests and human PK studies can provide stronger scientific rationale to inform design and execution of translational studies to move AGN toward evidence-based herbal medicine. PMID:26623248

Cancer Chemoprevention with Korean Angelica: Active Compounds, Pharmacokinetics, and Human Translational Considerations.

PubMed

Lü, Junxuan; Zhang, Jinhui; Li, Li; Jiang, Cheng; Xing, Chengguo

2015-12-01

Angelica gigas Nakai (AGN) is a major medicinal herb used in Korea and several other Asian countries. Traditionally, its dried root has been used to treat anemia, pain, infection and articular rheumatism, most often through boiling in water to prepare the dosage forms. AGN extract or AGN-containing herbal mixtures are sold in the US and globally as dietary supplements for pain killing, memory enhancement and post-menopausal symptom relief. Decursin (D) and its isomer decursinol angelate (DA) are the major chemicals in the alcoholic extracts of the root of AGN. The anti-cancer activity of AGN alcoholic extract has been established in a number of animal cancer models, including a transgenic model of prostate carcinogenesis. Cell culture structure-activity studies have uncovered distinct cellular and molecular effects of D and DA vs. their pyranocoumarin core decursinol (DOH) with respect to cancer cells and those associated with their microenvironment. Pharmacokinetic (PK) study by us and others in rodent models indicated that DOH is the major and rapid in vivo first-pass liver metabolite of D and DA. Cognizant of metabolic differences among rodents and humans, we carried out a first-in-human PK study of D/DA to inform the translational relevance of efficacy and mechanism studies with rodent models. The combined use of vigorous animal tests and human PK studies can provide stronger scientific rationale to inform design and execution of translational studies to move AGN toward evidence-based herbal medicine.

Gene Therapy for Brain Cancer: Combination Therapies Provide Enhanced Efficacy and Safety

PubMed Central

Candolfi, Marianela; Kroeger, Kurt M.; Muhammad, A.K.M.G.; Yagiz, Kader; Farrokhi, Catherine; Pechnick, Robert N.; Lowenstein, Pedro R.; Castro, Maria G.

2009-01-01

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults. Despite significant advances in treatment and intensive research, the prognosis for patients with GBM remains poor. Therapeutic challenges for GBM include its invasive nature, the proximity of the tumor to vital brain structures often preventing total resection, and the resistance of recurrent GBM to conventional radiotherapy and chemotherapy. Gene therapy has been proposed as a useful adjuvant for GBM, to be used in conjunction with current treatment. Work from our laboratory has shown that combination of conditional cytotoxic with immunotherapeutic approaches for the treatment of GBM elicits regression of large intracranial tumor masses and anti-tumor immunological memory in syngeneic rodent models of GBM. In this review we examined the currently available animal models for GBM, including rodent transplantable models, endogenous rodent tumor models and spontaneous GBM in dogs. We discuss non-invasive surrogate end points to assess tumor progression and therapeutic efficacy, such as behavioral tests and circulating biomarkers. Growing preclinical and clinical data contradict the old dogma that cytotoxic anti-cancer therapy would lead to an immune-suppression that would impair the ability of the immune system to mount an anti-tumor response. The implications of the findings reviewed indicate that combination of cytotoxic therapy with immunotherapy will lead to synergistic antitumor efficacy with reduced neurotoxicity and supports the clinical implementation of combined cytotoxic-immunotherapeutic strategies for the treatment of patients with GBM. PMID:19860655

Chronic neuromuscular electrical stimulation of paralyzed hindlimbs in a rodent model.

PubMed

Jung, Ranu; Ichihara, Kazuhiko; Venkatasubramanian, Ganapriya; Abbas, James J

2009-10-15

Neuromuscular electrical stimulation (NMES) can be used to activate paralyzed or paretic muscles to generate functional or therapeutic movements. The goal of this research was to develop a rodent model of NMES-assisted movement therapy after spinal cord injury (SCI) that will enable investigation of mechanisms of NMES-induced plasticity, from the molecular to systems level. Development of the model requires accurate mapping of electrode and muscle stimulation sites, the capability to selectively activate muscles to produce graded contractions of sufficient strength, stable anchoring of the implanted electrode within the muscles and stable performance with functional reliability over several weeks of the therapy window. Custom designed electrodes were implanted chronically in hindlimb muscles of spinal cord transected rats. Mechanical and electrical stability of electrodes and the ability to achieve appropriate muscle recruitment and joint angle excursion were assessed by characterizing the strength duration curves, isometric torque recruitment curves and kinematics of joint angle excursion over 6-8 weeks post implantation. Results indicate that the custom designed electrodes and implantation techniques provided sufficient anchoring and produced stable and reliable recruitment of muscles both in the absence of daily NMES (for 8 weeks) as well as with daily NMES that is initiated 3 weeks post implantation (for 6 weeks). The completed work establishes a rodent model that can be used to investigate mechanisms of neuroplasticity that underlie NMES-based movement therapy after spinal cord injury and to optimize the timing of its delivery.

Ancient Anxiety Pathways Influence Drosophila Defense Behaviors.

PubMed

Mohammad, Farhan; Aryal, Sameer; Ho, Joses; Stewart, James Charles; Norman, Nurul Ayuni; Tan, Teng Li; Eisaka, Agnese; Claridge-Chang, Adam

2016-04-04

Anxiety helps us anticipate and assess potential danger in ambiguous situations [1-3]; however, the anxiety disorders are the most prevalent class of psychiatric illness [4-6]. Emotional states are shared between humans and other animals [7], as observed by behavioral manifestations [8], physiological responses [9], and gene conservation [10]. Anxiety research makes wide use of three rodent behavioral assays-elevated plus maze, open field, and light/dark box-that present a choice between sheltered and exposed regions [11]. Exposure avoidance in anxiety-related defense behaviors was confirmed to be a correlate of rodent anxiety by treatment with known anxiety-altering agents [12-14] and is now used to characterize anxiety systems. Modeling anxiety with a small neurogenetic animal would further aid the elucidation of its neuronal and molecular bases. Drosophila neurogenetics research has elucidated the mechanisms of fundamental behaviors and implicated genes that are often orthologous across species. In an enclosed arena, flies stay close to the walls during spontaneous locomotion [15, 16], a behavior proposed to be related to anxiety [17]. We tested this hypothesis with manipulations of the GABA receptor, serotonin signaling, and stress. The effects of these interventions were strikingly concordant with rodent anxiety, verifying that these behaviors report on an anxiety-like state. Application of this method was able to identify several new fly anxiety genes. The presence of conserved neurogenetic pathways in the insect brain identifies Drosophila as an attractive genetic model for the study of anxiety and anxiety-related disorders, complementing existing rodent systems. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Isoflurane: An Ideal Anesthetic for Rodent Orthotopic Liver Transplantation Surgery?

PubMed

Cao, D; Liu, Y; Li, J; Gong, J

2016-10-01

Because the choice of anesthetic affects the rodent orthotopic liver transplantation (OLT) model, we compared the effects of isoflurane, ketamine, chloral hydrate, and pentobarbital on the OLT model. OLT was performed using the two-cuff technique. Two hundred male rats were randomly divided into five groups: control, isoflurane, ketamine, chloral hydrate, and pentobarbital groups. Rectal temperatures, respiratory rates, arterial blood values (pH, PaCO 2 , PaO 2 , and SatO 2 ), liver function tests and histopathology, recovery times, and anhepatic stage mortality rates were assessed. Compared with controls, respiratory rates decreased by 20% in the isoflurane group, and decreased by 40%-50% in the ketamine, chloral hydrate, and pentobarbital groups. The PaO 2 , SatO 2 , and pH levels in the ketamine, chloral hydrate, and pentobarbital groups were significantly lower than those in the isoflurane and control groups (P < .05). Only the pentobarbital group displayed significant liver histopathologic changes along with significantly higher levels of serum alanine aminotransferase and total bilirubin, but a significantly lower level of serum albumin, compared with the control group (P < .05). The isoflurane group had a 0% anhepatic stage mortality rate compared with rates of 30%-40% in the other anesthetic groups. Isoflurane should be the preferred anesthetic for rodent OLT surgery due to its minimal respiratory and hepatic physiological effects as well as its low anhepatic phase mortality rate. Secondary to isoflurane, ketamine and chloral hydrate may be administered as donor anesthetics. Pentobarbital use should be avoided entirely in rodent OLT surgery due to its significant hepatotoxic effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Hindlimb Suspension as a Model to Study Ophthalmic Complications in Microgravity Status Report: Optimization of Rat Retina Flat Mounts Staining to Study Vascular Remodeling

NASA Technical Reports Server (NTRS)

Theriot, Corey A.; Zanello, Susana B.

2014-01-01

Preliminary data from a prior tissue-sharing experiment has suggested that early growth response protein-1 (Egr1), a transcription factor involved in various stress responses in the vasculature, is induced in the rat retina after 14 days of hindlimb suspension (HS) and may be evidence that mechanical stress is occurring secondary to the cephalad fluid shift. This mechanical stress could cause changes in oxygenation of the retina, and the subsequent ischemia- or inflammation-driven hypoxia may lead to microvascular remodeling. This microvascular remodeling process can be studied using image analysis of retinal vessels and can be then be quantified by the VESsel GENeration Analysis (VESGEN) software, a computational tool that quantifies remodeling patterns of branching vascular trees and capillary or vasculogenic networks. Our project investigates whether rodent HS is a valid model to study the effects of simulated-weightlessness on ocular structures and their relationship with intracranial pressure (ICP). One of the hypotheses to be tested is that HS-induced cephalad fluid shift is accompanied by vascular engorgement that produces changes in retinal oxygenation, leading to oxidative stress, hypoxia, microvascular remodeling, and cellular degeneration. We have optimized the procedure to obtain flat mounts of rat retina, staining of the endothelial lining in vasculature and acquisition of high quality images suitable for VESGEN analysis. Briefly, eyes were fixed in 4% paraformaldehyde for 24 hours and retinas were detached and then mounted flat on microscope slides. The microvascular staining was done with endothelial cell-specific isolectin binding, coupled to Alexa-488 fluorophore. Image acquisition at low magnification and high resolution was performed using a new Leica SP8 confocal microscope in a tile pattern across the X,Y plane and multiple sections along the Z-axis. This new confocal microscope has the added capability of dye separation using the Linear Unmixing method and allows us to remove the autofluorescence originating from the photoreceptor layer. In summary, we have an improved method for studying the retinal microvasculature that will provide an increase in the quality of images captured and will be applied throughout the various animal cohorts of the recentlyinitiated study that will evaluate rodent HS as a model to study ophthalmic complications in microgravity.

The effect of area size and predation on the time to extinction of prairie vole populations. simulation studies via SERDYCA: a Spatially-Explicit Individual-Based Model of Rodent Dynamics

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

Kostova, T; Carlsen, T

2003-11-21

We present a spatially-explicit individual-based computational model of rodent dynamics, customized for the prairie vole species, M. Ochrogaster. The model is based on trophic relationships and represents important features such as territorial competition, mating behavior, density-dependent predation and dispersal out of the modeled spatial region. Vegetation growth and vole fecundity are dependent on climatic components. The results of simulations show that the model correctly predicts the overall temporal dynamics of the population density. Time-series analysis shows a very good match between the periods corresponding to the peak population density frequencies predicted by the model and the ones reported in themore » literature. The model is used to study the relation between persistence, landscape area and predation. We introduce the notions of average time to extinction (ATE) and persistence frequency to quantify persistence. While the ATE decreases with decrease of area, it is a bell-shaped function of the predation level: increasing for 'small' and decreasing for 'large' predation levels.« less

Rodent-borne diseases and their public health importance in Iran.

PubMed

Rabiee, Mohammad Hasan; Mahmoudi, Ahmad; Siahsarvie, Roohollah; Kryštufek, Boris; Mostafavi, Ehsan

2018-04-01

Rodents are reservoirs and hosts for several zoonotic diseases such as plague, leptospirosis, and leishmaniasis. Rapid development of industry and agriculture, as well as climate change throughout the globe, has led to change or increase in occurrence of rodent-borne diseases. Considering the distribution of rodents throughout Iran, the aim of this review is to assess the risk of rodent-borne diseases in Iran. We searched Google Scholar, PubMed, Science Direct, Scientific Information Database (SID), and Magiran databases up to September 2016 to obtain articles reporting occurrence of rodent-borne diseases in Iran and extract information from them. Out of 70 known rodent-borne diseases, 34 were reported in Iran: 17 (50%) parasitic diseases, 13 (38%) bacterial diseases, and 4 (12%) viral diseases. Twenty-one out of 34 diseases were reported from both humans and rodents. Among the diseases reported in the rodents of Iran, plague, leishmaniasis, and hymenolepiasis were the most frequent. The most infected rodents were Rattus norvegicus (16 diseases), Mus musculus (14 diseases), Rattus rattus (13 diseases), Meriones persicus (7 diseases), Apodemus spp. (5 diseases), Tatera indica (4 diseases), Meriones libycus (3 diseases), Rhombomys opimus (3 diseases), Cricetulus migratorius (3 diseases), and Nesokia indica (2 diseases). The results of this review indicate the importance of rodent-borne diseases in Iran. Considering notable diversity of rodents and their extensive distribution throughout the country, it is crucial to pay more attention to their role in spreading infectious diseases for better control of the diseases.

[Strategies for sustainable management of commensal rodents. Definitions of control objectives at communal level].

PubMed

Plenge-Bönig, A; Schmolz, E

2014-05-01

The German Act on the Prevention and Control of Infectious Diseases in Man (Infektionsschutzgesetz, IfSG) provides a legal framework for activities and responsibilities concerning communal rodent control. However, actual governance of communal rodent control is relatively heterogeneous, as federal states (Bundesländer) have different or even no regulations for prevention and management of commensal rodent infestations (e.g. brown rats, roof rats and house mice). Control targets and control requirements are rarely precisely defined and often do not go beyond general measures and objectives. Although relevant regulations provide information about agreed preventive measures against rodents, the concept of sustainability is not expressed as such. A centrally managed database-supported municipal rodent control is a key factor for sustainability because it allows a systematic and analytical approach to identify and reduce rodent populations. The definition of control objectives and their establishment in legal decrees is mandatory for the implementation of a sustainable management strategy of rodent populations at a local level. Systematic recording of rodent infestations through municipal-operated monitoring provides the essential data foundation for a targeted rodent management which is already implemented in some German and European cities and nationwide in Denmark. A sustainable rodent management includes a more targeted rodenticide application which in the long-term will lead to an overall reduction of rodenticide use. Thus, the benefits of sustainable rodent management will be a reduction of rodenticide exposure to the environment, prevention of resistance and long-term economical savings.

Pulmonary oxidative stress, inflammation and dysregulated iron homeostatis in rat models of cardiovascular disease

EPA Science Inventory

Underlying cardiovascular disease (CVD) is considered a risk factor for the exacerbation of air pollution health effects. Therefore, rodent models of CVD are increasingly used to examine mechanisms ofvariation in susceptibility. Pulmonary oxidative stress, inflammation and altere...

Thyroid Hormone Disruption Effects Lamination of the Neocortex but not the Cerebellum in a Model of Developmental Hypothyroidism and Hypothyroxinemia

EPA Science Inventory

Introduction: Research on neurodevelopmental changes resulting from thyroid hormone (TH) disruption has important basic and clinical implications. We previously demonstrated, in a rodent model, that developmental hypothyroidism or hypothyroxinemia can cause ...

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

NASA Astrophysics Data System (ADS)

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.

Construction and Evaluation of Rodent-Specific rTMS Coils.

PubMed

Tang, Alexander D; Lowe, Andrea S; Garrett, Andrew R; Woodward, Robert; Bennett, William; Canty, Alison J; Garry, Michael I; Hinder, Mark R; Summers, Jeffery J; Gersner, Roman; Rotenberg, Alexander; Thickbroom, Gary; Walton, Joseph; Rodger, Jennifer

2016-01-01

Rodent models of transcranial magnetic stimulation (TMS) play a crucial role in aiding the understanding of the cellular and molecular mechanisms underlying TMS induced plasticity. Rodent-specific TMS have previously been used to deliver focal stimulation at the cost of stimulus intensity (12 mT). Here we describe two novel TMS coils designed to deliver repetitive TMS (rTMS) at greater stimulation intensities whilst maintaining spatial resolution. Two circular coils (8 mm outer diameter) were constructed with either an air or pure iron-core. Peak magnetic field strength for the air and iron-cores were 90 and 120 mT, respectively, with the iron-core coil exhibiting less focality. Coil temperature and magnetic field stability for the two coils undergoing rTMS, were similar at 1 Hz but varied at 10 Hz. Finite element modeling of 10 Hz rTMS with the iron-core in a simplified rat brain model suggests a peak electric field of 85 and 12.7 V/m, within the skull and the brain, respectively. Delivering 10 Hz rTMS to the motor cortex of anaesthetized rats with the iron-core coil significantly increased motor evoked potential amplitudes immediately after stimulation (n = 4). Our results suggest these novel coils generate modest magnetic and electric fields, capable of altering cortical excitability and provide an alternative method to investigate the mechanisms underlying rTMS-induced plasticity in an experimental setting.

76 FR 3150 - Office of Biotechnology Activities; Recombinant DNA Research: Action Under the NIH Guidelines for...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-19

... recombinant DNA technology, or breeding one or more transgenic rodents to create a new transgenic rodent (i.e., breeding of two different transgenic rodents or the breeding of a transgenic rodent and a non-transgenic... NIH Guidelines so as to exempt breeding of almost all transgenic rodents that can be housed at BL1...

Behavioral testing in rodent models of orofacial neuropathic and inflammatory pain

PubMed Central

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

Modelling the emergence of rodent filial huddling from physiological huddling

NASA Astrophysics Data System (ADS)

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.

Integrative strategies to identify candidate genes in rodent models of human alcoholism.

PubMed

Treadwell, Julie A

2006-01-01

The search for genes underlying alcohol-related behaviours in rodent models of human alcoholism has been ongoing for many years with only limited success. Recently, new strategies that integrate several of the traditional approaches have provided new insights into the molecular mechanisms underlying ethanol's actions in the brain. We have used alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) genetic strains of mice in an integrative strategy combining high-throughput gene expression screening, genetic segregation analysis, and mapping to previously published quantitative trait loci to uncover candidate genes for the ethanol-preference phenotype. In our study, 2 genes, retinaldehyde binding protein 1 (Rlbp1) and syntaxin 12 (Stx12), were found to be strong candidates for ethanol preference. Such experimental approaches have the power and the potential to greatly speed up the laborious process of identifying candidate genes for the animal models of human alcoholism.

Importance of Toxicokinetics to Assess the Utility of Zebrafish Larvae as Model for Psychoactive Drug Screening Using Meta-Chlorophenylpiperazine (mCPP) as Example

PubMed Central

Kirla, Krishna Tulasi; Groh, Ksenia J.; Poetzsch, Michael; Banote, Rakesh Kumar; Stadnicka-Michalak, Julita; Eggen, Rik I. L.; Schirmer, Kristin; Kraemer, Thomas

2018-01-01

The number of new psychoactive substances (NPS) increases rapidly, harming society and fuelling the need for alternative testing strategies. These should allow the ever-increasing number of drugs to be tested more effectively for their toxicity and psychoactive effects. One proposed strategy is to complement rodent models with zebrafish (Danio rerio) larvae. Yet, our understanding of the toxicokinetics in this model, owing to the waterborne drug exposure and the distinct physiology of the fish, is incomplete. We here explore the toxicokinetics and behavioral effects of an NPS, meta-chlorophenylpiperazine (mCPP), in zebrafish larvae. Uptake kinetics of mCPP, supported by toxicokinetic modeling, strongly suggested the existence of active transport processes. Internal distribution showed a dominant accumulation in the eye, implying that in zebrafish, like in mammals, melanin could serve as a binding site for basic drugs. We confirmed this by demonstrating significantly lower drug accumulation in two types of hypo-pigmented fish. Comparison of the elimination kinetics between mCPP and previously characterized cocaine demonstrated that drug affinities to melanin in zebrafish vary depending on the structure of the test compound. As expected from mCPP-elicited responses in rodents and humans, zebrafish larvae displayed hypoactive behavior. However, significant differences were seen between zebrafish and rodents with regard to the concentration-dependency of the behavioral response and the comparability of tissue levels, corroborating the need to consider the organism-internal distribution of the chemical to allow appropriate dose modeling while evaluating effects and concordance between zebrafish and mammals. Our results highlight commonalities and differences of mammalian versus the fish model in need of further exploration. PMID:29755353

Importance of Toxicokinetics to Assess the Utility of Zebrafish Larvae as Model for Psychoactive Drug Screening Using Meta-Chlorophenylpiperazine (mCPP) as Example.

PubMed

Kirla, Krishna Tulasi; Groh, Ksenia J; Poetzsch, Michael; Banote, Rakesh Kumar; Stadnicka-Michalak, Julita; Eggen, Rik I L; Schirmer, Kristin; Kraemer, Thomas

2018-01-01

The number of new psychoactive substances (NPS) increases rapidly, harming society and fuelling the need for alternative testing strategies. These should allow the ever-increasing number of drugs to be tested more effectively for their toxicity and psychoactive effects. One proposed strategy is to complement rodent models with zebrafish ( Danio rerio ) larvae. Yet, our understanding of the toxicokinetics in this model, owing to the waterborne drug exposure and the distinct physiology of the fish, is incomplete. We here explore the toxicokinetics and behavioral effects of an NPS, meta-chlorophenylpiperazine (mCPP), in zebrafish larvae. Uptake kinetics of mCPP, supported by toxicokinetic modeling, strongly suggested the existence of active transport processes. Internal distribution showed a dominant accumulation in the eye, implying that in zebrafish, like in mammals, melanin could serve as a binding site for basic drugs. We confirmed this by demonstrating significantly lower drug accumulation in two types of hypo-pigmented fish. Comparison of the elimination kinetics between mCPP and previously characterized cocaine demonstrated that drug affinities to melanin in zebrafish vary depending on the structure of the test compound. As expected from mCPP-elicited responses in rodents and humans, zebrafish larvae displayed hypoactive behavior. However, significant differences were seen between zebrafish and rodents with regard to the concentration-dependency of the behavioral response and the comparability of tissue levels, corroborating the need to consider the organism-internal distribution of the chemical to allow appropriate dose modeling while evaluating effects and concordance between zebrafish and mammals. Our results highlight commonalities and differences of mammalian versus the fish model in need of further exploration.

Recognition and management of rodent-borne infectious disease outbreaks after heavy rainfall and flooding.

PubMed

Diaz, James H

2014-01-01

Climatic events, especially heavy rains and flooding following periods of relative drought, have precipitated both arthropod-borne and rodent-borne infectious disease outbreaks. Heavy rainfall encourages excessive wild grass seed production that supports increased outdoor rodent populations, and flooding forces rodents from their burrows near water sources into the built environment and closer to humans. The objectives of this review are to alert clinicians to the climatic conditions common to hurricane-prone regions, such as Louisiana, that can precipitate outbreaks of the two rodent-borne diseases most often associated with periods of heavy rainfall and flooding, leptospirosis (LS) and hantavirus pulmonary syndrome (HPS). It will also describe the epidemiology, presenting clinical manifestations and outcomes of these rodent-borne infectious diseases, and recommend both prophylactic therapies and effective control and prevention strategies for rodent-borne infectious disease outbreaks. Healthcare providers should maintain high levels of suspicion for LS in patients developing febrile illnesses after contaminated freshwater exposures during flooding or recreational events, and for HPS in patients with febrile illnesses that progress rapidly to respiratory failure following rodent exposures in enclosed spaces. Public health educational strategies should encourage limiting human contact with all wild and peridomestic rats and mice, avoiding all contact with rodent excreta, safely disposing of all rodent excreta, and modifying the built environment to deter rodents from colonizing households and workplaces.

21 CFR 1250.96 - Rodent control.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 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. ...

21 CFR 1250.96 - Rodent control.

Code of Federal Regulations, 2010 CFR

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. ...

21 CFR 1250.96 - Rodent control.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 8 2012-04-01 2012-04-01 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. ...

21 CFR 1250.96 - Rodent control.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 8 2011-04-01 2011-04-01 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. ...

21 CFR 1250.96 - Rodent control.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 8 2013-04-01 2013-04-01 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. ...

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

PubMed Central

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

Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit

PubMed Central

Bezaire, Marianne J; Raikov, Ivan; Burk, Kelly; Vyas, Dhrumil; Soltesz, Ivan

2016-01-01

The hippocampal theta rhythm plays important roles in information processing; however, the mechanisms of its generation are not well understood. We developed a data-driven, supercomputer-based, full-scale (1:1) model of the rodent CA1 area and studied its interneurons during theta oscillations. Theta rhythm with phase-locked gamma oscillations and phase-preferential discharges of distinct interneuronal types spontaneously emerged from the isolated CA1 circuit without rhythmic inputs. Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation. These simulations reveal new insights into the spatiotemporal organization of the CA1 circuit during theta oscillations. DOI: http://dx.doi.org/10.7554/eLife.18566.001 PMID:28009257

At Home with Mastomys and Rattus: Human-Rodent Interactions and Potential for Primary Transmission of Lassa Virus in Domestic Spaces

PubMed Central

Bonwitt, Jesse; Sáez, Almudena Mari; Lamin, Joseph; Ansumana, Rashid; Dawson, Michael; Buanie, Jacob; Lamin, Joyce; Sondufu, Diana; Borchert, Matthias; Sahr, Foday; Fichet-Calvet, Elisabeth; Brown, Hannah

2017-01-01

The multimammate mouse (Mastomys natalensis) is the reservoir for Lassa virus (LASV). Zoonotic transmission occurs when humans are directly or indirectly exposed to fluids of the multimammate mouse, such as urine, saliva, and blood. Housing characteristics and domestic organization affect rodent density in and around households and villages, and are likely to be a risk factor for Lassa fever in humans where the reservoir exists. We use semi-structured interviews (N = 51), a quantitative survey (N = 429), direct observations, and a rodent ecology study to provide new insights into how the organization of domestic spaces brings together humans and rodents and creates pathways for infection in rural settlements in Bo District, Sierra Leone. Rodents were frequently reported inside houses (92.4% of respondents), in which we predominantly trapped M. natalensis (57% of trapped rodents) and Rattus rattus (38% of trapped rodents). Building design and materials provide hiding and nesting places for rodents and lead to close proximity with humans. Patterns of contact are both unintentional and intentional and research participants reported high levels of contact with rodents (34.2% of respondents) and rodent fluids (52.8% of respondents). Rodents are also perceived as a serious threat to food security. These results present detailed knowledge about how humans live with and come into contact with rodents, including the LASV reservoir. Our results argue for further collaborative research in housing and environmental modification such as ceiling construction, food storage, and sanitation as prevention against zoonotic LASV transmission. PMID:28167603

Rodent-borne diseases and their public health importance in Iran

PubMed Central

Mahmoudi, Ahmad; Siahsarvie, Roohollah; Kryštufek, Boris; Mostafavi, Ehsan

2018-01-01

Background Rodents are reservoirs and hosts for several zoonotic diseases such as plague, leptospirosis, and leishmaniasis. Rapid development of industry and agriculture, as well as climate change throughout the globe, has led to change or increase in occurrence of rodent-borne diseases. Considering the distribution of rodents throughout Iran, the aim of this review is to assess the risk of rodent-borne diseases in Iran. Methodology/Principal finding We searched Google Scholar, PubMed, Science Direct, Scientific Information Database (SID), and Magiran databases up to September 2016 to obtain articles reporting occurrence of rodent-borne diseases in Iran and extract information from them. Out of 70 known rodent-borne diseases, 34 were reported in Iran: 17 (50%) parasitic diseases, 13 (38%) bacterial diseases, and 4 (12%) viral diseases. Twenty-one out of 34 diseases were reported from both humans and rodents. Among the diseases reported in the rodents of Iran, plague, leishmaniasis, and hymenolepiasis were the most frequent. The most infected rodents were Rattus norvegicus (16 diseases), Mus musculus (14 diseases), Rattus rattus (13 diseases), Meriones persicus (7 diseases), Apodemus spp. (5 diseases), Tatera indica (4 diseases), Meriones libycus (3 diseases), Rhombomys opimus (3 diseases), Cricetulus migratorius (3 diseases), and Nesokia indica (2 diseases). Conclusions/Significance The results of this review indicate the importance of rodent-borne diseases in Iran. Considering notable diversity of rodents and their extensive distribution throughout the country, it is crucial to pay more attention to their role in spreading infectious diseases for better control of the diseases. PMID:29672510

Integrated scanning laser ophthalmoscopy and optical coherence tomography for quantitative multimodal imaging of retinal degeneration and autofluorescence

NASA Astrophysics Data System (ADS)

Issaei, Ali; Szczygiel, Lukasz; Hossein-Javaheri, Nima; Young, Mei; Molday, L. L.; Molday, R. S.; Sarunic, M. V.

2011-03-01

Scanning Laser Ophthalmoscopy (SLO) and Coherence Tomography (OCT) are complimentary retinal imaging modalities. Integration of SLO and OCT allows for both fluorescent detection and depth- resolved structural imaging of the retinal cell layers to be performed in-vivo. System customization is required to image rodents used in medical research by vision scientists. We are investigating multimodal SLO/OCT imaging of a rodent model of Stargardt's Macular Dystrophy which is characterized by retinal degeneration and accumulation of toxic autofluorescent lipofuscin deposits. Our new findings demonstrate the ability to track fundus autofluorescence and retinal degeneration concurrently.

Wood thrush nest success and post-fledging survival across a temporal pulse of small mammal abundance in an oak forest.

PubMed

Schmidt, Kenneth A; Rush, Scott A; Ostfeld, Richard S

2008-07-01

1. Synchronized mass production of seed crops, such as acorns, produces a resource pulse that may have far-reaching consequences for songbird populations through its effects on avian predators. Seed production in these forests represents only the first of several pulsed events. Secondary pulses emerge as mast-consuming rodents numerically respond to seed production and tertiary pulses emerge as generalist predators, such as raptors, numerically respond to rodents. In turn, these two groups reduce nest productivity and juvenile survivorship 1 and 2 years, respectively, after the initial pulse in seed production. 2. At our study site in south-eastern New York, USA, autumn acorn abundance (primary pulse) largely determines rodent abundance (secondary pulse) the following spring. We tested the hypotheses that the population dynamics of a shrub-nesting passerine (wood thrush Hylocichla mustelina), is influenced by rodents through the: (a) direct effect of predation by rodents; (b) indirect effect of rodents on the abundance of raptors (tertiary pulse); and (c) indirect effect of rodent abundance on raptor diet. The latter specifically hypothesizes that a crash in the rodent population in the wake of region-wide failure of acorn production leads to an extreme diet shift in raptors that increases post-fledging mortality in birds. 3. We conducted a 3-year study to examine variation in wood thrush nest success and fledgling survival, using radio telemetry, across a pulse of rodent abundance (i.e. low, medium and high). We also updated and reanalysed regional wood thrush population growth rates as a function of the annual variation in rodent abundance. 4. Fledgling survivorship, but not nest success, varied in relation to annual rodent abundance. Raptors and eastern chipmunks Tamias striatus were the most commonly identified predators on fledglings. Fledgling survivorship was greatest at intermediate rodent abundance consistent with a shift in raptor diet. Regional rate of wood thrush population growth showed a unimodal relationship with rodent abundance, peaking during years with intermediate rodent abundance. This unimodal pattern was due to wood thrush population growth rates near or below zero during rodent population crashes. 5. The telemetry study, pattern of regional abundance and synchronized population dynamics of coexisting thrushes suggest a common mechanism of behavioural changes in raptors in response to declines in rodent prey, which in turn affects thrush population dynamics.

Studies on rodents role as reservoir hosts of leishmaniasis with specical reference to their ectoparasites in Suez Governorate.

PubMed

Shoukry, Nahla M; El-Naggar, Mostafa H; Darwish, Ahmed B; Soliman, Belal A; El-Sawaf, Bahira M

2006-04-01

The distribution of rodents was studied in three different habitats. Seven rodent species were identified: Rattus norvegicus, R. alexandrinus, R. frugivorous, Mus musculus, Acomys russatus, Meriones sacramenti and Gerbillus pyramidum. The species distribution varied with the habitat type. The highest density of rodents was in July and August and the lowest one was in January. However, some species were collected all the year round. The rodents were investigated for the endo- and ecto-parasites. No Leishmania parasites were found. The ectoparasites were: Xenopsylla cheopis, Leptopsylla segnis and Ctenocephalides felis, Polyplax spinulos, Hyalomma dromedarii (nymph) and Echinolaelaps echidninus and Hemolaelaps glassgowi. Ecto-parasites were on rodents all year-round in domestic habitat and peridomestic habitats. In wild one, ecto-parasites activity was from March to December. The rodents' role as reservoir for L. major was experimentally studied. Rodents inoculated with L. major together with hamster and BALB-c mice developed cutaneous lesions. The active lesions, the rodents' ecological habitats and the presence of insect-vector may pave the way to an epidemic zoonotic leishmaniasis role.

Review on intrauterine programming: Consequences in rodent models of mild diabetes and mild fat overfeeding are not mild.

PubMed

Jawerbaum, A; White, V

2017-04-01

An adverse intrauterine programming occurs in diabetes and obesity as the consequence of an adverse maternal environment that affects the appropriate fetoplacental development and growth. Experimental models of diabetes and fat overfeeding have provided relevant tools to address putative mechanisms of the adverse intrauterine programming. The current knowledge far extends from the original thoughts of the resulting intrauterine programming of metabolic and cardiovascular diseases to a full range of alterations that affect multiple tissues, organs, and systems that will compromise the long-life health of the offspring. This review examines the postnatal effects of rodent models of mild diabetes and fat overfeeding, identifying the multiple organ derangements in the offspring resulting from mild maternal adverse conditions. In addition, the comparison of experimental models of severe diabetes and fat overfeeding and the crucial role of the placenta are discussed, providing an update of the actual scenario of the putative mechanisms and adverse consequences of maternal metabolic derangements. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison between nonspecific and necrosis-avid gadolinium contrast agents in vascular disrupting agent-induced necrosis of rodent tumors at 3.0T.

PubMed

Wang, Huaijun; Miranda Cona, Marlein; Chen, Feng; Li, Junjie; Yu, Jie; Feng, Yuanbo; Peeters, Ronald; De Keyzer, Frederik; Marchal, Guy; Ni, Yicheng

2011-09-01

: To compare a commercial contrast agent (CA) Dotarem and a necrosis-avid CA (NACA) for their ability to evaluate the therapeutic necrosis with a vascular disrupting agent (VDA) on magnetic resonance imaging in rodent liver tumors to determine which could better correlate with the histopathologic outcome. : After the VDA treatment, 16 rats with 32 liver rhabdomyosarcomas were randomized into Dotarem and NACA groups (n = 8 per group) for both interindividual and intraindividual comparisons. T2-weighted imaging, T1-weighted imaging (T1WI), contrast-enhanced T1-weighted imaging (CE-T1WI), and diffusion-weighted imaging were performed at baseline, after VDA treatment and CA injections. The enhancing efficacy of CAs at immediate and delayed enhancement on CE-T1WI in viable tumor and necrosis was compared. Tumor necrosis ratios calculated from NACA and Dotarem were compared and correlated with gold-standard histopathology. : On the immediate CE-T1WI, viable tumor was enhanced by either CA. On the delayed CE-T1WI at 30 minutes, both CAs failed to demarcate viable tumor from necrosis. At 24 hours post-NACA, the necrosis was clearly distinguished from viable tumor and thus derived necrosis ratio matched that from histopathology (P = 0.99); necrosis ratio from Dotarem was significantly lower than that from NACA and histopathology (P < 0.05, both), with a higher correlation of NACA than that of Dotarem with histopathology (r = 0.99 vs. r = 0.82). : NACA better evaluated VDA-induced tumor necrosis than nonspecific CA on T1WI in tumor models of rat liver. NACA showed a closer correlation with histopathology than nonspecific CA for the delineation of true necrosis. Delayed enhancement on T1WI with nonspecific CA is not suitable for the assessment of VDA-induced tumor necrosis.

Ethical and Animal Welfare Considerations in Relation to Species Selection for Animal Experimentation

PubMed Central

Webster, John

2014-01-01

Simple Summary When making a choice of species for animal experimentation we must balance its suitability as a model for human medicine against the potential harms to the animals both from the procedures and the quality of their lifetime experience. The capacity to experience pain may be similar in mammals, birds and fish. The capacity to suffer from fear is governed more by sentience than cognitive ability, so it cannot be assumed that rodents or farm animals suffer less than dogs or primates. I suggest that it is unethical to base the choice of species for animal experimentation simply on the basis that it will cause less distress within society. Abstract Ethical principles governing the conduct of experiments with animals are reviewed, especially those relating to the choice of species. Legislation requires that the potential harm to animals arising from any procedure should be assessed in advance and justified in terms of its possible benefit to society. Potential harms may arise both from the procedures and the quality of the animals’ lifetime experience. The conventional approach to species selection is to use animals with the “lowest degree of neurophysiological sensitivity”. However; this concept should be applied with extreme caution in the light of new knowledge. The capacity to experience pain may be similar in mammals, birds and fish. The capacity to suffer from fear is governed more by sentience than cognitive ability, so it cannot be assumed that rodents or farm animals suffer less than dogs or primates. I suggest that it is unethical to base the choice of species for animal experimentation simply on the basis that it will cause less distress within society. A set of responsibilities is outlined for each category of moral agent. These include regulators, operators directly concerned with the conduct of scientific experiments and toxicology trials, veterinarians and animal care staff; and society at large. PMID:26479009

Estimating Hantavirus Risk in Southern Argentina: A GIS-Based Approach Combining Human Cases and Host Distribution

PubMed Central

Andreo, Veronica; Neteler, Markus; Rocchini, Duccio; Provensal, Cecilia; Levis, Silvana; Porcasi, Ximena; Rizzoli, Annapaola; Lanfri, Mario; Scavuzzo, Marcelo; Pini, Noemi; Enria, Delia; Polop, Jaime

2014-01-01

We use a Species Distribution Modeling (SDM) approach along with Geographic Information Systems (GIS) techniques to examine the potential distribution of hantavirus pulmonary syndrome (HPS) caused by Andes virus (ANDV) in southern Argentina and, more precisely, define and estimate the area with the highest infection probability for humans, through the combination with the distribution map for the competent rodent host (Oligoryzomys longicaudatus). Sites with confirmed cases of HPS in the period 1995–2009 were mostly concentrated in a narrow strip (~90 km × 900 km) along the Andes range from northern Neuquén to central Chubut province. This area is characterized by high mean annual precipitation (~1,000 mm on average), but dry summers (less than 100 mm), very low percentages of bare soil (~10% on average) and low temperatures in the coldest month (minimum average temperature −1.5 °C), as compared to the HPS-free areas, features that coincide with sub-Antarctic forests and shrublands (especially those dominated by the invasive plant Rosa rubiginosa), where rodent host abundances and ANDV prevalences are known to be the highest. Through the combination of predictive distribution maps of the reservoir host and disease cases, we found that the area with the highest probability for HPS to occur overlaps only 28% with the most suitable habitat for O. longicaudatus. With this approach, we made a step forward in the understanding of the risk factors that need to be considered in the forecasting and mapping of risk at the regional/national scale. We propose the implementation and use of thematic maps, such as the one built here, as a basic tool allowing public health authorities to focus surveillance efforts and normally scarce resources for prevention and control actions in vast areas like southern Argentina. PMID:24424500

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

PubMed

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 (P<0.01). Energy restriction induced an increase in exercise 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. © 2015 Society for Endocrinology.

Perampanel, an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models.

PubMed

Zwart, R; Sher, E; Ping, X; Jin, X; Sims, J R; Chappell, A S; Gleason, S D; Hahn, P J; Gardinier, K; Gernert, D L; Hobbs, J; Smith, J L; Valli, S N; Witkin, J M

2014-10-01

Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 μM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 μM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

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

PubMed

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 require the use of animal models for gathering robust data about mechanisms leading to IUGR and for testing the effectiveness and safety of the intervention among pregnant women.

Single oral dose pharmacokinetics of decursin and decursinol angelate in healthy adult men and women.

PubMed

Zhang, Jinhui; Li, Li; Hale, Thomas W; Chee, Wayne; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

2015-01-01

The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (Tmax) of 2.1, 2.4 and 3.3 h and mean peak concentration (Cmax) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h∙nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation. ClinicalTrials.gov NCT02114957.

Single Oral Dose Pharmacokinetics of Decursin and Decursinol Angelate in Healthy Adult Men and Women

PubMed Central

Zhang, Jinhui; Li, Li; Hale, Thomas W.; Chee, Wayne; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

2015-01-01

The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (Tmax) of 2.1, 2.4 and 3.3 h and mean peak concentration (Cmax) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h∙nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation. Trial Registration ClinicalTrials.gov NCT02114957 PMID:25695490

Influence of household rat infestation on leptospira transmission in the urban slum environment.

PubMed

Costa, Federico; Ribeiro, Guilherme S; Felzemburgh, Ridalva D M; Santos, Norlan; Reis, Renato Barbosa; Santos, Andreia C; Fraga, Deborah Bittencourt Mothe; Araujo, Wildo N; Santana, Carlos; Childs, James E; Reis, Mitermayer G; Ko, Albert I

2014-12-01

The Norway rat (Rattus norvegicus) is the principal reservoir for leptospirosis in many urban settings. Few studies have identified markers for rat infestation in slum environments while none have evaluated the association between household rat infestation and Leptospira infection in humans or the use of infestation markers as a predictive model to stratify risk for leptospirosis. We enrolled a cohort of 2,003 urban slum residents from Salvador, Brazil in 2004, and followed the cohort during four annual serosurveys to identify serologic evidence for Leptospira infection. In 2007, we performed rodent infestation and environmental surveys of 80 case households, in which resided at least one individual with Leptospira infection, and 109 control households. In the case-control study, signs of rodent infestation were identified in 78% and 42% of the households, respectively. Regression modeling identified the presence of R. norvegicus feces (OR, 4.95; 95% CI, 2.13-11.47), rodent burrows (2.80; 1.06-7.36), access to water (2.79; 1.28-6.09), and un-plastered walls (2.71; 1.21-6.04) as independent risk factors associated with Leptospira infection in a household. We developed a predictive model for infection, based on assigning scores to each of the rodent infestation risk factors. Receiver operating characteristic curve analysis found that the prediction score produced a good/excellent fit based on an area under the curve of 0.78 (0.71-0.84). Our study found that a high proportion of slum households were infested with R. norvegicus and that rat infestation was significantly associated with the risk of Leptospira infection, indicating that high level transmission occurs among slum households. We developed an easily applicable prediction score based on rat infestation markers, which identified households with highest infection risk. The use of the prediction score in community-based screening may therefore be an effective risk stratification strategy for targeting control measures in slum settings of high leptospirosis transmission.

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

PubMed Central

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 require the use of animal models for gathering robust data about mechanisms leading to IUGR and for testing the effectiveness and safety of the intervention among pregnant women. PMID:29230179

Hantavirus infection--southwestern United States: interim recommendations for risk reduction. Centers for Disease Control and Prevention.

PubMed

Childs, J E; Kaufmann, A F; Peters, C J; Ehrenberg, R L

1993-07-30

This report provides interim recommendations for prevention and control of hantavirus infections associated with rodents in the southwestern United States. It is based on principles of rodent and infection control and contains specific recommendations for reducing rodent shelter and food sources in and around the home, recommendations for eliminating rodents inside the home and preventing them from entering the home, precautions for preventing hantavirus infection while rodent-contaminated areas are being cleaned up, prevention measures for persons who have occupational exposure to wild rodents, and precautions for campers and hikers.

The role of rodents in avian influenza outbreaks in poultry farms: a review.

PubMed

Velkers, Francisca C; Blokhuis, Simon J; Veldhuis Kroeze, Edwin J B; Burt, Sara A

2017-12-01

Wild migratory birds are associated with global avian influenza virus (AIV) spread. Although direct contact with wild birds and contaminated fomites is unlikely in modern non-free range poultry farms applying biosecurity measures, AIV outbreaks still occur. This suggests involvement of other intermediate factors for virus transmission between wild birds and poultry. This review describes current evidence of the potential role of rodents in AIV transmission from wild birds to poultry and between poultry houses. Rodents can be abundant around poultry houses, share their habitat with waterfowl and can readily enter poultry houses. Survival of AIV from waterfowl in poultry house surroundings and on the coat of rodents suggests that rodents are likely to act as mechanical vector. AIVs can replicate in rodents without adaptation, resulting in high viral titres in lungs and nasal turbinates, virus presence in nasal washes and saliva, and transmission to naïve contact animals. Therefore, active AIV shedding by infected rodents may play a role in transmission to poultry. Further field and experimental studies are needed to provide evidence for a role of rodents in AIV epidemiology. Making poultry houses rodent-proof and the immediate surroundings unattractive for rodents are recommended as preventive measures against possible AIV introduction.

Knowledge Gaps in Rodent Pancreas Biology: Taking Human Pluripotent Stem Cell-Derived Pancreatic Beta Cells into Our Own Hands

PubMed Central

Santosa, Munirah Mohamad; Low, Blaise Su Jun; Pek, Nicole Min Qian; Teo, Adrian Kee Keong

2016-01-01

In the field of stem cell biology and diabetes, we and others seek to derive mature and functional human pancreatic β cells for disease modeling and cell replacement therapy. Traditionally, knowledge gathered from rodents is extended to human pancreas developmental biology research involving human pluripotent stem cells (hPSCs). While much has been learnt from rodent pancreas biology in the early steps toward Pdx1+ pancreatic progenitors, much less is known about the transition toward Ngn3+ pancreatic endocrine progenitors. Essentially, the later steps of pancreatic β cell development and maturation remain elusive to date. As a result, the most recent advances in the stem cell and diabetes field have relied upon combinatorial testing of numerous growth factors and chemical compounds in an arbitrary trial-and-error fashion to derive mature and functional human pancreatic β cells from hPSCs. Although this hit-or-miss approach appears to have made some headway in maturing human pancreatic β cells in vitro, its underlying biology is vaguely understood. Therefore, in this mini-review, we discuss some of these late-stage signaling pathways that are involved in human pancreatic β cell differentiation and highlight our current understanding of their relevance in rodent pancreas biology. Our efforts here unravel several novel signaling pathways that can be further studied to shed light on unexplored aspects of rodent pancreas biology. New investigations into these signaling pathways are expected to advance our knowledge in human pancreas developmental biology and to aid in the translation of stem cell biology in the context of diabetes treatments. PMID:26834702

Anaerobic threshold employed on exercise training prescription and performance assessment for laboratory rodents: A short review.

PubMed

Abreu, Phablo; Mendes, Sávio Victor Diogenes; Leal-Cardoso, José Henrique; Ceccatto, Vânia Marilande

2016-04-15

Several studies have generated numerous terms in the field of exercise training prescription and performance assessment that often do not match the information previously demonstrated by many other works, generating much debate and resulting in an immense pool of scientific results. Several protocols in exercise training prescription and performance assessment have been proposed for these purposes by many reasons. In the field of exercise science, the protocol must be thoroughly investigated and provide real tools to be reproducible. Many laboratories have been adapting and developing evaluation protocols and testing on physical training of rodents in different experimental conditions. In this context, mice, rats and rabbits are preferentially chosen due to easy manipulation and good response to exercise, and comparable at results obtained with humans in compatible effort intensities. But, the exercise training programs and aerobic-anaerobic transition assessment proposed for animal models vary extensively, depending on the species, gender, age, type of stimulus, type of exercise, type of method and also on the specific objectives of the program. This short review demonstrates the need in offering tools performed by invasive measurement to assess the anaerobic threshold by blood lactate employed on evolution of aerobic-anaerobic parameters of rodents. The objective of this short review was to present and to discuss physical evaluation protocols applications to rodents. The table submitted may give a basis for anaerobic threshold employed on exercise training prescription and performance assessment for laboratory rodents in future research. Copyright © 2016 Elsevier Inc. All rights reserved.

Knowledge Gaps in Rodent Pancreas Biology: Taking Human Pluripotent Stem Cell-Derived Pancreatic Beta Cells into Our Own Hands.

PubMed

Santosa, Munirah Mohamad; Low, Blaise Su Jun; Pek, Nicole Min Qian; Teo, Adrian Kee Keong

2015-01-01

In the field of stem cell biology and diabetes, we and others seek to derive mature and functional human pancreatic β cells for disease modeling and cell replacement therapy. Traditionally, knowledge gathered from rodents is extended to human pancreas developmental biology research involving human pluripotent stem cells (hPSCs). While much has been learnt from rodent pancreas biology in the early steps toward Pdx1(+) pancreatic progenitors, much less is known about the transition toward Ngn3(+) pancreatic endocrine progenitors. Essentially, the later steps of pancreatic β cell development and maturation remain elusive to date. As a result, the most recent advances in the stem cell and diabetes field have relied upon combinatorial testing of numerous growth factors and chemical compounds in an arbitrary trial-and-error fashion to derive mature and functional human pancreatic β cells from hPSCs. Although this hit-or-miss approach appears to have made some headway in maturing human pancreatic β cells in vitro, its underlying biology is vaguely understood. Therefore, in this mini-review, we discuss some of these late-stage signaling pathways that are involved in human pancreatic β cell differentiation and highlight our current understanding of their relevance in rodent pancreas biology. Our efforts here unravel several novel signaling pathways that can be further studied to shed light on unexplored aspects of rodent pancreas biology. New investigations into these signaling pathways are expected to advance our knowledge in human pancreas developmental biology and to aid in the translation of stem cell biology in the context of diabetes treatments.

Ecology of phlebotomine sandflies and putative reservoir hosts of leishmaniasis in a border area in Northeastern Mexico: implications for the risk of transmission of Leishmania mexicana in Mexico and the USA

PubMed Central

Rodríguez-Rojas, Jorge J.; Rodríguez-Moreno, Ángel; Berzunza-Cruz, Miriam; Gutiérrez-Granados, Gabriel; Becker, Ingeborg; Sánchez-Cordero, Victor; Stephens, Christopher R.; Fernández-Salas, Ildefonso; Rebollar-Téllez, Eduardo A.

2017-01-01

Leishmaniases are a group of important diseases transmitted to humans through the bite of sandfly vectors. Several forms of leishmaniases are endemic in Mexico and especially in the Southeast region. In the Northeastern region, however, there have only been isolated reports of cases and scanty records of sandfly vectors. The main objective of this study was to analyze the diversity of sandflies and potential reservoir hosts of Leishmania spp. in the states of Nuevo León and Tamaulipas. Species richness and abundances of sandflies and rodents were recorded. A fraction of the caught sandflies was analyzed by PCR to detect Leishmania spp. Tissues from captured rodents were also screened for infection. Ecological Niche Models (ENMs) were computed for species of rodent and their association with crop-growing areas. We found 13 species of sandflies, several of which are first records for this region. Medically important species such as Lutzomyia anthophora, Lutzomyia diabolica, Lutzomyia cruciata, and Lutzomyia shannoni were documented. Leishmania spp. infection was not detected in sandflies. Nine species of rodents were recorded, and Leishmania (Leishmania) mexicana infection was found in four species of Peromyscus and Sigmodon. ENMs showed that potential distribution of rodent pest species overlaps with allocated crop areas. This shows that Leishmania (L.) mexicana infection is present in the Northeastern region of Mexico, and that previously unrecorded sandfly species occur in the same areas. These findings suggest a potential risk of transmission of Leishmania (L.) mexicana. PMID:28825400

EEG Radiotelemetry in Small Laboratory Rodents: A Powerful State-of-the Art Approach in Neuropsychiatric, Neurodegenerative, and Epilepsy Research

PubMed Central

Lundt, Andreas; Wormuth, Carola; Siwek, Magdalena Elisabeth; Müller, Ralf; Henseler, Christina; Broich, Karl; Papazoglou, Anna; Weiergräber, Marco

2016-01-01

EEG radiotelemetry plays an important role in the neurological characterization of transgenic mouse models of neuropsychiatric and neurodegenerative diseases as well as epilepsies providing valuable insights into underlying pathophysiological mechanisms and thereby facilitating the development of new translational approaches. We elaborate on the major advantages of nonrestraining EEG radiotelemetry in contrast to restraining procedures such as tethered systems or jacket systems containing recorders. Whereas a main disadvantage of the latter is their unphysiological, restraining character, telemetric EEG recording overcomes these disadvantages. It allows precise and highly sensitive measurement under various physiological and pathophysiological conditions. Here we present a detailed description of a straightforward successful, quick, and efficient technique for intraperitoneal as well as subcutaneous pouch implantation of a standard radiofrequency transmitter in mice and rats. We further present computerized 3D-stereotaxic placement of both epidural and deep intracerebral electrodes. Preoperative preparation of mice and rats, suitable anaesthesia, and postoperative treatment and pain management are described in detail. A special focus is on fields of application, technical and experimental pitfalls, and technical connections of commercially available radiotelemetry systems with other electrophysiological setups. PMID:26819775

Restraint training for awake functional brain scanning of rodents can cause long-lasting changes in pain and stress responses

PubMed Central

Low, Lucie A.; Bauer, Lucy C.; Pitcher, Mark H.; Bushnell, M. Catherine

2016-01-01

Abstract With the increased interest in longitudinal brain imaging of awake rodents, it is important to understand both the short-term and long-term effects of restraint on sensory and emotional processing in the brain. To understand the effects of repeated restraint on pain behaviors and stress responses, we modeled a restraint protocol similar to those used to habituate rodents for magnetic resonance imaging scanning, and studied sensory sensitivity and stress hormone responses over 5 days. To uncover lasting effects of training, we also looked at responses to the formalin pain test 2 weeks later. We found that while restraint causes acute increases in the stress hormone corticosterone, it can also cause lasting reductions in nociceptive behavior in the formalin test, coupled with heightened corticosterone levels and increased activation of the “nociceptive” central nucleus of the amygdala, as seen by Fos protein expression. These results suggest that short-term repeated restraint, similar to that used to habituate rats for awake functional brain scanning, could potentially cause long-lasting changes in physiological and brain responses to pain stimuli that are stress-related, and therefore could potentially confound the functional activation patterns seen in awake rodents in response to pain stimuli. PMID:27058679

Restraint training for awake functional brain scanning of rodents can cause long-lasting changes in pain and stress responses.

PubMed

Low, Lucie A; Bauer, Lucy C; Pitcher, Mark H; Bushnell, M Catherine

2016-08-01

With the increased interest in longitudinal brain imaging of awake rodents, it is important to understand both the short-term and long-term effects of restraint on sensory and emotional processing in the brain. To understand the effects of repeated restraint on pain behaviors and stress responses, we modeled a restraint protocol similar to those used to habituate rodents for magnetic resonance imaging scanning, and studied sensory sensitivity and stress hormone responses over 5 days. To uncover lasting effects of training, we also looked at responses to the formalin pain test 2 weeks later. We found that while restraint causes acute increases in the stress hormone corticosterone, it can also cause lasting reductions in nociceptive behavior in the formalin test, coupled with heightened corticosterone levels and increased activation of the "nociceptive" central nucleus of the amygdala, as seen by Fos protein expression. These results suggest that short-term repeated restraint, similar to that used to habituate rats for awake functional brain scanning, could potentially cause long-lasting changes in physiological and brain responses to pain stimuli that are stress-related, and therefore could potentially confound the functional activation patterns seen in awake rodents in response to pain stimuli.

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

PubMed

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.

Rodent Brain Microinjection to Study Molecular Substrates of Motivated Behavior

PubMed Central

Poland, Ryan S.; Bull, Cecilia; Syed, Wahab A.; Bowers, M. Scott

2015-01-01

Brain microinjection can aid elucidation of the molecular substrates of complex behaviors, such as motivation. For this purpose rodents can serve as appropriate models, partly because the response to behaviorally relevant stimuli and the circuitry parsing stimulus-action outcomes is astonishingly similar between humans and rodents. In studying molecular substrates of complex behaviors, the microinjection of reagents that modify, augment, or silence specific systems is an invaluable technique. However, it is crucial that the microinjection site is precisely targeted in order to aid interpretation of the results. We present a method for the manufacture of surgical implements and microinjection needles that enables accurate microinjection and unlimited customizability with minimal cost. Importantly, this technique can be successfully completed in awake rodents if conducted in conjunction with other JoVE articles that covered requisite surgical procedures. Additionally, there are many behavioral paradigms that are well suited for measuring motivation. The progressive ratio is a commonly used method that quantifies the efficacy of a reinforcer to maintain responding despite an (often exponentially) increasing work requirement. This assay is sensitive to reinforcer magnitude and pharmacological manipulations, which allows reinforcing efficacy and/ or motivation to be determined. We also present a straightforward approach to program operant software to accommodate a progressive ratio reinforcement schedule. PMID:26437131

Sequencing the transcriptome of milk production: milk trumps mammary tissue.

PubMed

Lemay, Danielle G; Hovey, Russell C; Hartono, Stella R; Hinde, Katie; Smilowitz, Jennifer T; Ventimiglia, Frank; Schmidt, Kimberli A; Lee, Joyce W S; Islas-Trejo, Alma; Silva, Pedro Ivo; Korf, Ian; Medrano, Juan F; Barry, Peter A; German, J Bruce

2013-12-12

Studies of normal human mammary gland development and function have mostly relied on cell culture, limited surgical specimens, and rodent models. Although RNA extracted from human milk has been used to assay the mammary transcriptome non-invasively, this assay has not been adequately validated in primates. Thus, the objectives of the current study were to assess the suitability of lactating rhesus macaques as a model for lactating humans and to determine whether RNA extracted from milk fractions is representative of RNA extracted from mammary tissue for the purpose of studying the transcriptome of milk-producing cells. We confirmed that macaque milk contains cytoplasmic crescents and that ample high-quality RNA can be obtained for sequencing. Using RNA sequencing, RNA extracted from macaque milk fat and milk cell fractions more accurately represented RNA from mammary epithelial cells (cells that produce milk) than did RNA from whole mammary tissue. Mammary epithelium-specific transcripts were more abundant in macaque milk fat, whereas adipose or stroma-specific transcripts were more abundant in mammary tissue. Functional analyses confirmed the validity of milk as a source of RNA from milk-producing mammary epithelial cells. RNA extracted from the milk fat during lactation accurately portrayed the RNA profile of milk-producing mammary epithelial cells in a non-human primate. However, this sample type clearly requires protocols that minimize RNA degradation. Overall, we validated the use of RNA extracted from human and macaque milk and provided evidence to support the use of lactating macaques as a model for human lactation.

Fast simultaneous assessment of renal and liver function using polymethine dyes in animal models of chronic and acute organ injury.

PubMed

Press, A T; Butans, M J; Haider, T P; Weber, C; Neugebauer, S; Kiehntopf, M; Schubert, U S; Clemens, M G; Bauer, M; Kortgen, A

2017-11-13

Simultaneous assessment of excretory liver and kidney function is still an unmet need in experimental stress models as well as in critical care. The aim of the study was to characterize two polymethine-dyes potentially suitable for this purpose in vivo. Plasma disappearance rate and elimination measurements of simultaneously injected fluorescent dyes DY-780 (hepato-biliary elimination) and DY-654(renal elimination) were conducted using catheter techniques and intravital microscopy in animals subjected to different organ injuries, i.e. polymicrobial sepsis by peritoneal contamination and infection, ischemia-reperfusion-injury and glycerol-induced acute kidney-injury. DY-780 and DY-654 showed organ specific and determined elimination routes in both healthy and diseased animals. They can be measured simultaneously using near-infrared imaging and spectrophotometry. Plasma-disappearance rates of DY-780 and DY-654 are superior to conventional biomarkers in indicating hepatic or kidney dysfunction in different animal models. Greatest impact on liver function was found in animals with polymicrobial sepsis whereas glomerular damage due to glycerol-induced kidney-injury had strongest impact on DY-654 elimination. We therefore conclude that hepatic elimination and renal filtration can be assessed in rodents measuring plasma-disappearance rates of both dyes. Further, assessment of organ dysfunction by polymethine dyes correlates with, but outperforms conventional biomarkers regarding sensitivity and the option of spatial resolution if biophotonic strategies are applied. Polymethine-dye clearance thereby allows sensitive point-of-care assessment of both organ functions simultaneously.

Contrasting Patterns in Mammal–Bacteria Coevolution: Bartonella and Leptospira in Bats and Rodents

PubMed Central

Lei, Bonnie R.; Olival, Kevin J.

2014-01-01

Background Emerging bacterial zoonoses in bats and rodents remain relatively understudied. We conduct the first comparative host–pathogen coevolutionary analyses of bacterial pathogens in these hosts, using Bartonella spp. and Leptospira spp. as a model. Methodology/Principal Findings We used published genetic data for 51 Bartonella genotypes from 24 bat species, 129 Bartonella from 38 rodents, and 26 Leptospira from 20 bats. We generated maximum likelihood and Bayesian phylogenies for hosts and bacteria, and tested for coevoutionary congruence using programs ParaFit, PACO, and Jane. Bartonella spp. and their bat hosts had a significant coevolutionary fit (ParaFitGlobal = 1.9703, P≤0.001; m2 global value = 7.3320, P≤0.0001). Bartonella spp. and rodent hosts also indicated strong overall patterns of cospeciation (ParaFitGlobal = 102.4409, P≤0.001; m2 global value = 86.532, P≤0.0001). In contrast, we were unable to reject independence of speciation events in Leptospira and bats (ParaFitGlobal = 0.0042, P = 0.84; m2 global value = 4.6310, P = 0.5629). Separate analyses of New World and Old World data subsets yielded results congruent with analysis from entire datasets. We also conducted event-based cophylogeny analyses to reconstruct likely evolutionary histories for each group of pathogens and hosts. Leptospira and bats had the greatest number of host switches per parasite (0.731), while Bartonella and rodents had the fewest (0.264). Conclusions/Significance In both bat and rodent hosts, Bartonella exhibits significant coevolution with minimal host switching, while Leptospira in bats lacks evolutionary congruence with its host and has high number of host switches. Reasons underlying these variable coevolutionary patterns in host range are likely due to differences in disease-specific transmission and host ecology. Understanding the coevolutionary patterns and frequency of host-switching events between bacterial pathogens and their hosts will allow better prediction of spillover between mammal reservoirs, and ultimately to humans. PMID:24651646

The occurrence of the larval cestode Cysticercus fasciolaris in rodent populations from the Cuxtal ecological reserve, Yucatan, Mexico.

PubMed

Rodríguez-Vivas, R I; Panti-May, J A; Parada-López, J; Hernández-Betancourt, S F; Ruiz-Piña, H A

2011-12-01

Cysticercus fasciolaris is the larval stage of the cestode Taenia taeniaeformis, whose definitive hosts are mainly cats. This larval stage uses a wide variety of small rodents, and occasionally birds and humans, as intermediate hosts. In the Yucatan, there are no reports of the presence of this cestode in animal populations. The aim of this study was to evaluate the occurrence of C. fasciolaris in rodent populations from the Cuxtal ecological reserve, Yucatan, Mexico. Trapping of rodents was conducted from October 2009 to April 2010 in 40 households in Molas, in which Sherman traps were placed both inside and outside backyards. Rodents were dissected to inspect the liver for the presence of the worm. To determine risk factors associated with infection, univariate analysis was performed using sex, age, species, trapping site, and season as independent variables. Variables with a P value <  0.2 were analysed using a logistic regression model. In this study, 411 individuals of six rodent species were trapped; Mus musculus was the most abundant (78%), followed by Rattus rattus (13%) and the wild species Peromyscus yucatanicus, Ototylomys phyllotis, Heteromys gaumeri and Reithrodontomys gracilis (9%). Only 7.5% (n = 31) of M. musculus and R. rattus were infected with C. fasciolaris (demonstrated by the presence of liver cysts) with a prevalence of 9.0% and 3.5%, respectively. Both adults and male mice were 4.33 and 3.46 (OR values) times more likely to have C. fasciolaris than juveniles and females respectively. We can conclude that in the Cuxtal Reserve, Yucatan, Mexico, the prevalence of C. fasciolaris is higher in M. musculus, and that adult males had a higher probability of infection. Wild species, mainly P. yucatanicus, were not found to be infected with the cestode, but its presence in the backyards of households could result in a potential risk of acquiring this infection.

Adult neurogenesis and its anatomical context in the hippocampus of three mole-rat species

PubMed Central

Amrein, Irmgard; Becker, Anton S.; Engler, Stefanie; Huang, Shih-hui; Müller, Julian; Slomianka, Lutz; Oosthuizen, Maria K.

2014-01-01

African mole-rats (family Bathyergidae) are small to medium sized, long-lived, and strictly subterranean rodents that became valuable animal models as a result of their longevity and diversity in social organization. The formation and integration of new hippocampal neurons in adult mammals (adult hippocampal neurogenesis, AHN) correlates negatively with age and positively with habitat complexity. Here we present quantitative data on AHN in wild-derived mole-rats of 1 year and older, and briefly describe its anatomical context including markers of neuronal function (calbindin and parvalbumin). Solitary Cape mole-rats (Georychus capensis), social highveld mole-rats (Cryptomys hottentotus pretoriae), and eusocial naked mole-rats (Heterocephalus glaber) were assessed. Compared to other rodents, the hippocampal formation in mole-rats is small, but shows a distinct cytoarchitecture in the dentate gyrus and CA1. Distributions of the calcium-binding proteins differ from those seen in rodents; e.g., calbindin in CA3 of naked mole-rats distributes similar to the pattern seen in early primate development, and calbindin staining extends into the stratum lacunosum-moleculare of Cape mole-rats. Proliferating cells and young neurons are found in low numbers in the hippocampus of all three mole-rat species. Resident granule cell numbers are low as well. Proliferating cells expressed as a percentage of resident granule cells are in the range of other rodents, while the percentage of young neurons is lower than that observed in surface dwelling rodents. Between mole-rat species, we observed no difference in the percentage of proliferating cells. The percentages of young neurons are high in social highveld and naked mole-rats, and low in solitary Cape mole-rats. The findings support that proliferation is regulated independently of average life expectancy and habitat. Instead, neuronal differentiation reflects species-specific demands, which appear lower in subterranean rodents. PMID:24904308

Barnes maze testing strategies with small and large rodent models.

PubMed

Rosenfeld, Cheryl S; Ferguson, Sherry A

2014-02-26

Spatial learning and memory of laboratory rodents is often assessed via navigational ability in mazes, most popular of which are the water and dry-land (Barnes) mazes. Improved performance over sessions or trials is thought to reflect learning and memory of the escape cage/platform location. Considered less stressful than water mazes, the Barnes maze is a relatively simple design of a circular platform top with several holes equally spaced around the perimeter edge. All but one of the holes are false-bottomed or blind-ending, while one leads to an escape cage. Mildly aversive stimuli (e.g. bright overhead lights) provide motivation to locate the escape cage. Latency to locate the escape cage can be measured during the session; however, additional endpoints typically require video recording. From those video recordings, use of automated tracking software can generate a variety of endpoints that are similar to those produced in water mazes (e.g. distance traveled, velocity/speed, time spent in the correct quadrant, time spent moving/resting, and confirmation of latency). Type of search strategy (i.e. random, serial, or direct) can be categorized as well. Barnes maze construction and testing methodologies can differ for small rodents, such as mice, and large rodents, such as rats. For example, while extra-maze cues are effective for rats, smaller wild rodents may require intra-maze cues with a visual barrier around the maze. Appropriate stimuli must be identified which motivate the rodent to locate the escape cage. Both Barnes and water mazes can be time consuming as 4-7 test trials are typically required to detect improved learning and memory performance (e.g. shorter latencies or path lengths to locate the escape platform or cage) and/or differences between experimental groups. Even so, the Barnes maze is a widely employed behavioral assessment measuring spatial navigational abilities and their potential disruption by genetic, neurobehavioral manipulations, or drug/ toxicant exposure.

Hunting, Food Preparation, and Consumption of Rodents in Lao PDR

PubMed Central

Suwannarong, Kanokwan; Chapman, Robert S.; Lantican, Cecile; Michaelides, Tula; Zimicki, Susan

2015-01-01

A cross-sectional study was conducted in 29 villages of Khamkeuth District in Bolikhamxay Province in the Lao PDR during March to May 2013. The study aimed to determine the characteristics associated with rodent consumption and related behaviors among different ethnic groups, ages, and genders. Five-hundred-eighty-four (584) males and females from 18-50 years of age participated in this study. Half of them were Hmong (292, 50%) while 152 respondents were Lao-Tai (26%) or other ethnic groups (140, 24%). Most of the respondents (79.5%) had farming as their main occupation. Prevalences of the studied outcomes were high: 39.9 for hunting or capturing rodents in the previous year, 77.7% for preparing rodents as food, and 86.3% for rodent consumption. Multivariable logistic regression analysis showed that likelihood of these types of rodent contact was more consistently associated with behavioral factors (gathering things from the forest and elsewhere, cultivation-related activities, and taking measures to prevent rodent-borne disease) than with socio-demographic, environmental, or cultural factors. The strongest associations were observed for gathering things; these associations were consistently positive and statistically significant. Although this study did not directly assess rodent-borne zoonosis risk, we believe that study findings raise concern that such risk may be substantial in the study area and other similar areas. Further epidemiological studies on the association between rodent-borne disease infection and rodent hunting, preparation for food, and consumption are recommended. Moreover, further studies are needed on the association between these potential exposure factors (i.e., rodent hunting, preparation for food, and consumption) and rodent-borne infections, especially among ethnic groups like the Hmong in Lao PDR and those in neighboring countries with similar socio-demographic, environmental, behavioral and cultural contexts. PMID:26196134

Hunting, Food Preparation, and Consumption of Rodents in Lao PDR.

PubMed

Suwannarong, Kanokwan; Chapman, Robert S; Lantican, Cecile; Michaelides, Tula; Zimicki, Susan

2015-01-01

A cross-sectional study was conducted in 29 villages of Khamkeuth District in Bolikhamxay Province in the Lao PDR during March to May 2013. The study aimed to determine the characteristics associated with rodent consumption and related behaviors among different ethnic groups, ages, and genders. Five-hundred-eighty-four (584) males and females from 18-50 years of age participated in this study. Half of them were Hmong (292, 50%) while 152 respondents were Lao-Tai (26%) or other ethnic groups (140, 24%). Most of the respondents (79.5%) had farming as their main occupation. Prevalences of the studied outcomes were high: 39.9 for hunting or capturing rodents in the previous year, 77.7% for preparing rodents as food, and 86.3% for rodent consumption. Multivariable logistic regression analysis showed that likelihood of these types of rodent contact was more consistently associated with behavioral factors (gathering things from the forest and elsewhere, cultivation-related activities, and taking measures to prevent rodent-borne disease) than with socio-demographic, environmental, or cultural factors. The strongest associations were observed for gathering things; these associations were consistently positive and statistically significant. Although this study did not directly assess rodent-borne zoonosis risk, we believe that study findings raise concern that such risk may be substantial in the study area and other similar areas. Further epidemiological studies on the association between rodent-borne disease infection and rodent hunting, preparation for food, and consumption are recommended. Moreover, further studies are needed on the association between these potential exposure factors (i.e., rodent hunting, preparation for food, and consumption) and rodent-borne infections, especially among ethnic groups like the Hmong in Lao PDR and those in neighboring countries with similar socio-demographic, environmental, behavioral and cultural contexts.

Glaucoma

MedlinePlus

... damage in animal models of elevated IOP. Nerve cell regeneration is another approach to repairing neuronal tissue damaged ... or injury. NIH-supported researchers recently provoked nerve cell regeneration in rodents by activating a nerve cell’s natural ...

Epidemiological Distribution of Rodents as Potent Reservoirs for Infectious Diseases in the Provinces of Mazandaran, Gilan and Golestan, Northern Iran

PubMed Central

Esfandiari, Behzad; Pourshafie, Mohammad Reza; Gouya, Mohammad Mehdi; Khaki, Pejvak; Mostafavi, Ehsan; Darvish, Jamshid; Hanifi, Hamed

2017-01-01

Rodents are mammals that comprise more than 2000 species and approximately 30 families. There are many morphological and ecological differences among them as variations in their shape, size, weight and habitat. In addition to significant economic losses, rodents have a major role in the dissemination of infectious diseases caused by viruses, bacteria, parasites or other micro-organisms. Rodents are important reservoirs of diseases which have been observed in many cities of Iran provinces especially along Caspian Sea border to Alborz Mountain. The aim of this study is to assess the geographical distribution of rodents in three provinces of northern part of Iran as reservoir of potential endemic infectious diseases. Rodents in 10 major parts of each of the three provinces of Mazandaran, Gilan and Golestan, northern Iran were collected and a total of 404 rodents were trapped alive. They were determined by the key characteristics such as gender, genus, species, different locations and topological situation. Statistical analysis was performed to characterize the study sample and to correlate all variables and parameters. The distribution frequencies of three, five and six genera of rodents were identified in Mazandaran, Gilan and Golestan provinces respectively. The overall distribution frequency of eight genera of rodents in the three provinces were identified as Rattus (R.) norvegicus (67.3%), R. rattus (13.6%), Apodemus sylvaticus (13.9%), Arvicola (1%), Mus musculus (0.3%), Nesokia indica (2.5%), Cricetulus migrates (0.7%) and Rhombomys opimus (0.7%). The results of this study determined the geographic distribution of the rodents in the three northern provinces of Iran. It is indicated the association of various distribution and diversity of rodents with provincial location. The overall distribution frequency of eight genera of rodents was recognized in the above three provinces geographical locations. This study confirms epidemiological distribution of various rodents as potent reservoirs for infectious diseases, such as leptospirosis, salmonellosis, tularemia, leishmaniasis, etc. in the three provinces. PMID:28626537

Characterization of a Melamino Nitroheterocycle as a Potential Lead for the Treatment of Human African Trypanosomiasis

PubMed Central

Giordani, Federica; Buschini, Annamaria; Baliani, Alessandro; Kaiser, Marcel; Brun, Reto; Barrett, Michael P.; Pellacani, Claudia; Poli, Paola

2014-01-01

This paper reports an evaluation of a melamino nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties, and potential for toxicity are described. The compound previously had been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse model T. brucei rhodesiense STIB 900 when given intraperitoneally at 40 mg/kg of body weight. Nevertheless, activity was only moderate when the oral route was used, and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage by a mechanism apparently independent from nitroreduction and involving the introduction of base pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential. PMID:25022590

An acellular biologic scaffold does not regenerate appreciable de novo muscle tissue in rat models of volumetric muscle loss injury.

PubMed

Aurora, Amit; Roe, Janet L; Corona, Benjamin T; Walters, Thomas J

2015-10-01

Extracellular matrix (ECM) derived scaffolds continue to be investigated for the treatment of volumetric muscle loss (VML) injuries. Clinically, ECM scaffolds have been used for lower extremity VML repair; in particular, MatriStem™, a porcine urinary bladder matrix (UBM), has shown improved functional outcomes and vascularization, but limited myogenesis. However, efficacy of the scaffold for the repair of traumatic muscle injuries has not been examined systematically. In this study, we demonstrate that the porcine UBM scaffold when used to repair a rodent gastrocnemius musculotendinous junction (MTJ) and tibialis anterior (TA) VML injury does not support muscle tissue regeneration. In the MTJ model, the scaffold was completely resorbed without tissue remodeling, suggesting that the scaffold may not be suitable for the clinical repair of muscle-tendon injuries. In the TA VML injury, the scaffold remodeled into a fibrotic tissue and showed functional improvement, but not due to muscle fiber regeneration. The inclusion of physical rehabilitation also did not improve functional response or tissue remodeling. We conclude that the porcine UBM scaffold when used to treat VML injuries may hasten the functional recovery through the mechanism of scaffold mediated functional fibrosis. Thus for appreciable muscle regeneration, repair strategies that incorporate myogenic cells, vasculogenic accelerant and a myoconductive scaffold need to be developed. Published by Elsevier Ltd.

Adult-Onset Fluoxetine Treatment Does Not Improve Behavioral Impairments and May Have Adverse Effects on the Ts65Dn Mouse Model of Down Syndrome

PubMed Central

Heinen, Markus; Hettich, Moritz M.; Ryan, Devon P.; Schnell, Susanne; Paesler, Katharina; Ehninger, Dan

2012-01-01

Down syndrome is caused by triplication of chromosome 21 and is associated with neurocognitive phenotypes ranging from severe intellectual disability to various patterns of more selective neuropsychological deficits, including memory impairments. In the Ts65Dn mouse model of Down syndrome, excessive GABAergic neurotransmission results in local over-inhibition of hippocampal circuits, which dampens hippocampal synaptic plasticity and contributes to cognitive impairments. Treatments with several GABAA receptor antagonists result in increased plasticity and improved memory deficits in Ts65Dn mice. These GABAA receptor antagonists are, however, not suitable for clinical applications. The selective serotonin reuptake inhibitor fluoxetine, in contrast, is a widely prescribed antidepressant that can also enhance plasticity in the adult rodent brain by lowering GABAergic inhibition. For these reasons, we wondered if an adult-onset 4-week oral fluoxetine treatment restores spatial learning and memory impairments in Ts65Dn mice. Fluoxetine did not measurably improve behavioral impairments of Ts65Dn mice. On the contrary, we observed seizures and mortality in fluoxetine-treated Ts65Dn mice, raising the possibility of a drug × genotype interaction with respect to these adverse treatment outcomes. Future studies should re-address this in larger animal cohorts and determine if fluoxetine treatment is associated with adverse treatment effects in individuals with Down syndrome. PMID:22848851

Prevalence of Lassa virus among rodents trapped in three South-South States of Nigeria.

PubMed

Agbonlahor, D E; Erah, A; Agba, I M; Oviasogie, F E; Ehiaghe, A F; Wankasi, M; Eremwanarue, O A; Ehiaghe, I J; Ogbu, E C; Iyen, R I; Abbey, S; Tatfeng, M Y; Uhunmwangho, J

2017-01-01

Lassa fever has been endemic in Nigeria since 1969. The rodent Mastomys natalensis has been widely claimed to be the reservoir host of the Lassa virus. This study was designed to investigate the dis- tribution of species of rodents in three states (Edo, Delta and Bayelsa) of Nigeria and to determine the prevalence of Lassa virus amongst trapped rodents in the selected states. Rodents were trapped during November 2015 to October 2016 from the three states in South-South re- gion of Nigeria. Total RNA was extracted from the blood collected from the trapped rodents. Reverse transcription polymerase chain reaction (RT-PCR) was used to confirm the presence of Lassa virus in the rodents. The results revealed that six species of rodents were predominantly present in these geographical locations. Mus musculus (39.4%) had the highest prevalence, closely followed by Rattus rattus (36.1%), R. fuscipus (20.3%), M. natalensis (2%), Myosoricinae soricidae (1.2%) and R. norvegicus (1%). The overall positivity (carrier rate) of Lassa virus was 1.6% amongst the 1500 rodents caught in the three states. In Edo and Delta States, the RT-PCR results showed presence of Lassa virus in R. rattus, M. musculus and M. natalensis. On the other hand, only M. na- talensis was detected with the virus, amongst the species of rodents caught in Bayelsa State. M. natalensis recorded the highest Lassa virus among rodents trapped in Edo (87%), Delta (50%) and Bayelsa (11%) States respectively. The rather low Lassa virus positive among rodents in Bayelsa State of Nigeria may explain the absence of reports of outbreak of Lassa fever over the past 48 yr in the state. The results also confirmed that apart from Mastomys natalensis, other rodents such as Rattus rattus and Mus musculus may also serve as res- ervoirs for Lassa virus. From the findings of this cross-sectional study, it was concluded that a more comprehensive study on rodents as reservoir host, need to be undertaken across the entire states of Nigeria, for better understanding of the epidemiology and endemicity of Lassa fever.

Mode of action in relevance of rodent liver tumors to human cancer risk.

PubMed

Holsapple, Michael P; Pitot, Henri C; Cohen, Samuel M; Cohen, Samuel H; Boobis, Alan R; Klaunig, James E; Pastoor, Timothy; Dellarco, Vicki L; Dragan, Yvonne P

2006-01-01

Hazard identification and risk assessment paradigms depend on the presumption of the similarity of rodents to humans, yet species specific responses, and the extrapolation of high-dose effects to low-dose exposures can affect the estimation of human risk from rodent data. As a consequence, a human relevance framework concept was developed by the International Programme on Chemical Safety (IPCS) and International Life Sciences Institute (ILSI) Risk Science Institute (RSI) with the central tenet being the identification of a mode of action (MOA). To perform a MOA analysis, the key biochemical, cellular, and molecular events need to first be established, and the temporal and dose-dependent concordance of each of the key events in the MOA can then be determined. The key events can be used to bridge species and dose for a given MOA. The next step in the MOA analysis is the assessment of biological plausibility for determining the relevance of the specified MOA in an animal model for human cancer risk based on kinetic and dynamic parameters. Using the framework approach, a MOA in animals could not be defined for metal overload. The MOA for phenobarbital (PB)-like P450 inducers was determined to be unlikely in humans after kinetic and dynamic factors were considered. In contrast, after these factors were considered with reference to estrogen, the conclusion was drawn that estrogen-induced tumors were plausible in humans. Finally, it was concluded that the induction of rodent liver tumors by porphyrogenic compounds followed a cytotoxic MOA, and that liver tumors formed as a result of sustained cytotoxicity and regenerative proliferation are considered relevant for evaluating human cancer risk if appropriate metabolism occurs in the animal models and in humans.

Estrogen receptors in skeletal metabolism: lessons from genetically modified models of receptor function.

PubMed

McCauley, Laurie K; Tözüm, Tolga F; Rosol, Thomas J

2002-01-01

Estrogens have long been known to be important for skeletal homeostasis, but their precise mechanisms of action in bone are still unclear. Mice with targeted deletions of the estrogen receptors alpha (ERalpha) and beta (ERbeta) have been generated by two research groups and several studies performed characterizing the phenotype of ERalpha knockout (ERKOalpha), ERbeta knockout (ERKObeta), or double deletion of ERalpha and ERbeta (DERKO) mice. Initial studies reported a reduction in bone mineral density in male ERKOalpha mice. More extensive analyses have been puzzling, likely because of compensatory mechanisms in ERKO mice. Furthermore, the existence of a third ER continues to be a potential explanation for some actions of estrogen in bone. Other rodent models, including the testicular feminized mouse and rat, the aromatase knockout mouse, and a rat with a dominant negative ER mutation, have added information regarding estrogen's actions in bone. This review summarizes many reports characterizing available rodent models with genetic alterations relevant to estrogen action. The sum of these reports suggests that the ERbeta is not highly protective in bone because loss of its function results in minimal alterations in the skeleton. Furthermore, loss of both the ERalpha and the ERbeta does not account for loss of estrogen action in bone, because the impact of DERKO is seemingly not as great as the impact of gonadectomy on the skeleton. Finally, through studies of ERKO mice and other rodent models of altered sex steroid action, it appears that estrogen may be more protective in the skeleton than androgens.

Genomic variants in an inbred mouse model predict mania-like behaviors.

PubMed

Saul, Michael C; Stevenson, Sharon A; Zhao, Changjiu; Driessen, Terri M; Eisinger, Brian E; Gammie, Stephen C

2018-01-01

Contemporary rodent models for bipolar disorders split the bipolar spectrum into complimentary behavioral endophenotypes representing mania and depression. Widely accepted mania models typically utilize single gene transgenics or pharmacological manipulations, but inbred rodent strains show great potential as mania models. Their acceptance is often limited by the lack of genotypic data needed to establish construct validity. In this study, we used a unique strategy to inexpensively explore and confirm population allele differences in naturally occurring candidate variants in a manic rodent strain, the Madison (MSN) mouse strain. Variants were identified using whole exome resequencing on a small population of animals. Interesting candidate variants were confirmed in a larger population with genotyping. We enriched these results with observations of locomotor behavior from a previous study. Resequencing identified 447 structural variants that are mostly fixed in the MSN strain relative to control strains. After filtering and annotation, we found 11 non-synonymous MSN variants that we believe alter protein function. The allele frequencies for 6 of these variants were consistent with explanatory variants for the Madison strain's phenotype. The variants are in the Npas2, Cp, Polr3c, Smarca4, Trpv1, and Slc5a7 genes, and many of these genes' products are in pathways implicated in human bipolar disorders. Variants in Smarca4 and Polr3c together explained over 40% of the variance in locomotor behavior in the Hsd:ICR founder strain. These results enhance the MSN strain's construct validity and implicate altered nucleosome structure and transcriptional regulation as a chief molecular system underpinning behavior.

Activation of the maternal immune system during pregnancy alters behavioral development of rhesus monkey offspring.

PubMed

Bauman, Melissa D; Iosif, Ana-Maria; Smith, Stephen E P; Bregere, Catherine; Amaral, David G; Patterson, Paul H

2014-02-15

Maternal infection during pregnancy is associated with an increased risk of schizophrenia and autism in the offspring. Supporting this correlation, experimentally activating the maternal immune system during pregnancy in rodents produces offspring with abnormal brain and behavioral development. We have developed a nonhuman primate model to bridge the gap between clinical populations and rodent models of maternal immune activation (MIA). A modified form of the viral mimic, synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-L-lysine) was delivered to two separate groups of pregnant rhesus monkeys to induce MIA: 1) late first trimester MIA (n = 6), and 2) late second trimester MIA (n = 7). Control animals (n = 11) received saline injections at the same first or second trimester time points or were untreated. Sickness behavior, temperature, and cytokine profiles of the pregnant monkeys confirmed a strong inflammatory response to MIA. Behavioral development of the offspring was studied for 24 months. Following weaning at 6 months of age, MIA offspring exhibited abnormal responses to separation from their mothers. As the animals matured, MIA offspring displayed increased repetitive behaviors and decreased affiliative vocalizations. When evaluated with unfamiliar conspecifics, first trimester MIA offspring deviated from species-typical macaque social behavior by inappropriately approaching and remaining in immediate proximity of an unfamiliar animal. In this rhesus monkey model, MIA yields offspring with abnormal repetitive behaviors, communication, and social interactions. These results extended the findings in rodent MIA models to more human-like behaviors resembling those in both autism and schizophrenia. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

[Population change of farmland rodent and the influences of climate and cultivation factors in Fengxian District of Shanghai, China].

PubMed

Fei, Lei; Wang, Zu-guo; Yao, Yao; Xu, Xiang-ming; Gu, Pin-qiang

2015-02-01

We analyzed the changes of rodent population from 1988 to 2013 in Fengxian District, Shanghai, and discussed the relevance of rodent population dynamics and climate, and ecological factors. Results showed that the average rat density was 1.3% from 1988 to 2013, and the dominant species was Apodemus agrarius. There was little change of density between years. The average composition ratio was 97.5%. The peak of rodent density appeared from February to May, highest in March. Average density and peak decreased obviously year after year. Numbers of adult rodents of 1st group were positively correlated, while that of adult rodents of 2nd group and elderly group negatively correlated with years. Rat age presented a shortened trend annually. Rodent density and temperature factors were negatively correlated except in January. Extreme warmth in February had a lagged, positive effect on the rat density. Precipitation factors had no significant correlation with the density of rodents. Relative humidity was positively correlated with the density, mostly. Planting structure adjustment and reduction of planting acreage were significantly correlated with the reduction of rodent density. Increased deratization rate was also correlated with the reduction.

Hair corticosterone measurement in mouse models of type 1 and type 2 diabetes mellitus.

PubMed

Erickson, Rebecca L; Browne, Caroline A; Lucki, Irwin

2017-09-01

In diabetes, glucocorticoid secretion increases secondary to hyperglycemia and is associated with an extensive list of disease complications. Levels of cortisol in humans, or corticosterone in rodents, are usually measured as transitory biomarkers of stress in blood or saliva. Glucocorticoid concentrations accumulate in human or animal hair over weeks and could more accurately measure the cumulative stress burden of diseases like chronic diabetes. In this study, corticosterone levels were measured in hair in verified rodent models of diabetes mellitus. To induce type 1 diabetes, C57BL/6J mice were injected with streptozotocin and blood and hair samples were collected 28days following induction. Leptin receptor deficient (db/db) mice were used as a spontaneous model of type 2 diabetes and blood and hair samples were collected at 8weeks of age, after the development of hyperglycemia and obesity. Corticosterone levels from serum, new growth hair and total growth hair were analyzed using an enzyme immunoassay. Corticosterone levels in new growth hair and serum were significantly elevated in both models of diabetes compared to controls. In contrast, corticosterone levels in old hair growth did not differ significantly between diabetic and non-diabetic animals. Thus, hair removal and sampling of new hair growth was a more sensitive procedure for detecting changes in hair corticosterone levels induced by periods of hyperglycemia lasting for 4weeks in mice. These results validate the use of hair to measure long-term changes in corticosterone induced by diabetes in rodent models. Further studies are now needed to validate the utility of hair cortisol as a tool for measuring the stress burden of individuals with diabetes and for following the effects of long-term medical treatments. Copyright © 2017 Elsevier Inc. All rights reserved.

20 CFR 654.415 - Insect and rodent control.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Insect and rodent control. 654.415 Section 654.415 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF LABOR SPECIAL... Insect and rodent control. Housing and facilities shall be free of insects, rodents, and other vermin. ...