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Sample records for adult rodent models

  1. Rodent models of osteoporosis

    PubMed Central

    Sophocleous, Antonia; Idris, Aymen I

    2014-01-01

    The aim of this protocol is to provide a detailed description of male and female rodent models of osteoporosis. In addition to indications on the methods of performing the surgical procedures, the choice of reliable and safe anaesthetics is also described. Post-operative care, including analgesia administration for pain management, is also discussed. Ovariectomy in rodents is a procedure where ovaries are surgically excised. Hormonal changes resulting from ovary removal lead to an oestrogen-deprived state, which enhances bone remodelling, causes bone loss and increases bone fracture risk. Therefore, ovariectomy has been considered as the most common preclinical model for understanding the pathophysiology of menopause-associated events and for developing new treatment strategies for tackling post-menopausal osteoporosis. This protocol also provides a detailed description of orchidectomy, a model for androgen-deficient osteoporosis in rodents. Endocrine changes following testes removal lead to hypogonadism, which results in accelerated bone loss, increasing osteoporosis risk. Orchidectomised rodent models have been proposed to mimic male osteoporosis and therefore remain a valuable tool for understanding androgen deficiency in aged men. Although it would have been particularly difficult to assemble an internationally acceptable description of surgical procedures, here we have attempted to provide a comprehensive guide for best practice in performing ovariectomy and orchidectomy in laboratory rodents. Research scientists are reminded that they should follow their own institution's interpretation of such guidelines. Ultimately, however, all animal procedures must be overseen by the local Animal Welfare and Ethical Review Body and conducted under licences approved by a regulatory ethics committee. PMID:25852854

  2. Moxidectin causes adult worm mortality of human lymphatic filarial parasite Brugia malayi in rodent models.

    PubMed

    Verma, Meenakshi; Pathak, Manisha; Shahab, Mohd; Singh, Kavita; Mitra, Kalyan; Misra-Bhattacharya, Shailja

    2014-12-01

    Moxidectin is a macrocyclic lactone belonging to milbemycin family closely related to ivermectin and is currently progressing towards Phase III clinical trial against human infection with the filaria Onchocerca volvulus (Leuckart, 1894). There is a single report on the microfilaricidal and embryostatic activity of moxidectin in case of the human lymphatic filarial parasite Brugia malayi (Brug, 1927) in Mastomys coucha (Smith) but without any adulticidal action. In the present study, the in vitro and in vivo antifilarial efficacy of moxidectin was evaluated on, B. malayi. In vitro moxidectin showed 100% reduction in adult female worm motility at 0.6 μM concentration within 7 days with 68% inhibition in the reduction of MTT (3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye) (which is used to detect viability of worms). A 50% inhibitory concentration (IC50) of moxidectin for adult female parasite was 0.242 μM, for male worm 0.186 μM and for microfilaria IC50 was 0.813 μM. In adult B. malayi-transplanted primary screening model (Meriones unguiculatus Milne-Edwards), moxidectin at a single optimal dose of 20 mg/kg by oral and subcutaneous route was found effective on both adult parasites and microfilariae. In secondary screening (M coucha, subcutaneously inoculated with infective larvae), moxidectin at the same dose by subcutaneous route brought about death of 49% of adult worms besides causing sterilisation in 54% of the recovered live female worms. The treated animals exhibited a continuous and sustained reduction in peripheral blood microfilaraemia throughout the observation period of 90 days. The mechanism of action of moxidectin is suggested to be similar to avermectins. The in silico studies were also designed to explore the interaction of moxidectin with glutamate-gated chloride channels of B. malayi. The docking results revealed a close interaction of moxidectin with various GluCl ligand sites of B. malayi. PMID:25651699

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

    PubMed Central

    Bonaccorsi, Joyce; Berardi, Nicoletta; Sale, Alessandro

    2014-01-01

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

  4. Rodent models of cerebral ischemia

    SciTech Connect

    Ginsberg, M.D.; Busto, R. )

    1989-12-01

    The use of physiologically regulated, reproducible animal models is crucial to the study of ischemic brain injury--both the mechanisms governing its occurrence and potential therapeutic strategies. Several laboratory rodent species (notably rats and gerbils), which are readily available at relatively low cost, are highly suitable for the investigation of cerebral ischemia and have been widely employed for this purpose. We critically examine and summarize several rodent models of transient global ischemia, resulting in selective neuronal injury within vulnerable brain regions, and focal ischemia, typically giving rise to localized brain infarction. We explore the utility of individual models and emphasize the necessity for meticulous experimental control of those variables that modulate the severity of ischemic brain injury.169 references.

  5. Voluntary exercise induces adult hippocampal neurogenesis and BDNF expression in a rodent model of fetal alcohol spectrum disorders.

    PubMed

    Boehme, Fanny; Gil-Mohapel, Joana; Cox, Adrian; Patten, Anna; Giles, Erica; Brocardo, Patricia S; Christie, Brian R

    2011-05-01

    Alcohol consumption during pregnancy can result in a myriad of health problems in the affected offspring ranging from growth deficiencies to central nervous system impairments that result in cognitive deficits. Adult hippocampal neurogenesis is thought to play a role in cognition (i.e. learning and memory) and can be modulated by extrinsic factors such as alcohol consumption and physical exercise. We examined the impact of voluntary physical exercise on adult hippocampal neurogenesis in a rat model of fetal alcohol spectrum disorders (FASD). Intragastric intubation was used to deliver ethanol to rats in a highly controlled fashion through all three trimester equivalents (i.e. throughout gestation and during the first 10 days of postnatal life). Ethanol-exposed animals and their pair-fed and ad libitum controls were left undisturbed until they reached a young adult stage at which point they had free access to a running wheel for 12 days. Prenatal and early postnatal ethanol exposure altered cell proliferation in young adult female rats and increased early neuronal maturation without affecting cell survival in the dentate gyrus (DG) of the hippocampus. Voluntary wheel running increased cell proliferation, neuronal maturation and cell survival as well as levels of brain-derived neurotrophic factor in the DG of both ethanol-exposed female rats and their pair-fed and ad libitum controls. These results indicate that the capacity of the brain to respond to exercise is not impaired in this model of FASD, highlighting the potential therapeutic value of physical exercise for this developmental disorder. PMID:21535455

  6. Active training for amblyopia in adult rodents

    PubMed Central

    Sale, Alessandro; Berardi, Nicoletta

    2015-01-01

    Amblyopia is the most diffused form of visual function impairment affecting one eye, with a prevalence of 1–5% in the total world population. Amblyopia is usually caused by an early functional imbalance between the two eyes, deriving from anisometropia, strabismus, or congenital cataract, leading to severe deficits in visual acuity, contrast sensitivity and stereopsis. While amblyopia can be efficiently treated in children, it becomes irreversible in adults, as a result of a dramatic decline in visual cortex plasticity which occurs at the end of the critical period (CP) in the primary visual cortex. Notwithstanding this widely accepted dogma, recent evidence in animal models and in human patients have started to challenge this view, revealing a previously unsuspected possibility to enhance plasticity in the adult visual system and to achieve substantial visual function recovery. Among the new proposed intervention strategies, non invasive procedures based on environmental enrichment, physical exercise or visual perceptual learning (vPL) appear particularly promising in terms of future applicability in the clinical setting. In this survey, we will review recent literature concerning the application of these behavioral intervention strategies to the treatment of amblyopia, with a focus on possible underlying molecular and cellular mechanisms. PMID:26578911

  7. Active training for amblyopia in adult rodents.

    PubMed

    Sale, Alessandro; Berardi, Nicoletta

    2015-01-01

    Amblyopia is the most diffused form of visual function impairment affecting one eye, with a prevalence of 1-5% in the total world population. Amblyopia is usually caused by an early functional imbalance between the two eyes, deriving from anisometropia, strabismus, or congenital cataract, leading to severe deficits in visual acuity, contrast sensitivity and stereopsis. While amblyopia can be efficiently treated in children, it becomes irreversible in adults, as a result of a dramatic decline in visual cortex plasticity which occurs at the end of the critical period (CP) in the primary visual cortex. Notwithstanding this widely accepted dogma, recent evidence in animal models and in human patients have started to challenge this view, revealing a previously unsuspected possibility to enhance plasticity in the adult visual system and to achieve substantial visual function recovery. Among the new proposed intervention strategies, non invasive procedures based on environmental enrichment, physical exercise or visual perceptual learning (vPL) appear particularly promising in terms of future applicability in the clinical setting. In this survey, we will review recent literature concerning the application of these behavioral intervention strategies to the treatment of amblyopia, with a focus on possible underlying molecular and cellular mechanisms. PMID:26578911

  8. Pediatric Rodent Models of Traumatic Brain Injury.

    PubMed

    Semple, Bridgette D; Carlson, Jaclyn; Noble-Haeusslein, Linda J

    2016-01-01

    Due to a high incidence of traumatic brain injury (TBI) in children and adolescents, age-specific studies are necessary to fully understand the long-term consequences of injuries to the immature brain. Preclinical and translational research can help elucidate the vulnerabilities of the developing brain to insult, and provide model systems to formulate and evaluate potential treatments aimed at minimizing the adverse effects of TBI. Several experimental TBI models have therefore been scaled down from adult rodents for use in juvenile animals. The following chapter discusses these adapted models for pediatric TBI, and the importance of age equivalence across species during model development and interpretation. Many neurodevelopmental processes are ongoing throughout childhood and adolescence, such that neuropathological mechanisms secondary to a brain insult, including oxidative stress, metabolic dysfunction and inflammation, may be influenced by the age at the time of insult. The long-term evaluation of clinically relevant functional outcomes is imperative to better understand the persistence and evolution of behavioral deficits over time after injury to the developing brain. Strategies to modify or protect against the chronic consequences of pediatric TBI, by supporting the trajectory of normal brain development, have the potential to improve quality of life for brain-injured children. PMID:27604726

  9. beta-Catenin initiates tooth neogenesis in adult rodent incisors.

    PubMed

    Liu, F; Dangaria, S; Andl, T; Zhang, Y; Wright, A C; Damek-Poprawa, M; Piccolo, S; Nagy, A; Taketo, M M; Diekwisch, T G H; Akintoye, S O; Millar, S E

    2010-09-01

    beta-Catenin signaling is required for embryonic tooth morphogenesis and promotes continuous tooth development when activated in embryos. To determine whether activation of this pathway in the adult oral cavity could promote tooth development, we induced mutation of epithelial beta-catenin to a stabilized form in adult mice. This caused increased proliferation of the incisor tooth cervical loop, outpouching of incisor epithelium, abnormal morphology of the epithelial-mesenchymal junction, and enhanced expression of genes associated with embryonic tooth development. Ectopic dental-like structures were formed from the incisor region following implantation into immunodeficient mice. Thus, forced activation of beta-catenin signaling can initiate an embryonic-like program of tooth development in adult rodent incisor teeth. PMID:20530729

  10. β-catenin Initiates Tooth Neogenesis in Adult Rodent Incisors

    PubMed Central

    Liu, F.; Dangaria, S.; Andl, T.; Zhang, Y.; Wright, A.C.; Damek-Poprawa, M.; Piccolo, S.; Nagy, A.; Taketo, M.M.; Diekwisch, T.G.H.; Akintoye, S.O.; Millar, S.E.

    2010-01-01

    β-catenin signaling is required for embryonic tooth morphogenesis and promotes continuous tooth development when activated in embryos. To determine whether activation of this pathway in the adult oral cavity could promote tooth development, we induced mutation of epithelial β-catenin to a stabilized form in adult mice. This caused increased proliferation of the incisor tooth cervical loop, outpouching of incisor epithelium, abnormal morphology of the epithelial-mesenchymal junction, and enhanced expression of genes associated with embryonic tooth development. Ectopic dental-like structures were formed from the incisor region following implantation into immunodeficient mice. Thus, forced activation of β-catenin signaling can initiate an embryonic-like program of tooth development in adult rodent incisor teeth. PMID:20530729

  11. Rodent models for compulsive alcohol intake

    PubMed Central

    Hopf, F. Woodward; Lesscher, Heidi M.B.

    2014-01-01

    Continued seeking and drinking of alcohol despite adverse legal, health, economic, and societal consequences is a central hallmark of human alcohol use disorders. This compulsive drive for alcohol, defined by resistance to adverse and deleterious consequences, represents a major challenge when attempting to treat alcoholism clinically. Thus, there has long been interest in developing pre-clinical rodent models for the compulsive drug use that characterizes drug addiction. Here, we review recent studies that have attempted to model compulsive aspects of alcohol and cocaine intake in rodents, and consider technical and conceptual issues that need to be addressed when trying to recapitulate compulsive aspects of human addiction. Aversion-resistant alcohol intake has been examined by pairing intake or seeking with the bitter tastant quinine or with footshock, and exciting recent work has used these models to identify neuroadaptations in the amygdala, cortex, and striatal regions that promote compulsive intake. Thus, rodent models do seem to reflect important aspects of compulsive drives that sustain human addiction, and will likely provide critical insights into the molecular and circuit underpinnings of aversion-resistant intake as well as novel therapeutic interventions for compulsive aspects of addiction. PMID:24731992

  12. Rodent models for compulsive alcohol intake.

    PubMed

    Hopf, F Woodward; Lesscher, Heidi M B

    2014-05-01

    Continued seeking and drinking of alcohol despite adverse legal, health, economic, and societal consequences is a central hallmark of human alcohol use disorders. This compulsive drive for alcohol, defined by resistance to adverse and deleterious consequences, represents a major challenge when attempting to treat alcoholism clinically. Thus, there has long been interest in developing pre-clinical rodent models for the compulsive drug use that characterizes drug addiction. Here, we review recent studies that have attempted to model compulsive aspects of alcohol and cocaine intake in rodents, and consider technical and conceptual issues that need to be addressed when trying to recapitulate compulsive aspects of human addiction. Aversion-resistant alcohol intake has been examined by pairing intake or seeking with the bitter tastant quinine or with footshock, and exciting recent work has used these models to identify neuroadaptations in the amygdala, cortex, and striatal regions that promote compulsive intake. Thus, rodent models do seem to reflect important aspects of compulsive drives that sustain human addiction, and will likely provide critical insights into the molecular and circuit underpinnings of aversion-resistant intake as well as novel therapeutic interventions for compulsive aspects of addiction. PMID:24731992

  13. Experimentally induced rodent models of type 2 diabetes.

    PubMed

    Islam, Md Shahidul; Wilson, Rachel Dorothy

    2012-01-01

    Diabetes is one of the major global public health problems and is gradually getting worse particularly in developing nations where 95% of patients are suffering from type 2 diabetes (T2D). Animal models in diabetes research are very common where rodents are the best choice of use due to being smaller in size, easy to handle, omnivorous in nature, and non-wild tranquil behavior. Normally rodent models are classified into two major classes namely: (1) genetic or spontaneously induced models and (2) non-genetic or experimentally induced models. Non-genetic models are more popular compared to genetic models due to lower cost, wider availability, easier to induce diabetes, and of course easier to maintain compared to genetic models. A number of non-genetic models have been developed in last three decades for diabetes research including adult alloxan/streptozotocin (STZ) models, partial pancreatectomy model, high-fat (HF) diet-fed models, fructose-fed models, HF diet-fed STZ models, nicotinamide-STZ models, monosodium-glutamate (MSG) induced models, and intrauterine growth retardation (IUGR) models. A T2D model should have the all major pathogenesis of the disease usually found in humans; however, none of the above-mentioned models are without limitations. This chapter comparatively evaluates most of the experimentally induced rodent models of T2D with their limitations, advantages, disadvantages, and criticality of development in order to help diabetes research groups to more appropriately select the animal models to work on their specific research question. PMID:22893406

  14. 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

  15. Rodent models of treatment-resistant depression

    PubMed Central

    Caldarone, Barbara J.; Zachariou, Venetia; King, Sarah L

    2015-01-01

    Major depression is a prevalent and debilitating disorder and a substantial proportion of patients fail to reach remission following standard antidepressant pharmacological treatment. Limited efficacy with currently available antidepressant drugs highlights the need to develop more effective medications for treatment resistant patients and emphasizes the importance of developing better preclinical models that focus on treatment resistant populations. This review discusses methods to adapt and refine rodent behavioral models that are predictive of antidepressant efficacy to identify populations that show reduced responsiveness or are resistant to traditional antidepressants. Methods include separating antidepressant responders from non-responders, administering treatments that render animals resistant to traditional pharmacological treatments, and identifying genetic models that show antidepressant resistance. This review also examines pharmacological and non-pharmacological treatments regimes that have been effective in refractory patients and how some of these approaches have been used to validate animal models of treatment-resistant depression. The goals in developing rodent models of treatment-resistant depression are to understand the neurobiological mechanisms involved in antidepressant resistance and to develop valid models to test novel therapies that would be effective in patients that do not respond to traditional monoaminergic antidepressants. PMID:25460020

  16. Rodent Models of Amyotrophic Lateral Sclerosis

    PubMed Central

    Philips, Thomas; Rothstein, Jeffrey D.

    2015-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the CNS. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3-5 years after disease onset. ALS may be familial (fALS 10%) or sporadic ALS (sALS, 90%). The large majority of fALS) cases are due to genetic mutations in the Superoxide dismutase 1 gene (SOD1, 15% of fALS) and repeat nucleotide expansions in the gene encoding C9ORF72 (around 40-50% of fALS and ~10% of sALS). From a wide range of pathological studies the general conclusion is that ALS disease is mediated through aberrant protein homeostasis (ie ER stress and autophagy) and/or changes in RNA processing (as seen in all non-SOD1-mediated ALS). In all of these cases, animal models suggest that the disease is mediated non-cell-autonomously, i.e. not only motor neurons are involved, but glial cells including microglia, astrocytes and oligodendrocytes and other neuronal subpopulations are also implicated in disease pathogenesis. This overview will give a chronological overview of a wide range of different ALS rodent models generated so far with a thorough description of their intrinsic advantages and disadvantages. We will focus on their respective correlation with disease as seen in humans and their potential for understanding basic disease biology. As RNA processing has more recently come to the foreground of ALS research, we will mainly focus on a thorough description of the most recently generated ALS rodent models. PMID:26344214

  17. Hindlimb unloading rodent model: technical aspects

    NASA Technical Reports Server (NTRS)

    Morey-Holton, Emily R.; Globus, Ruth K.

    2002-01-01

    Since its inception at the National Aeronautics and Space Administration (NASA) Ames Research Center in the mid-1970s, many laboratories around the world have used the rat hindlimb unloading model to simulate weightlessness and to study various aspects of musculoskeletal loading. In this model, the hindlimbs of rodents are elevated to produce a 30 degrees head-down tilt, which results in a cephalad fluid shift and avoids weightbearing by the hindquarters. Although several reviews have described scientific results obtained with this model, this is the first review to focus on the technical aspects of hindlimb unloading. This review includes a history of the technique, a brief comparison with spaceflight data, technical details, extension of the model to mice, and other important technical considerations (e.g., housing, room temperature, unloading angle, the potential need for multiple control groups, age, body weight, the use of the forelimb tissues as internal controls, and when to remove animals from experiments). This paper is intended as a reference for researchers, reviewers of manuscripts, and institutional animal care and use committees. Over 800 references, related to the hindlimb unloading model, can be accessed via the electronic version of this article.

  18. 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...

  19. Rodent models of aging bone: an update.

    PubMed

    Syed, Farhan A; Melim, Terry

    2011-12-01

    With an increase in the average life span especially in the Western hemisphere, there is renewed interest in treating maladies of old age including osteoporosis. Age-related bone loss and resultant osteoporosis substantially increase risk of fractures and morbidity in the geriatric population leading to both a decline in the quality of life for the elderly as well as a substantial burden on the health care system. Herein, we review recent research in murine and rodent models looking at how both extrinsic and intrinsic factors such as hormones, biochemicals, neuromodulators, inflammatory cytokines, oxidative stress, nutrition, and exercise influence the skeleton with age. Recent studies on the relationship between bone and fat in the marrow, and the fate of the marrow mesenchymal stromal cell population, which can give rise to either bone-forming osteoblasts or fat-forming adipocytic cells as a function of age, have also been highlighted. An appreciable range of studies using aging murine as well as cellular models are discussed, as these studies have broadened our understanding of the pathways and players in the aging bone. Impactful information regarding aging and the bone may then allow the application of better pharmacologic as well as nonpharmacologic regimens to alleviate bone loss due to aging. PMID:21918858

  20. Live Imaging of Adult Neural Stem Cells in Rodents

    PubMed Central

    Ortega, Felipe; Costa, Marcos R.

    2016-01-01

    The generation of cells of the neural lineage within the brain is not restricted to early development. New neurons, oligodendrocytes, and astrocytes are produced in the adult brain throughout the entire murine life. However, despite the extensive research performed in the field of adult neurogenesis during the past years, fundamental questions regarding the cell biology of adult neural stem cells (aNSCs) remain to be uncovered. For instance, it is crucial to elucidate whether a single aNSC is capable of differentiating into all three different macroglial cell types in vivo or these distinct progenies constitute entirely separate lineages. Similarly, the cell cycle length, the time and mode of division (symmetric vs. asymmetric) that these cells undergo within their lineage progression are interesting questions under current investigation. In this sense, live imaging constitutes a valuable ally in the search of reliable answers to the previous questions. In spite of the current limitations of technology new approaches are being developed and outstanding amount of knowledge is being piled up providing interesting insights in the behavior of aNSCs. Here, we will review the state of the art of live imaging as well as the alternative models that currently offer new answers to critical questions. PMID:27013941

  1. Rodent model of direct cranial blast injury.

    PubMed

    Kuehn, Reed; Simard, Philippe F; Driscoll, Ian; Keledjian, Kaspar; Ivanova, Svetlana; Tosun, Cigdem; Williams, Alicia; Bochicchio, Grant; Gerzanich, Volodymyr; Simard, J Marc

    2011-10-01

    Traumatic brain injury resulting from an explosive blast is one of the most serious wounds suffered by warfighters, yet the effects of explosive blast overpressure directly impacting the head are poorly understood. We developed a rodent model of direct cranial blast injury (dcBI), in which a blast overpressure could be delivered exclusively to the head, precluding indirect brain injury via thoracic transmission of the blast wave. We constructed and validated a Cranium Only Blast Injury Apparatus (COBIA) to deliver blast overpressures generated by detonating .22 caliber cartridges of smokeless powder. Blast waveforms generated by COBIA replicated those recorded within armored vehicles penetrated by munitions. Lethal dcBI (LD(50) ∼ 515 kPa) was associated with: (1) apparent brainstem failure, characterized by immediate opisthotonus and apnea leading to cardiac arrest that could not be overcome by cardiopulmonary resuscitation; (2) widespread subarachnoid hemorrhages without cortical contusions or intracerebral or intraventricular hemorrhages; and (3) no pulmonary abnormalities. Sub-lethal dcBI was associated with: (1) apnea lasting up to 15 sec, with transient abnormalities in oxygen saturation; (2) very few delayed deaths; (3) subarachnoid hemorrhages, especially in the path of the blast wave; (4) abnormal immunolabeling for IgG, cleaved caspase-3, and β-amyloid precursor protein (β-APP), and staining for Fluoro-Jade C, all in deep brain regions away from the subarachnoid hemorrhages, but in the path of the blast wave; and (5) abnormalities on the accelerating Rotarod that persisted for the 1 week period of observation. We conclude that exposure of the head alone to severe explosive blast predisposes to significant neurological dysfunction. PMID:21639724

  2. Experimental osteonecrosis: development of a model in rodents administered alendronate.

    PubMed

    Conte, Nicolau; Spolidorio, Luis Carlos; Andrade, Cleverton Roberto de; Esteves, Jônatas Caldeira; Marcantonio, Elcio

    2016-01-01

    The main objective of this study was to cause bisphosphonate-related osteonecrosis of the jaws to develop in a rodent model. Adult male Holtzman rats were assigned to one of two experimental groups to receive alendronate (AL; 1 mg/kg/week; n = 6) or saline solution (CTL; n = 6). After 60 days of drug therapy, all animals were subjected to first lower molar extraction, and 28 days later, animals were euthanized. All rats treated with alendronate developed osteonecrosis, presenting as ulcers and necrotic bone, associated with a significant infection process, especially at the inter-alveolar septum area and crestal regions. The degree of vascularization, the levels of C-telopeptide cross-linked collagen type I and bone-specific alkaline phosphatase, as well as the bone volume were significantly reduced in these animals. Furthermore, on radiographic analysis, animals treated with alendronate presented evident sclerosis of the lamina dura of the lower first molar alveolar socket associated with decreased radiographic density in this area. These findings indicate that the protocol developed in the present study opens new perspectives and could be a good starting model for future property design. PMID:27556684

  3. Revisiting rodent models: Octodon degus as Alzheimer's disease model?

    PubMed

    Steffen, Johannes; Krohn, Markus; Paarmann, Kristin; Schwitlick, Christina; Brüning, Thomas; Marreiros, Rita; Müller-Schiffmann, Andreas; Korth, Carsten; Braun, Katharina; Pahnke, Jens

    2016-01-01

    Alzheimer's disease primarily occurs as sporadic disease and is accompanied with vast socio-economic problems. The mandatory basic research relies on robust and reliable disease models to overcome increasing incidence and emerging social challenges. Rodent models are most efficient, versatile, and predominantly used in research. However, only highly artificial and mostly genetically modified models are available. As these 'engineered' models reproduce only isolated features, researchers demand more suitable models of sporadic neurodegenerative diseases. One very promising animal model was the South American rodent Octodon degus, which was repeatedly described as natural 'sporadic Alzheimer's disease model' with 'Alzheimer's disease-like neuropathology'. To unveil advantages over the 'artificial' mouse models, we re-evaluated the age-dependent, neurohistological changes in young and aged Octodon degus (1 to 5-years-old) bred in a wild-type colony in Germany. In our hands, extensive neuropathological analyses of young and aged animals revealed normal age-related cortical changes without obvious signs for extensive degeneration as seen in patients with dementia. Neither significant neuronal loss nor enhanced microglial activation were observed in aged animals. Silver impregnation methods, conventional, and immunohistological stains as well as biochemical fractionations revealed neither amyloid accumulation nor tangle formation. Phosphoepitope-specific antibodies against tau species displayed similar intraneuronal reactivity in both, young and aged Octodon degus.In contrast to previous results, our study suggests that Octodon degus born and bred in captivity do not inevitably develop cortical amyloidosis, tangle formation or neuronal loss as seen in Alzheimer's disease patients or transgenic disease models. PMID:27566602

  4. Habitat-specific shaping of proliferation and neuronal differentiation in adult hippocampal neurogenesis of wild rodents

    PubMed Central

    Cavegn, Nicole; van Dijk, R. Maarten; Menges, Dominik; Brettschneider, Helene; Phalanndwa, Mashudu; Chimimba, Christian T.; Isler, Karin; Lipp, Hans-Peter; Slomianka, Lutz; Amrein, Irmgard

    2013-01-01

    Daily life of wild mammals is characterized by a multitude of attractive and aversive stimuli. The hippocampus processes complex polymodal information associated with such stimuli and mediates adequate behavioral responses. How newly generated hippocampal neurons in wild animals contribute to hippocampal function is still a subject of debate. Here, we test the relationship between adult hippocampal neurogenesis (AHN) and habitat types. To this end, we compare wild Muridae species of southern Africa [Namaqua rock mouse (Micaelamys namaquensis), red veld rat (Aethomys chrysophilus), highveld gerbil (Tatera brantsii), and spiny mouse (Acomys spinosissimus)] with data from wild European Muridae [long-tailed wood mice (Apodemus sylvaticus), pygmy field mice (Apodemus microps), yellow-necked wood mice (Apodemus flavicollis), and house mice (Mus musculus domesticus)] from previous studies. The pattern of neurogenesis, expressed in normalized numbers of Ki67- and Doublecortin(DCX)-positive cells to total granule cells (GCs), is similar for the species from a southern African habitat. However, we found low proliferation, but high neuronal differentiation in rodents from the southern African habitat compared to rodents from the European environment. Within the African rodents, we observe additional regulatory and morphological traits in the hippocampus. Namaqua rock mice with previous pregnancies showed lower AHN compared to males and nulliparous females. The phylogenetically closely related species (Namaqua rock mouse and red veld rat) show a CA4, which is not usually observed in murine rodents. The specific features of the southern environment that may be associated with the high number of young neurons in African rodents still remain to be elucidated. This study provides the first evidence that a habitat can shape adult neurogenesis in rodents across phylogenetic groups. PMID:23616743

  5. The effect of suramin on healing adult rodent dermal wounds.

    PubMed Central

    Chamberlain, J; Shah, M; Ferguson, M W

    1995-01-01

    Scarring, leading to impaired function, growth and appearance, is a major problem following many forms of surgery. Fetal wounds, unlike those in the adult, are characterised by a reduced growth factor profile and the absence of scar tissue (Whitby & Ferguson, 1991 a, b). The antiparasitic drug, suramin (a heparin analogue) inhibits binding of various growth factors (e.g. PDGF, bFGF, TGF-beta, EGF, IGF-I, IGF-II) to their receptors in vitro. These growth factors play key roles in wound healing. We attempted to manipulate experimentally their effectiveness in healing adult rat dermal incisional wounds by injecting suramin into the wound margins and comparing the resultant healing with an unmanipulated control wound in the same animal. Immunohistochemical staining demonstrated that, on d 7 and 14 postwounding, the numbers of monocytes/macrophages and blood vessels are markedly increased in suramin treated wounds compared with controls. Extracellular matrix deposition is lower, although very compact in organisation, lacking the usual honeycombed appearance of normal skin. These effects are widespread, being present not only in the wound area, but also in the surrounding tissue. No difference was detected at 70 d postwounding between the scars of suramin-treated and unmanipulated control wounds in the same animals. All such effects are increased slightly through the concentration range of 0.04-40 mg/kg suramin, with no significant change as concentrations greater than 40 mg/kg are applied. This suggests that suramin has marked effects on the early stages of wound healing, which plateau at 40 mg/kg concentration, but has no effect on scar formation. Images Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:7649820

  6. Clinical spectrum associated with MOG autoimmunity in adults: significance of sharing rodent MOG epitopes.

    PubMed

    Sepúlveda, Maria; Armangue, Thaís; Martinez-Hernandez, Eugenia; Arrambide, Georgina; Sola-Valls, Nuria; Sabater, Lidia; Téllez, Nieves; Midaglia, Luciana; Ariño, Helena; Peschl, Patrick; Reindl, Markus; Rovira, Alex; Montalban, Xavier; Blanco, Yolanda; Dalmau, Josep; Graus, Francesc; Saiz, Albert

    2016-07-01

    The aim of this study was to report the clinical spectrum associated with antibodies to myelin oligodendrocyte glycoprotein (MOG) in adult patients, and to assess whether phenotypic variants are dependent on recognition of rodent MOG epitopes. We retrospectively analyzed the features, course and outcome of 56 patients whose samples were investigated by brain tissue immunohistochemistry and cell-based assays using human and rodent MOG. The median age at symptom onset was 37 years (range 18-70); 35 patients (63 %) were female. After a median follow-up of 43 months (range 4-554), only 14 patients (25 %) developed a neuromyelitis optica spectrum disorder (NMOSD), 27 patients (47 %) retained the initial diagnosis of isolated optic neuritis, 7 (12 %) of longitudinally extensive transverse myelitis, and 2 (4 %) of acute disseminated encephalomyelitis; 6 patients (11 %) developed atypical demyelinating syndromes (4 had relapsing episodes of short myelitis lesions which in one occurred with optic neuritis; 1 had relapsing brainstem symptoms, and 1 relapsing demyelinating encephalomyelitis). The course was frequently associated with relapses (71 %) and good outcome. Twenty-seven patients (49 %) had antibodies that recognized rodent MOG epitopes, and 9 of them (16 %) showed a myelin staining pattern in rodent tissue. Only the myelin staining pattern was linked to NMOSD (p = 0.005). In conclusion, MOG autoimmunity in adult patients associates with a clinical spectrum wider than the one expected for patients with suspected NMOSD and overall good outcome. Antibodies to rodent MOG epitopes do not associate with any phenotypic variant. PMID:27147513

  7. Experimental models of renal calcium stones in rodents

    PubMed Central

    Bilbault, Héloïse; Haymann, Jean-Philippe

    2016-01-01

    In human nephrolithiasis, most stones are containing calcium and are located within urinary cavities; they may contain monohydrate calcium oxalate, dihydrate calcium oxalate and/or calcium phosphates in various proportion. Nephrolithiasis may also be associated with nephrocalcinosis, i.e., crystal depositions in tubular lumen and/or interstitium, an entity which suggests specific pathological processes. Several rodents models have been developed in order to study the pathophysiology of intrarenal crystal formation. We review here calcium rodent models classified upon the presence of nephrolithiasis and/or nephrocalcinosis. As rodents are not prone to nephrolithiasis, models require the induction of a long standing hypercalciuria or hyperoxaluria (thus explaining the very few studies reported), conversely to nephrocalcinosis which may occur within hours or days. Whereas a nephrotoxicity leading to tubular injury and regeneration appears as a critical event for crystal retention in nephrocalcinosis models, surprisingly very little is known about the physiopathology of crystal attachment to urothelium in nephrolithiasis. Creating new models of nephrolithiasis especially in different genetic mice strains appears an important challenge in order to unravel the early mechanisms of urinary stone formation in papilla and fornices. PMID:26981444

  8. Experimental models of renal calcium stones in rodents.

    PubMed

    Bilbault, Héloïse; Haymann, Jean-Philippe

    2016-03-01

    In human nephrolithiasis, most stones are containing calcium and are located within urinary cavities; they may contain monohydrate calcium oxalate, dihydrate calcium oxalate and/or calcium phosphates in various proportion. Nephrolithiasis may also be associated with nephrocalcinosis, i.e., crystal depositions in tubular lumen and/or interstitium, an entity which suggests specific pathological processes. Several rodents models have been developed in order to study the pathophysiology of intrarenal crystal formation. We review here calcium rodent models classified upon the presence of nephrolithiasis and/or nephrocalcinosis. As rodents are not prone to nephrolithiasis, models require the induction of a long standing hypercalciuria or hyperoxaluria (thus explaining the very few studies reported), conversely to nephrocalcinosis which may occur within hours or days. Whereas a nephrotoxicity leading to tubular injury and regeneration appears as a critical event for crystal retention in nephrocalcinosis models, surprisingly very little is known about the physiopathology of crystal attachment to urothelium in nephrolithiasis. Creating new models of nephrolithiasis especially in different genetic mice strains appears an important challenge in order to unravel the early mechanisms of urinary stone formation in papilla and fornices. PMID:26981444

  9. Rodent models and imaging techniques to study liver regeneration.

    PubMed

    Wei, Weiwei; Dirsch, Olaf; Mclean, Anna Lawson; Zafarnia, Sara; Schwier, Michael; Dahmen, Uta

    2015-01-01

    The liver has the unique capability of regeneration from various injuries. Different animal models and in vitro methods are used for studying the processes and mechanisms of liver regeneration. Animal models were established either by administration of hepatotoxic chemicals or by surgical approach. The administration of hepatotoxic chemicals results in the death of liver cells and in subsequent hepatic regeneration and tissue repair. Surgery includes partial hepatectomy and portal vein occlusion or diversion: hepatectomy leads to compensatory regeneration of the remnant liver lobe, whereas portal vein occlusion leads to atrophy of the ipsilateral lobe and to compensatory regeneration of the contralateral lobe. Adaptation of modern radiological imaging technologies to the small size of rodents made the visualization of rodent intrahepatic vascular anatomy possible. Advanced knowledge of the detailed intrahepatic 3D anatomy enabled the establishment of refined surgical techniques. The same technology allows the visualization of hepatic vascular regeneration. The development of modern histological image analysis tools improved the quantitative assessment of hepatic regeneration. Novel image analysis tools enable us to quantify reliably and reproducibly the proliferative rate of hepatocytes using whole-slide scans, thus reducing the sampling error. In this review, the refined rodent models and the newly developed imaging technology to study liver regeneration are summarized. This summary helps to integrate the current knowledge of liver regeneration and promises an enormous increase in hepatological knowledge in the near future. PMID:25402256

  10. A new rodent model of cerebral hyperperfusion

    PubMed Central

    Jia, Bin; Zhao, Lei; Xiao, Wei; Cai, Bing; Wang, Tian-Long; Li, Dong-Guo

    2015-01-01

    Background: Most studies of hyperperfusion and hyperperfusion syndrome after carotid endarterectomy or carotid stenting are based on clinical observation or meta-analyses in patients, whereas there is little corresponding fundamental research since proper animal model that can reproduce phenotype stably is not available. Therefore, we developed a rat model in which the pathophysiologic process of hyperperfusion can be mimicked. Methods: Global ischemia was induced by occluding bilateral common carotid arteries (BCAO) for 2 weeks. After that, the ligature was loosened to allow reperfusion. Phenylephrine was administered at concentrations of 10, 20, 30, 40, 50, 80, and 120 μg/mL for rapidly elevating blood pressure. Relative cerebral blood flow in relation to mean arterial pressure (MAP) was measured with Laser Doppler techniques. Sham animals underwent the same surgical operation but without artery-occlusion and received the same concentrations of phenylephrine. Results: Mild hypertension rapidly increased cerebral blood flow. Phenylephrine at different concentrations produced different effects on blood pressure. Hyperperfusion can be induced by phenylephrine at around 30 μg/mL, whereas phenylephrine at 80 μg/ml or higher induced arrhythmia and further cardiac dysfunction thus failed to induce hyperperfusion. Conclusions: Our data suggest that 30-50 μg/mL phenylephrine mildly elevated MAP and cerebral blood flow to the level exceeding 100% of baseline. This hyperperfusion model possesses several advantages including high phenotype reproducibility, low experimental failure rate and low animal mortality rate. It can be applied to study carotid stenosis or ischemia/reperfusion injury in rats. PMID:26770334

  11. Rodent Models and Behavioral Outcomes of Cervical Spinal Cord Injury

    PubMed Central

    Geissler, Sydney A.; Schmidt, Christine E.; Schallert, Timothy

    2014-01-01

    Rodent spinal cord injury (SCI) models have been developed to examine functional and physiological deficits after spinal cord injury with the hope that these models will elucidate information about human SCI. Models are needed to examine possible treatments and to understand histopathology after SCI; however, they should be considered carefully and chosen based on the goals of the study being performed. Contusion, compression, transection, and other models exist and have the potential to reveal important information about SCI that may be related to human SCI and the outcomes of treatment and timing of intervention. PMID:25309824

  12. Rodent Models of Traumatic Brain Injury: Methods and Challenges.

    PubMed

    Marklund, Niklas

    2016-01-01

    Traumatic brain injury (TBI) has been named the most complex disease in the most complex organ of the body. It is the most common cause of death and disability in the Western world in people <40 years old and survivors commonly suffer from persisting cognitive deficits, impaired motor function, depression and personality changes. TBI may vary in severity from uniformly fatal to mild injuries with rapidly resolving symptoms and without doubt, it is a markedly heterogeneous disease. Its different subtypes differs in their pathophysiology, treatment options and long-term consequences and to date, there are no pharmacological treatments with proven clinical benefit available to TBI patients. To enable development of novel treatment options for TBI, clinically relevant animal models are needed. Due to their availability and low costs, numerous rodent models have been developed which have substantially contributed to our current understanding of the pathophysiology of TBI. The most common animal models used in laboratories worldwide are likely the controlled cortical impact (CCI) model, the central and lateral fluid percussion injury (FPI) models, and weight drop/impact acceleration (I/A) models. Each of these models has inherent advantages and disadvantages; these need to be thoroughly considered when selecting the rodent TBI model according to the hypothesis and design of the study. Since TBI is not one disease, refined animal models must take into account the clinical features and complexity of human TBI. To enhance the possibility of establishing preclinical efficacy of a novel treatment, the preclinical use of several different experimental models is encouraged as well as varying the species, gender, and age of the animal. In this chapter, the methods, limitations, and challenges of the CCI and FPI models of TBI used in rodents are described. PMID:27604711

  13. Towards an integrative model of sociality in caviomorph rodents

    PubMed Central

    Hayes, Loren D.; Burger, Joseph Robert; Soto-Gamboa, Mauricio; Sobrero, Raúl; Ebensperger, Luis A

    2012-01-01

    In the late 1990s and early 2000s it was recognized that behavioral ecologists needed to study the sociality of caviomorph rodents (New World hystricognaths) before generalizations about rodent sociality could be made. Researchers identified specific problems facing individuals interested in caviomorph sociality, including a lack of information on the proximate mechanisms of sociality, role of social environment in development, and geographical or intraspecific variation in social systems. Since then researchers have described the social systems of many previously understudied species, including some with broad geographical ranges. Researchers have done a good job of determining the role of social environments in development and identifying the costs and benefits of social living. However, relatively little is known about the proximate mechanisms of social behavior and fitness consequences, limiting progress toward the development of integrative (evolutionary-mechanistic) models for sociality. To develop integrative models behavioral ecologists studying caviomorph rodents must generate information on the fitness consequences of different types of social organization, brain mechanisms, and endocrine substrates of sociality. We review our current understanding and future directions for research in these conceptual areas. A greater understanding of disease ecology, particularly in species carrying Old World parasites, is needed before we can identify potential links between social phenotypes, mechanism, and fitness. PMID:22328791

  14. Assessment of rodents as animal models for Reston ebolavirus.

    PubMed

    de Wit, Emmie; Munster, Vincent J; Metwally, Samia A; Feldmann, Heinz

    2011-11-01

    The emergence of Reston ebolavirus (REBOV) in domestic swine in the Philippines has caused a renewed interest in REBOV pathogenicity. Here, the use of different rodent species as animal disease models for REBOV was investigated. BALB/c and STAT1(-)(/-) mice, Hartley guinea pigs, and Syrian hamsters were inoculated intraperitoneally with REBOV strain Pennsylvania or Reston08-A. Although virus replication occurred in guinea pigs, hamsters, and STAT1(-/-) mice, progression to disease was only observed in STAT1(-)(/-) mice. Moreover, REBOV Pennsylvania was more pathogenic than REBOV Reston08-A in this model. Thus, STAT1(-)(/-) mice may be used for research of REBOV pathogenicity and intervention strategies. PMID:21987777

  15. A protocol for a lung neovascularization model in rodents

    PubMed Central

    Jones, Rosemary C; Capen, Diane E; Petersen, Bodil; Jain, Rakesh K; Duda, Dan G

    2009-01-01

    By providing insight into the cellular events of vascular injury and repair, experimental model systems seek to promote timely therapeutic strategies for human disease. The goal of many current studies of neovascularization is to identify cells critical to the process and their role in vascular channel assembly. We propose here a protocol to analyze, in an in vivo rodent model, vessel and capillary remodeling (reorganization and growth) in the injured lung. Sequential analyses of stages in the assembly of vascular structures, and of relevant cell types, provide further opportunities to study the molecular and cellular determinants of lung neovascularization. PMID:18323809

  16. 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

  17. Spontaneous and transgenic rodent models of inflammatory bowel disease

    PubMed Central

    Jurjus, Abdo

    2015-01-01

    Inflammatory Bowel Disease (IBD) is a multifactorial disorder with many different putative influences mediating disease onset, severity, progression and diminution. Spontaneous natural IBD is classically expressed as Crohn's Disease (CD) and Ulcerative Colitis (UC) commonly found in primates; lymphoplasmocytic enteritis, eosinophilic gastritis and colitis, and ulcerative colitis with neuronal hyperplasia in dogs; and colitis in horses. Spontaneous inflammatory bowel disease has been noted in a number of rodent models which differ in genetic strain background, induced mutation, microbiota influences and immunopathogenic pathways. Histological lesions in Crohn's Disease feature noncaseating granulomatous inflammation while UC lesions typically exhibit ulceration, lamina propria inflammatory infiltrates and lack of granuloma development. Intestinal inflammation caused by CD and UC is also associated with increased incidence of intestinal neoplasia. Transgenic murine models have determined underlying etiological influences and appropriate therapeutic targets in IBD. This literature review will discuss current opinion and findings in spontaneous IBD, highlight selected transgenic rodent models of IBD and discuss their respective pathogenic mechanisms. It is very important to provide accommodation of induced putative deficits in activities of daily living and to assess discomfort and pain levels in the face of significant morbidity and/or mortality in these models. Epigenetic, environmental (microbiome, metabolome) and nutritional factors are important in IBD pathogenesis, and evaluating ways in which they influence disease expression represent potential investigative approaches with the greatest potential for new discoveries. PMID:26155200

  18. Hemodynamic Characterization of Rodent Models of Pulmonary Arterial Hypertension.

    PubMed

    Ma, Zhiyuan; Mao, Lan; Rajagopal, Sudarshan

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary vasculature characterized by endothelial cell apoptosis, smooth muscle proliferation and obliteration of pulmonary arterioles. This in turn results in right ventricular (RV) failure, with significant morbidity and mortality. Rodent models of PAH, in the mouse and the rat, are important for understanding the pathophysiology underlying this rare disease. Notably, different models of PAH may be associated with different degrees of pulmonary hypertension, RV hypertrophy and RV failure. Therefore, a complete hemodynamic characterization of mice and rats with PAH is critical in determining the effects of drugs or genetic modifications on the disease. Here we demonstrate standard procedures for assessment of right ventricular function and hemodynamics in both rat and mouse PAH models. Echocardiography is useful in determining RV function in rats, although obtaining standard views of the right ventricle is challenging in the awake mouse. Access for right heart catheterization is obtained by the internal jugular vein in closed-chest mice and rats. Pressures can be measured using polyethylene tubing with a fluid pressure transducer or a miniature micromanometer pressure catheter. Pressure-volume loop analysis can be performed in the open chest. After obtaining hemodynamics, the rodent is euthanized. The heart can be dissected to separate the RV free wall from the left ventricle (LV) and septum, allowing an assessment of RV hypertrophy using the Fulton index (RV/(LV+S)). Then samples can be harvested from the heart, lungs and other tissues as needed. PMID:27167679

  19. Modelling cognitive affective biases in major depressive disorder using rodents.

    PubMed

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

    2014-10-01

    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. PMID:24467454

  20. Early origins of adult disease: approaches for investigating the programmable epigenome in humans, nonhuman primates, and rodents.

    PubMed

    Ganu, Radhika S; Harris, R Alan; Collins, Kiara; Aagaard, Kjersti M

    2012-01-01

    According to the developmental origins of health and disease hypothesis, in utero experiences reprogram an individual for immediate adaptation to gestational perturbations, with the sequelae of later-in-life risk of metabolic disease. An altered gestational milieu with resultant adult metabolic disease has been observed in instances of both in utero constraint (e.g., from famine or uteroplacental insufficiency) and overt caloric abundance (e.g., from a maternal high-fat, caloric-dense diet). The commonality of the adult metabolic phenotype begs the question of how diverse in utero experiences (i.e., reprogramming events) converge on common metabolic pathways and how the memory of these events is maintained across the lifespan. We and others have investigated the molecular mechanisms underlying fetal programming and observed that epigenetic modifications to the fetal and placental epigenome accompany these reprogramming events. Based on several lines of emerging data in human and nonhuman primates, it is now felt that modified epigenetic signature--and the histone code in particular--underlies alterations in postnatal gene expression and metabolic pathways central to accurate functioning and maintenance of health. Because of the tissue lineage specificity of many of these modifications, nonhuman primates serve as an apt model system for the capacity to recapitulate human gene expression and regulation during development. This review summarizes recent epigenetic advances using rodent and primate (both human and nonhuman) models during in utero development and contributing to adult diseases later in life. PMID:23744969

  1. Early Origins of Adult Disease: Approaches for Investigating the Programmable Epigenome in Humans, Nonhuman Primates, and Rodents

    PubMed Central

    Ganu, Radhika S.; Harris, R. Alan; Collins, Kiara; Aagaard, Kjersti M.

    2012-01-01

    According to the developmental origins of health and disease hypothesis, in utero experiences reprogram an individual for immediate adaptation to gestational perturbations, with the sequelae of later-in-life risk of metabolic disease. An altered gestational milieu with resultant adult metabolic disease has been observed in instances of both in utero constraint (e.g., from famine or uteroplacental insufficiency) and overt caloric abundance (e.g., from a maternal high-fat, caloric-dense diet). The commonality of the adult metabolic phenotype begs the question of how diverse in utero experiences (i.e., reprogramming events) converge on common metabolic pathways and how the memory of these events is maintained across the lifespan. We and others have investigated the molecular mechanisms underlying fetal programming and observed that epigenetic modifications to the fetal and placental epigenome accompany these reprogramming events. Based on several lines of emerging data in human and nonhuman primates, it is now felt that modified epigenetic signature—and the histone code in particular—underlies alterations in postnatal gene expression and metabolic pathways central to accurate functioning and maintenance of health. Because of the tissue lineage specificity of many of these modifications, nonhuman primates serve as an apt model system for the capacity to recapitulate human gene expression and regulation during development. This review summarizes recent epigenetic advances using rodent and primate (both human and nonhuman) models during in utero development and contributing to adult diseases later in life. PMID:23744969

  2. N-acetylcysteine decreases binge eating in a rodent model.

    PubMed

    Hurley, M M; Resch, J M; Maunze, B; Frenkel, M M; Baker, D A; Choi, S

    2016-07-01

    Binge-eating behavior involves rapid consumption of highly palatable foods leading to increased weight gain. Feeding in binge disorders resembles other compulsive behaviors, many of which are responsive to N-acetylcysteine (NAC), which is a cysteine prodrug often used to promote non-vesicular glutamate release by a cystine-glutamate antiporter. To examine the potential for NAC to alter a form of compulsive eating, we examined the impact of NAC on binge eating in a rodent model. Specifically, we monitored consumption of standard chow and a high-fat, high carbohydrate western diet (WD) in a rodent limited-access binge paradigm. Before each session, rats received either a systemic or intraventricular injection of NAC. Both systemic and central administration of NAC resulted in significant reductions of binge eating the WD without decreasing standard chow consumption. The reduction in WD was not attributable to general malaise as NAC did not produce condition taste aversion. These results are consistent with the clinical evidence of NAC to reduce or reverse compulsive behaviors, such as, drug addiction, skin picking and hair pulling. PMID:26975440

  3. Zacopride: anxiolytic profile in rodent and primate models of anxiety.

    PubMed

    Costall, B; Domeney, A M; Gerrard, P A; Kelly, M E; Naylor, R J

    1988-04-01

    Zacopride, a substituted benzamide derivative, was compared with diazepam in three models of experimental or provoked anxiety. The drug's action (i) in reducing aversion to a brightly lit environment was assessed in mice using a two compartment black and white test box system, (ii) in disinhibiting a suppressed behaviour was measured in the rat social interaction test under high light/unfamiliar conditions and (iii) in antagonizing a defensive response in the marmoset was assessed using the threat of a human presence. Both zacopride and diazepam enhanced exploratory behaviour and social interaction in the mouse and rat models and antagonized the defensive response in the marmoset, zacopride being 100 times more potent than diazepam. It is concluded that the 5-HT3 receptor antagonist, zacopride, alters rodent and primate behaviour in a manner consistent with that of an anxiolytic agent. PMID:2900320

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

    PubMed Central

    Yoshida, Saishu; Kato, Takako; Kato, Yukio

    2016-01-01

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

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

    PubMed

    Yoshida, Saishu; Kato, Takako; Kato, Yukio

    2016-01-01

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

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

    PubMed

    Stadlinger, B; Korn, P; Tödtmann, N; Eckelt, U; Range, U; Bürki, A; Ferguson, S J; Kramer, I; Kautz, A; Schnabelrauch, M; Kneissel, M; Schlottig, F

    2013-01-01

    The present study examined the impact of implant surface modifications on osseointegration in an osteoporotic rodent model. Sandblasted, acid-etched titanium implants were either used directly (control) or were further modified by surface conditioning with NaOH or by coating with one of the following active agents: collagen/chondroitin sulphate, simvastatin, or zoledronic acid. Control and modified implants were inserted into the proximal tibia of aged ovariectomised (OVX) osteoporotic rats (n = 32/group). In addition, aged oestrogen competent animals received either control or NaOH conditioned implants. Animals were sacrificed 2 and 4 weeks post-implantation. The excised tibiae were utilised for biomechanical and morphometric readouts (n = 8/group/readout). Biomechanical testing revealed at both time points dramatically reduced osseointegration in the tibia of oestrogen deprived osteoporotic animals compared to intact controls irrespective of NaOH exposure. Consistently, histomorphometric and microCT analyses demonstrated diminished bone-implant contact (BIC), peri-implant bone area (BA), bone volume/tissue volume (BV/TV) and bone-mineral density (BMD) in OVX animals. Surface coating with collagen/chondroitin sulphate had no detectable impact on osseointegration. Interestingly, statin coating resulted in a transient increase in BIC 2 weeks post-implantation; which, however, did not correspond to improvement of biomechanical readouts. Local exposure to zoledronic acid increased BIC, BA, BV/TV and BMD at 4 weeks. Yet this translated only into a non-significant improvement of biomechanical properties. In conclusion, this study presents a rodent model mimicking severely osteoporotic bone. Contrary to the other bioactive agents, locally released zoledronic acid had a positive impact on osseointegration albeit to a lesser extent than reported in less challenging models. PMID:23832686

  7. Protracted brain development in a rodent model of extreme longevity

    PubMed Central

    Penz, Orsolya K.; Fuzik, Janos; Kurek, Aleksandra B.; Romanov, Roman; Larson, John; Park, Thomas J.; Harkany, Tibor; Keimpema, Erik

    2015-01-01

    Extreme longevity requires the continuous and large-scale adaptation of organ systems to delay senescence. Naked mole rats are the longest-living rodents, whose nervous system likely undergoes life-long adaptive reorganization. Nevertheless, neither the cellular organization of their cerebral cortex nor indices of structural neuronal plasticity along extreme time-scales have been established. We find that adult neurogenesis and neuronal migration are not unusual in naked mole rat brains. Instead, we show the prolonged expression of structural plasticity markers, many recognized as being developmentally controlled, and multi-year-long postnatal neuromorphogenesis and spatial synapse refinement in hippocampal and olfactory structures of the naked mole rat brain. Neurophysiological studies on identified hippocampal neurons demonstrated that morphological differentiation is disconnected from the control of excitability in all neuronal contingents regardless of their ability to self-renew. Overall, we conclude that naked mole rats show an extremely protracted period of brain maturation that may permit plasticity and resilience to neurodegenerative processes over their decades-long life span. This conclusion is consistent with the hypothesis that naked mole rats are neotenous, with retention of juvenile characteristics to permit survival in a hypoxic environment, with extreme longevity a consequence of greatly retarded development. PMID:26118676

  8. Circulating microRNA Signatures in Rodent Models of Pain.

    PubMed

    Qureshi, Rehman A; Tian, Yuzhen; McDonald, Marguerite K; Capasso, Kathryn E; Douglas, Sabrina R; Gao, Ruby; Orlova, Irina A; Barrett, James E; Ajit, Seena K; Sacan, Ahmet

    2016-07-01

    MicroRNAs (miRNAs) remain stable in circulation and have been identified as potential biomarkers for a variety of conditions. We report miRNA changes in blood from multiple rodent models of pain, including spinal nerve ligation and spared nerve injury models of neuropathic pain; a complete Freund's adjuvant (CFA) model of inflammatory pain; and a chemotherapy-induced model of pain using the histone deacetylase inhibitor JNJ-26481585. The effect of celecoxib, a cyclooxygenase-2-selective nonsteroidal anti-inflammatory drug, was investigated in the CFA model as proof of principle for assessing the utility of circulating miRNAs as biomarkers in determining treatment response. Each study resulted in a unique miRNA expression profile. Despite differences in miRNAs identified from various models, computational target prediction and functional enrichment have identified biological pathways common among different models. The Wnt signaling pathway was affected in all models, suggesting a crucial role for this pathway in the pathogenesis of pain. Our studies demonstrate the utility of circulating miRNAs as pain biomarkers and suggest the potential for rigorous forward and reverse translational approaches. Evaluating alterations in miRNA fingerprints under different pain conditions and after administering therapeutic agents may be beneficial in evaluating clinical trial outcomes, predicting treatment response, and developing correlational outcomes between preclinical and human studies. PMID:26081151

  9. Use of rodents as models of human diseases

    PubMed Central

    Vandamme, Thierry F.

    2014-01-01

    Advances in molecular biology have significantly increased the understanding of the biology of different diseases. However, these discoveries have not yet been fully translated into improved treatments for patients with diseases such as cancers. One of the factors limiting the translation of knowledge from preclinical studies to the clinic has been the limitations of in vivo diseases models. In this brief review, we will discuss the advantages and disadvantages of rodent models that have been developed to simulate human pathologies, focusing in models that employ xenografts and genetic modification. Within the framework of genetically engineered mouse (GEM) models, we will review some of the current genetic strategies for modeling diseases in the mouse and the preclinical studies that have already been undertaken. We will also discuss how recent improvements in imaging technologies may increase the information derived from using these GEMs during early assessments of potential therapeutic pathways. Furthermore, it is interesting to note that one of the values of using a mouse model is the very rapid turnover rate of the animal, going through the process of birth to death in a very short timeframe relative to that of larger mammalian species. PMID:24459397

  10. 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 ...

  11. 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...

  12. 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...

  13. The Behavioral Actions of Lithium in Rodent Models

    PubMed Central

    O’Donnell, Kelley C.; Gould, Todd D.

    2007-01-01

    For nearly as long as lithium has been in clinical use for the treatment of bipolar disorder, depression, and other conditions, investigators have attempted to characterize its effects on behaviors in rodents. Lithium consistently decreases exploratory activity, rearing, aggression, and amphetamine-induced hyperlocomotion; and it increases the sensitivity to pilocarpine-induced seizures, decreases immobility time in the forced swim test, and attenuates reserpine-induced hypolocomotion. Lithium also predictably induces conditioned taste aversion and alterations in circadian rhythms. The modulation of stereotypy, sensitization, and reward behavior are less consistent actions of the drug. These behavioral models may be relevant to human symptoms and to clinical endophenotypes. It is likely that the actions of lithium in a subset of these animal models are related to the therapeutic efficacy, as well the side effects, of the drug. We conclude with a brief discussion of various molecular mechanisms by which these lithium-sensitive behaviors may be mediated, and comment on the ways in which rat and mouse models can be used more effectively in the future to address persistent questions about the therapeutically relevant molecular actions of lithium. PMID:17532044

  14. Traumatic Brain Injury – Modeling Neuropsychiatric Symptoms in Rodents

    PubMed Central

    Malkesman, Oz; Tucker, Laura B.; Ozl, Jessica; McCabe, Joseph T.

    2013-01-01

    Each year in the US, ∼1.5 million people sustain a traumatic brain injury (TBI). Victims of TBI can suffer from chronic post-TBI symptoms, such as sensory and motor deficits, cognitive impairments including problems with memory, learning, and attention, and neuropsychiatric symptoms such as depression, anxiety, irritability, aggression, and suicidal rumination. Although partially associated with the site and severity of injury, the biological mechanisms associated with many of these symptoms – and why some patients experience differing assortments of persistent maladies – are largely unknown. The use of animal models is a promising strategy for elucidation of the mechanisms of impairment and treatment, and learning, memory, sensory, and motor tests have widespread utility in rodent models of TBI and psychopharmacology. Comparatively, behavioral tests for the evaluation of neuropsychiatric symptomatology are rarely employed in animal models of TBI and, as determined in this review, the results have been inconsistent. Animal behavioral studies contribute to the understanding of the biological mechanisms by which TBI is associated with neurobehavioral symptoms and offer a powerful means for pre-clinical treatment validation. Therefore, further exploration of the utility of animal behavioral tests for the study of injury mechanisms and therapeutic strategies for the alleviation of emotional symptoms are relevant and essential. PMID:24109476

  15. Assays of homeopathic remedies in rodent behavioural and psychopathological models.

    PubMed

    Bellavite, Paolo; Magnani, Paolo; Marzotto, Marta; Conforti, Anita

    2009-10-01

    The first part of this paper reviews the effects of homeopathic remedies on several models of anxiety-like behaviours developed and described in rodents. The existing literature in this field comprises some fifteen exploratory studies, often published in non-indexed and non-peer-reviewed journals. Only a few results have been confirmed by multiple laboratories, and concern Ignatia, Gelsemium, Chamomilla (in homeopathic dilutions/potencies). Nevertheless, there are some interesting results pointing to the possible efficacy of other remedies, and confirming a statistically significant effect of high dilutions of neurotrophic molecules and antibodies. In the second part of this paper we report some recent results obtained in our laboratory, testing Aconitum, Nux vomica, Belladonna, Argentum nitricum, Tabacum (all 5CH potency) and Gelsemium (5, 7, 9 and 30CH potencies) on mice using ethological models of behaviour. The test was performed using coded drugs and controls in double blind (operations and calculations). After an initial screening that showed all the tested remedies (except for Belladonna) to have some effects on the behavioural parameters (light-dark test and open-field test), but with high experimental variability, we focused our study on Gelsemium, and carried out two complete series of experiments. The results showed that Gelsemium had several effects on the exploratory behaviour of mice, which in some models were highly statistically significant (p < 0.001), in all the dilutions/dynamizations used, but with complex differences according to the experimental conditions and test performed. Finally, some methodological issues of animal research in this field of homeopathy are discussed. The "Gelsemium model" - encompassing experimental studies in vitro and in vivo from different laboratories and with different methods, including significant effects of its major active principle gelsemine - may play a pivotal rule for investigations on other homeopathic

  16. Stress induced obesity: lessons from rodent models of stress

    PubMed Central

    Patterson, Zachary R.; Abizaid, Alfonso

    2013-01-01

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

  17. Metagonimus yokogawai: metacercariae survey in fishes and its development to adult worms in various rodents.

    PubMed

    Li, Ming-Hsien; Huang, Hai-I; Chen, Pei-Lain; Huang, Chiung-Hua; Chen, Yu-Hsuan; Ooi, Hong-Kean

    2013-04-01

    A parasitological survey for Metagonimus yokogawai metacercariae was carried out by examining a total of 321 freshwater fish comprising of 7 species. Of the 321 fish samples examined, 182 (56.7%) were found to be infected with M. yokogawai metacercariae. The prevalence of M. yokogawai metacercariae in Opsariichthys pachycephalus was 93.4% (86/92), Zacco platypus 75.0% (30/40), Distoechodon turmirostris 61.3% (38/62), Varicorhinus barbatulus 56.5% (13/23), Hemibarbus labeo 33.3% (1/3), Acrossocheilus formosanus 15.9% (14/88), and 0% in Sinibrama macrops (0/13), respectively. This is the first record of M. yokogawai infection in Z. platypus, D. turmirostris, V. barbatulus, and H. labeo in Taiwan. The major site of predilection of the metacercariae in the fishes was in the scale, but some metacercariae were also observed in the flesh and fins. The M. yokogawai metacercariae were orally inoculated into mice, rat, gerbil, and golden hamster to study their infectivity and also to obtain the adult worms for taxonomic study. Worm recovery in hamsters was 75.3%, in mice was 70.0%, in rats was 23.3%, and in gerbils was 6.0%, respectively. Moreover, larger worms were recovered from the golden hamster. Golden hamster was thus found to be the most susceptible experimental rodent host for the infectivity study of Metagonimus. Besides M. yokogawai, metacercariae of Centrocestus formosanus was also observed in the fishes examined. PMID:23388732

  18. Long-term Continuous EEG Monitoring in Small Rodent Models of Human Disease Using the Epoch Wireless Transmitter System

    PubMed Central

    Zayachkivsky, Andrew; Lehmkuhle, Mark J.; Dudek, F. Edward

    2015-01-01

    Many progressive neurologic diseases in humans, such as epilepsy, require pre-clinical animal models that slowly develop the disease in order to test interventions at various stages of the disease process. These animal models are particularly difficult to implement in immature rodents, a classic model organism for laboratory study of these disorders. Recording continuous EEG in young animal models of seizures and other neurological disorders presents a technical challenge due to the small physical size of young rodents and their dependence on the dam prior to weaning. Therefore, there is not only a clear need for improving pre-clinical research that will better identify those therapies suitable for translation to the clinic but also a need for new devices capable of recording continuous EEG in immature rodents. Here, we describe the technology behind and demonstrate the use of a novel miniature telemetry system, specifically engineered for use in immature rats or mice, which is also effective for use in adult animals. PMID:26274779

  19. Long-term Continuous EEG Monitoring in Small Rodent Models of Human Disease Using the Epoch Wireless Transmitter System.

    PubMed

    Zayachkivsky, Andrew; Lehmkuhle, Mark J; Dudek, F Edward

    2015-01-01

    Many progressive neurologic diseases in humans, such as epilepsy, require pre-clinical animal models that slowly develop the disease in order to test interventions at various stages of the disease process. These animal models are particularly difficult to implement in immature rodents, a classic model organism for laboratory study of these disorders. Recording continuous EEG in young animal models of seizures and other neurological disorders presents a technical challenge due to the small physical size of young rodents and their dependence on the dam prior to weaning. Therefore, there is not only a clear need for improving pre-clinical research that will better identify those therapies suitable for translation to the clinic but also a need for new devices capable of recording continuous EEG in immature rodents. Here, we describe the technology behind and demonstrate the use of a novel miniature telemetry system, specifically engineered for use in immature rats or mice, which is also effective for use in adult animals. PMID:26274779

  20. Potential clinical translation of juvenile rodent inactivity models to study the onset of childhood obesity.

    PubMed

    Roberts, Michael D; Company, Joseph M; Brown, Jacob D; Toedebusch, Ryan G; Padilla, Jaume; Jenkins, Nathan T; Laughlin, M Harold; Booth, Frank W

    2012-08-01

    According to the latest data from the Center for Disease Control and Prevention 17%, or 12.5 million, of children and adolescents aged 2-19 years in the United States are obese. Physical inactivity is designated as one of the actual causes of US deaths and undoubtedly contributes to the obesity epidemic in children and adults. Examining the effects of inactivity on physiological homeostasis during youth is crucial given that 58% of children between the ages 6-11 yr old fail to obtain the recommended 60 min/day of physical activity and 92% of adolescents fail to achieve this goal [Troiano et al. Med Sci Sports Exerc. 40, 2008]. Nonetheless, invasive mechanistic studies in children linking diminished physical activity with metabolic maladies are lacking for obvious ethical reasons. The rodent wheel lock (WL) model was adopted by our laboratory and others to study how different organ systems of juvenile rats respond to a cessation of daily physical activity. Our WL model houses rats in cages equipped with voluntary running wheels starting at 28 days of age. After a certain period of voluntary running (3 to 6 wk), the wheels are locked, thus preventing the rats' primary source of physical activity. The studies discussed herein suggest that obesity-associated maladies including skeletal muscle insulin resistance, hypothalamic leptin resistance, fatty acid oxidation impairments in skeletal muscle and adipose tissue, nonalcoholic fatty liver disease, and endothelial dysfunction are initiated in juvenile animals that are restrained from voluntary exercise via WL. The use of the juvenile rodent WL or other inactivity models will continue to provide a powerful clinical translational tool that can be used for primordial prevention of human childhood obesity. PMID:22696577

  1. Efficacy of ipamorelin, a ghrelin mimetic, on gastric dysmotility in a rodent model of postoperative ileus

    PubMed Central

    Greenwood-Van Meerveld, Beverley; Tyler, Karl; Mohammadi, Ehsan; Pietra, Claudio

    2012-01-01

    Background Delayed gastric emptying is a common disorder with few effective therapeutic options. The goal of this study was to investigate whether ipamorelin, a synthetic peptidomimetic that acts on the ghrelin receptor, accelerates gastric emptying in a rodent model of gastroparesis induced by abdominal surgery and intestinal manipulation. Methods Fasted adult male rats were subjected to laparotomy and intestinal manipulation. Following the surgery rats received ipamorelin (0.014–0.14 µmol/kg) or vehicle control via intravenous administration. Gastric emptying was measured by the percent of total recovered radioactivity remaining in the stomach 15 minutes after intragastric gavage of 1.5 mL of 99mTc (technicium-99m) sulfur colloid in 0.5% methylcellulose. In a separate group of rats subjected to laparotomy and intestinal manipulation, the gastric fundus was isolated and tissue segments were suspended in an organ bath to assess the effect of ipamorelin (1 µM) on gastric smooth muscle contractility induced by acetylcholine and electrical field stimulation. Results Abdominal surgery caused a delay in gastric emptying with 78% ± 5% of the meal remaining in the stomach in vehicle controls. Ipamorelin (0.014 µmol/kg intravenous) resulted in a significant acceleration (P < 0.05 vs vehicle-treated rat) of gastric emptying with 52% ± 11% of the meal remaining in the stomach compared to nonsurgical control animals with 44% ± 6%. Following abdominal surgery and intestinal manipulation, isolated preparations of gastric smooth muscle exhibited a marked inhibition of acetylcholine and electrical field stimulation-induced contractile responses, which were reversed by ipamorelin and ghrelin. Conclusion These results suggest that ipamorelin accelerates gastric emptying in a rodent model of postoperative ileus through the stimulation of gastric contractility by activating a ghrelin receptor-mediated mechanism involving cholinergic excitatory neurons.

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

    PubMed

    Cai, Bin; Wang, Ning

    2016-01-01

    Stroke is a leading cause of serious long-term disability worldwide and the second leading cause of death in many countries. Long-time attempts to salvage dying neurons via various neuroprotective agents have failed in stroke translational research, owing in part to the huge gap between animal stroke models and stroke patients, which also suggests that rodent models have limited predictive value and that alternate large animal models are likely to become important in future translational research. The genetic background, physiological characteristics, behavioral characteristics, and brain structure of large animals, especially nonhuman primates, are analogous to humans, and resemble humans in stroke. Moreover, relatively new regional imaging techniques, measurements of regional cerebral blood flow, and sophisticated physiological monitoring can be more easily performed on the same animal at multiple time points. As a result, we can use large animal stroke models to decrease the gap and promote translation of basic science stroke research. At the same time, we should not neglect the disadvantages of the large animal stroke model such as the significant expense and ethical considerations, which can be overcome by rodent models. Rodents should be selected as stroke models for initial testing and primates or cats are desirable as a second species, which was recommended by the Stroke Therapy Academic Industry Roundtable (STAIR) group in 2009. PMID:26463926

  3. Translating animal model research: does it matter that our rodents are cold?

    PubMed

    Maloney, Shane K; Fuller, Andrea; Mitchell, Duncan; Gordon, Christopher; Overton, J Michael

    2014-11-01

    Does it matter that rodents used as preclinical models of human biology are routinely housed below their thermoneutral zone? We compile evidence showing that such rodents are cold-stressed, hypermetabolic, hypertensive, sleep-deprived, obesity-resistant, fever-resistant, aging-resistant, and tumor-prone compared with mice housed at thermoneutrality. The same genotype of mouse has a very different phenotype and response to physiological or pharmacological intervention when raised below or at thermoneutrality. PMID:25362635

  4. Psychophysical testing in rodent models of glaucomatous optic neuropathy.

    PubMed

    Grillo, Stephanie L; Koulen, Peter

    2015-12-01

    Processing of visual information begins in the retina, with photoreceptors converting light stimuli into neural signals. Ultimately, signals are transmitted to the brain through signaling networks formed by interneurons, namely bipolar, horizontal and amacrine cells providing input to retinal ganglion cells (RGCs), which form the optic nerve with their axons. As part of the chronic nature of glaucomatous optic neuropathy, the increasing and irreversible damage and ultimately loss of neurons, RGCs in particular, occurs following progressive damage to the optic nerve head (ONH), eventually resulting in visual impairment and visual field loss. There are two behavioral assays that are typically used to assess visual deficits in glaucoma rodent models, the visual water task and the optokinetic drum. The visual water task can assess an animal's ability to distinguish grating patterns that are associated with an escape from water. The optokinetic drum relies on the optomotor response, a reflex turning of the head and neck in the direction of the visual stimuli, which usually consists of rotating black and white gratings. This reflex is a physiological response critical for keeping the image stable on the retina. Driven initially by the neuronal input from direction-selective RGCs, this reflex is comprised of a number of critical sensory and motor elements. In the presence of repeatable and defined stimuli, this reflex is extremely well suited to analyze subtle changes in the circuitry and performance of retinal neurons. Increasing the cycles of these alternating gratings per degree, or gradually reducing the contrast of the visual stimuli, threshold levels can be determined at which the animal is no longer tracking the stimuli, and thereby visual function of the animal can be determined non-invasively. Integrating these assays into an array of outcome measures that determine multiple aspects of visual function is a central goal in vision research and can be realized, for

  5. Barnes Maze Testing Strategies with Small and Large Rodent Models

    PubMed Central

    2014-01-01

    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

  6. Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research.

    PubMed

    Renner, Simone; Dobenecker, Britta; Blutke, Andreas; Zöls, Susanne; Wanke, Rüdiger; Ritzmann, Mathias; Wolf, Eckhard

    2016-07-01

    The prevalence of diabetes mellitus, which currently affects 387 million people worldwide, is permanently rising in both adults and adolescents. Despite numerous treatment options, diabetes mellitus is a progressive disease with severe comorbidities, such as nephropathy, neuropathy, and retinopathy, as well as cardiovascular disease. Therefore, animal models predictive of the efficacy and safety of novel compounds in humans are of great value to address the unmet need for improved therapeutics. Although rodent models provide important mechanistic insights, their predictive value for therapeutic outcomes in humans is limited. In recent years, the pig has gained importance for biomedical research because of its close similarity to human anatomy, physiology, size, and, in contrast to non-human primates, better ethical acceptance. In this review, anatomic, biochemical, physiological, and morphologic aspects relevant to diabetes research will be compared between different animal species, that is, mouse, rat, rabbit, pig, and non-human primates. The value of the pig as a model organism for diabetes research will be highlighted, and (dis)advantages of the currently available approaches for the generation of pig models exhibiting characteristics of metabolic syndrome or type 2 diabetes mellitus will be discussed. PMID:27180329

  7. Analysis of adult neurogenesis: evidence for a prominent "non-neurogenic" DCX-protein pool in rodent brain.

    PubMed

    Kremer, Thomas; Jagasia, Ravi; Herrmann, Annika; Matile, Hugues; Borroni, Edilio; Francis, Fiona; Kuhn, Hans Georg; Czech, Christian

    2013-01-01

    Here, we have developed a highly sensitive immunoassay for Dcx to characterize expression in brain and cerebrospinal fluid (CSF) of rodents. We demonstrate that Dcx is widely expressed during development in various brain regions and as well can be detected in cerebrospinal fluid of rats (up to 30 days postnatal). While Dcx protein level decline in adulthood and were detectable in neurogenic regions of the adult rodent brain, similar levels were also detectable in brain regions expected to bear no neurogenesis including the cerebral cortex and CA1/CA3 enriched hippocampus. We monitored DCX protein levels after paradigms to increase or severely decrease adult hippocampal neurogenesis, namely physical activity and cranial radiation, respectively. In both paradigms, Dcx protein- and mRNA-levels clearly reflected changes in neurogenesis in the hippocampus. However, basal Dcx-levels are unaffected in non-neurogenic regions (e.g. CA1/CA3 enriched hippocampus, cortex). These data suggest that there is a substantial "non-neurogenic" pool of Dcx- protein, whose regulation can be uncoupled from adult neurogenesis suggesting caution for the interpretation of such studies. PMID:23690918

  8. Analysis of Adult Neurogenesis: Evidence for a Prominent “Non-Neurogenic” DCX-Protein Pool in Rodent Brain

    PubMed Central

    Kremer, Thomas; Jagasia, Ravi; Herrmann, Annika; Matile, Hugues; Borroni, Edilio; Francis, Fiona; Kuhn, Hans Georg; Czech, Christian

    2013-01-01

    Here, we have developed a highly sensitive immunoassay for Dcx to characterize expression in brain and cerebrospinal fluid (CSF) of rodents. We demonstrate that Dcx is widely expressed during development in various brain regions and as well can be detected in cerebrospinal fluid of rats (up to 30 days postnatal). While Dcx protein level decline in adulthood and were detectable in neurogenic regions of the adult rodent brain, similar levels were also detectable in brain regions expected to bear no neurogenesis including the cerebral cortex and CA1/CA3 enriched hippocampus. We monitored DCX protein levels after paradigms to increase or severely decrease adult hippocampal neurogenesis, namely physical activity and cranial radiation, respectively. In both paradigms, Dcx protein- and mRNA-levels clearly reflected changes in neurogenesis in the hippocampus. However, basal Dcx-levels are unaffected in non-neurogenic regions (e.g. CA1/CA3 enriched hippocampus, cortex). These data suggest that there is a substantial “non-neurogenic” pool of Dcx- protein, whose regulation can be uncoupled from adult neurogenesis suggesting caution for the interpretation of such studies. PMID:23690918

  9. A Novel Rodent Model of Posterior Ischemic Optic Neuropathy

    PubMed Central

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

    2014-01-01

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

  10. A mathematical model of adult subventricular neurogenesis

    PubMed Central

    Ashbourn, J. M. A.; Miller, J. J.; Reumers, V.; Baekelandt, V.; Geris, L.

    2012-01-01

    Neurogenesis has been the subject of active research in recent years and many authors have explored the phenomenology of the process, its regulation and its purported purpose. Recent developments in bioluminescent imaging (BLI) allow direct in vivo imaging of neurogenesis, and in order to interpret the experimental results, mathematical models are necessary. This study proposes such a mathematical model that describes adult mammalian neurogenesis occurring in the subventricular zone and the subsequent migration of cells through the rostral migratory stream to the olfactory bulb (OB). This model assumes that a single chemoattractant is responsible for cell migration, secreted both by the OB and in an endocrine fashion by the cells involved in neurogenesis. The solutions to the system of partial differential equations are compared with the physiological rodent process, as previously documented in the literature and quantified through the use of BLI, and a parameter space is described, the corresponding solution to which matches that of the rodent model. A sensitivity analysis shows that this parameter space is stable to perturbation and furthermore that the system as a whole is sloppy. A large number of parameter sets are stochastically generated, and it is found that parameter spaces corresponding to physiologically plausible solutions generally obey constraints similar to the conditions reported in vivo. This further corroborates the model and its underlying assumptions based on the current understanding of the investigated phenomenon. Concomitantly, this leaves room for further quantitative predictions pertinent to the design of future proposed experiments. PMID:22572029

  11. 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

  12. Non-invasive muscle contraction assay to study rodent models of sarcopenia

    PubMed Central

    2011-01-01

    Background Age-related sarcopenia is a disease state of loss of muscle mass and strength that affects physical function and mobility leading to falls, fractures, and disability. The need for therapies to treat age-related sarcopenia has attracted intensive preclinical research. To facilitate the discovery of these therapies, we have developed a non-invasive rat muscle functional assay system to efficiently measure muscle force and evaluate the efficacy of drug candidates. Methods The lower leg muscles of anesthetized rats are artificially stimulated with surface electrodes on the knee holders and the heel support, causing the lower leg muscles to push isometric pedals that are attached to force transducers. We developed a stimulation protocol to perform a fatigability test that reveals functional muscle parameters like maximal force, the rate of fatigue, fatigue-resistant force, as well as a fatigable muscle force index. The system is evaluated in a rat aging model and a rat glucocorticoid-induced muscle loss model Results The aged rats were generally weaker than adult rats and showed a greater reduction in their fatigable force when compared to their fatigue-resistant force. Glucocorticoid treated rats mostly lost fatigable force and fatigued at a higher rate, indicating reduced force from glycolytic fibers with reduced energy reserves. Conclusions The involuntary contraction assay is a reliable system to assess muscle function in rodents and can be applied in preclinical research, including age-related sarcopenia and other myopathy. PMID:22035016

  13. Modeling susceptible infective recovered dynamics and plague persistence in California rodent-flea communities.

    PubMed

    Foley, Patrick; Foley, Janet

    2010-01-01

    Plague persists as an enzootic in several very different rodent-flea communities around the world. In California, a diversity of rodent-flea communities maintains the disease, and a single-host reservoir seems unlikely. Logistic regression of plague presence on climate and topographic variables predicts plague in many localities where it is absent. Thus, a dynamic community-based analysis was needed. Deterministic Susceptible Infective Recovered (SIR) models were adapted for plague and analyzed with an eye for insights concerning disease persistence. An R simulation program, Plaguesirs, was developed incorporating multihost and multivector SIR dynamics, demographic and environmental stochasticity, density dependence, and seasonal variation in birth and death. Flea-rodent utilization matrices allowed us to get transmission rates as well as flea carrying capacities. Rodent densities allowed us to estimate host carrying capacities, while maximum birth rates were mainly approximated through an examination of litter phenology and demography. We ran a set of simulations to assess the role of community structure in maintaining plague in a simulated version of Chuchupate campground in Ventura County. Although the actual campground comprises 10 rodent and 19 flea species, we focused on a subset suspected to act as a reservoir community. This included the vole Microtus californicus, the deer mouse Peromyscus maniculatus, the Ceratophyllid fleas Aetheca wagneri and Malareus telchinum, and the Leptopsyllid flea Peromyscopsylla hesperomys. The dynamics of 21 subsets of this community were simulated for 20 years. Single-rodent communities showed much lower disease persistence than two-rodent communities. However, so long as Malareus was present, endemicity was enhanced; removal of the other two fleas slightly increased disease persistence. Two critical features improved disease persistence: (1) host breeding season heterogeneity and (2) host population augmentation (due to two

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

    PubMed

    Stefano, J T; Pereira, I V A; Torres, M M; Bida, P M; Coelho, A M M; Xerfan, M P; Cogliati, B; Barbeiro, D F; Mazo, D F C; Kubrusly, M S; D'Albuquerque, L A C; Souza, H P; Carrilho, F J; Oliveira, C P

    2015-05-01

    Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg(-1)·day(-1) by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH. PMID:25714891

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

    PubMed Central

    Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M.; Coelho, A.M.M.; Xerfan, M.P.; Cogliati, B.; Barbeiro, D.F.; Mazo, D.F.C.; Kubrusly, M.S.; D'Albuquerque, L.A.C.; Souza, H.P.; Carrilho, F.J.; Oliveira, C.P.

    2015-01-01

    Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg-1·day-1 by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH. PMID:25714891

  16. 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

  17. Rodent models of pulmonary hypertension: harmonisation with the world health organisation's categorisation of human PH.

    PubMed

    Ryan, J; Bloch, K; Archer, S L

    2011-08-01

    The WHO classification of pulmonary hypertension (PH) recognises five distinct groups, all sharing a mean, resting, pulmonary artery pressure (PAP) > 25 mmHg. The aetiology of PH varies by group (1-pulmonary vascular disease, 2-high left heart filling pressures, 3-hypoxia, 4-unresolved pulmonary embolism and 5-miscellaneous). Inclusion in a group reflects shared histological, haemodynamic and pathophysiological features and has therapeutic implications. Advantages of using rodent models to understand the pathophysiology of human PH and to test experimental therapies include the economy, safety and mechanistic certainty they provide. As rodent models are meant to reflect human PH, they should be categorised by a parallel PH classification and limitations in achieving this ideal recognised. Challenges with rodent models include: accurate phenotypic characterisation (haemodynamics, histology and imaging), species and strain variations in the natural history of PH, and poor fidelity to the relevant human PH group. Rat models of group 1 PH include: monocrotaline (± pneumonectomy), chronic hypoxia + SU-5416 (a VEGF receptor inhibitor) and the fawn-hooded rat (FHR). Mouse models of group 1 PH include: transgenic mice overexpressing the serotonin transporter or dominant-negative mutants of bone morphogenetic protein receptor-2. Group 1 PH is also created by infecting S100A4/Mts1 mice with γ-herpesvirus. The histological features of group 1 PH, but not PH itself, are induced by exposure to Schistosoma mansoni or Stachybotrys chartarum. Group 3 PH is modelled by exposure of rats or mice to chronic hypoxia. Rodent models of groups 2, 4 and 5 PH are needed. Comprehensive haemodynamic, histological and molecular phenotyping, coupled with categorisation into WHO PH groups, enhances the utility of rodent models. PMID:21736677

  18. Rodent models of hepatic ischemia-reperfusion injury: time and percentage-related pathophysiological mechanisms.

    PubMed

    Karatzas, Theodore; Neri, Anna-Aikaterini; Baibaki, Maria-Eleni; Dontas, Ismene A

    2014-10-01

    Ischemia and reperfusion (IR) injury remains one of the major problems in liver surgery and transplantation, which determines the viability of the hepatic tissue after resection and of the grafted organ. This review aims to elucidate the mechanisms involved in IR injury of the liver in rodent experimental studies and the preventative methods and pharmacologic agents that have been applied. Many time- and percentage-related liver IR injury rodent models have been used to examine the pathophysiological mechanisms and the parameters implicated with different morbidity, mortality, and pathology findings. The most preferred experimental rodent model of liver IR is the induction of 70% IR for 45 min, which is associated with almost 100% survival. In this model, plasma levels of several parameters such as alanine transaminase, aspartate aminotransferase, gamma-glutamyltransferase, endothelin-1, malonodialdehyde, tumor necrosis factor α, interleukin 1b, inducible nitric oxide synthase, and caspases are increased. The increase of caspases is associated with the initiation of hepatic cellular apoptosis. The main injuries observed 24 h after reperfusion are nuclear pyknosis, cytoplasmic hypereosinophilia, severe necrosis, and loss of intercellular borders. Both ischemic pre- and post-conditioning preventative methods and pharmacologic agents are successfully applied to alleviate the IR injuries. The selection of the time- and percentage-related liver IR injury rodent model and the potential preventative method should be related to the clinical question being answered. PMID:25033703

  19. Comparative evaluation of establishing a human gut microbial community within rodent models

    PubMed Central

    Wos-Oxley, Melissa L.; Bleich, André; Oxley, Andrew P.A.; Kahl, Silke; Janus, Lydia M.; Smoczek, Anna; Nahrstedt, Hannes; Pils, Marina C.; Taudien, Stefan; Platzer, Matthias; Hedrich, Hans-Jürgen; Medina, Eva; Pieper, Dietmar H.

    2012-01-01

    The structure of the human gut microbial community is determined by host genetics and environmental factors, where alterations in its structure have been associated with the onset of different diseases. Establishing a defined human gut microbial community within inbred rodent models provides a means to study microbial-related pathologies, however, an in-depth comparison of the established human gut microbiota in the different models is lacking. We compared the efficiency of establishing the bacterial component of a defined human microbial community within germ-free (GF) rats, GF mice and antibiotic-treated specific pathogen-free mice. Remarkable differences were observed between the different rodent models. While the majority of abundant human-donor bacterial phylotypes were established in the GF rats, only a subset was present in the GF mice. Despite the fact that members of the phylum Bacteriodetes were well established in all rodent models, mice enriched for phylotypes related to species of Bacteroides. In contrary to the efficiency of Clostridiales to populate the GF rat in relative proportions to that of the human-donor, members of Clostridia cluster IV only poorly colonize the mouse gut. Thus, the genetic background of the different recipient rodent systems (that is, rats and mice) strongly influences the nature of the populating human gut microbiota, determining each model’s biological suitability. PMID:22572831

  20. Quantification of adipose tissue in a rodent model of obesity

    NASA Astrophysics Data System (ADS)

    Johnson, David H.; Flask, Chris; Wan, Dinah; Ernsberger, Paul; Wilson, David L.

    2006-03-01

    Obesity is a global epidemic and a comorbidity for many diseases. We are using MRI to characterize obesity in rodents, especially with regard to visceral fat. Rats were scanned on a 1.5T clinical scanner, and a T1W, water-spoiled image (fat only) was divided by a matched T1W image (fat + water) to yield a ratio image related to the lipid content in each voxel. The ratio eliminated coil sensitivity inhomogeneity and gave flat values across a fat pad, except for outlier voxels (> 1.0) due to motion. Following sacrifice, fat pad volumes were dissected and measured by displacement in canola oil. In our study of 6 lean (SHR), 6 dietary obese (SHR-DO), and 9 genetically obese rats (SHROB), significant differences in visceral fat volume was observed with an average of 29+/-16 ml increase due to diet and 84+/-44 ml increase due to genetics relative to lean control with a volume of 11+/-4 ml. Subcutaneous fat increased 14+/-8 ml due to diet and 198+/-105 ml due to genetics relative to the lean control with 7+/-3 ml. Visceral fat strongly correlated between MRI and dissection (R2 = 0.94), but MRI detected over five times the subcutaneous fat found with error-prone dissection. Using a semi-automated images segmentation method on the ratio images, intra-subject variation was very low. Fat pad composition as estimated from ratio images consistently differentiated the strains with SHROB having a greater lipid concentration in adipose tissues. Future work will include in vivo studies of diet versus genetics, identification of new phenotypes, and corrective measures for obesity; technical efforts will focus on correction for motion and automation in quantification.

  1. 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...

  2. 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

  3. 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

  4. Rodent models of impulsive-compulsive behaviors in Parkinson's disease: How far have we reached?

    PubMed

    Cenci, M Angela; Francardo, Veronica; O'Sullivan, Sean S; Lindgren, Hanna S

    2015-10-01

    There is increasing awareness that the medications used to treat the motor symptoms of Parkinson's disease (PD) contribute to the development of behavioral addictions, which have been clinically defined as impulsive-compulsive behaviors (ICBs). These features include pathological gambling, compulsive sexual behavior, binge eating, compulsive shopping, excessive hobbyism or punding, and the excessive use of dopaminergic medication. ICBs frequently have devastating effects on the social and occupational function of the affected individuals as well as their families. Although ICBs are an important clinical problem in PD, the number of studies in which these symptoms have been modeled in rodents is still limited. This may depend on uncertainties regarding, on one hand, the pathophysiology of these behaviors and, on the other hand, the experimental paradigms with which similar features can be induced in rodents. To help compose these uncertainties, we will here review the characteristics of ICBs in PD patients and then describe behavioral methods to approximate them in rodents. We will discuss both the challenges and the possibilities of applying these methods to animals with PD-like lesions, and review the recent progress made to this end. We will finally highlight important questions deserving further investigation. Rodent models having both face validity and construct validity to parkinsonian ICBs will be essential to further pathophysiological and therapeutic studies into this important area. PMID:26325219

  5. Early neural disruption and auditory processing outcomes in rodent models: implications for developmental language disability

    PubMed Central

    Fitch, R. Holly; Alexander, Michelle L.; Threlkeld, Steven W.

    2013-01-01

    Most researchers in the field of neural plasticity are familiar with the “Kennard Principle,” which purports a positive relationship between age at brain injury and severity of subsequent deficits (plateauing in adulthood). As an example, a child with left hemispherectomy can recover seemingly normal language, while an adult with focal injury to sub-regions of left temporal and/or frontal cortex can suffer dramatic and permanent language loss. Here we present data regarding the impact of early brain injury in rat models as a function of type and timing, measuring long-term behavioral outcomes via auditory discrimination tasks varying in temporal demand. These tasks were created to model (in rodents) aspects of human sensory processing that may correlate—both developmentally and functionally—with typical and atypical language. We found that bilateral focal lesions to the cortical plate in rats during active neuronal migration led to worse auditory outcomes than comparable lesions induced after cortical migration was complete. Conversely, unilateral hypoxic-ischemic (HI) injuries (similar to those seen in premature infants and term infants with birth complications) led to permanent auditory processing deficits when induced at a neurodevelopmental point comparable to human “term,” but only transient deficits (undetectable in adulthood) when induced in a “preterm” window. Convergent evidence suggests that regardless of when or how disruption of early neural development occurs, the consequences may be particularly deleterious to rapid auditory processing (RAP) outcomes when they trigger developmental alterations that extend into subcortical structures (i.e., lower sensory processing stations). Collective findings hold implications for the study of behavioral outcomes following early brain injury as well as genetic/environmental disruption, and are relevant to our understanding of the neurologic risk factors underlying developmental language disability in

  6. Dendrimers Target the Ischemic Lesion in Rodent and Primate Models of Nonarteritic Anterior Ischemic Optic Neuropathy

    PubMed Central

    Guo, Yan; Johnson, Mary A.; Mehrabian, Zara; Mishra, Manoj K.; Kannan, Rangaramanujam; Miller, Neil R.; Bernstein, Steven L.

    2016-01-01

    Introduction Polyamidoamine dendrimer nanoparticles (~ 4 nanometers) are inert polymers that can be linked to biologically active compounds. These dendrimers selectively target and accumulate in inflammatory cells upon systemic administration. Dendrimer-linked compounds enable sustained release of therapeutic compounds directly at the site of damage. The purpose of this study was to determine if dendrimers can be used to target the optic nerve (ON) ischemic lesion in our rodent and nonhuman primate models of nonarteritic anterior ischemic optic neuropathy (NAION), a disease affecting >10,000 individuals in the US annually, and for which there currently is no effective treatment. Methods NAION was induced in male Long-Evans rats (rNAION) and in one adult male rhesus monkey (pNAION) using previously described procedures. Dendrimers were covalently linked to near-infrared cyanine-5 fluorescent dye (D-Cy5) and injected both intravitreally and systemically (in the rats) or just systemically (in the monkey) to evaluate D-Cy5 tissue accumulation in the eye and optic nerve following induction of NAION. Results Following NAION induction, Cy-5 dendrimers selectively accumulated in astrocytes and circulating macrophages. Systemic dendrimer administration provided the best penetration of the ON lesion site when injected shortly after induction. Systemic administration 1 day post-induction in the pNAION model gave localization similar to that seen in the rats. Conclusions Dendrimers selectively target the ischemic ON lesion after induction of both rNAION and pNAION. Systemic nanoparticle-linked therapeutics thus may provide a powerful, targeted and safe approach to NAION treatment by providing sustained and focused treatment of the cells directly affected by ischemia. PMID:27128315

  7. Rodent models of cardiopulmonary disease: their potential applicability in studies of air pollutant susceptibility.

    PubMed Central

    Kodavanti, U P; Costa, D L; Bromberg, P A

    1998-01-01

    The mechanisms by which increased mortality and morbidity occur in individuals with preexistent cardiopulmonary disease following acute episodes of air pollution are unknown. Studies involving air pollution effects on animal models of human cardiopulmonary diseases are both infrequent and difficult to interpret. Such models are, however, extensively used in studies of disease pathogenesis. Primarily they comprise those developed by genetic, pharmacologic, or surgical manipulations of the cardiopulmonary system. This review attempts a comprehensive description of rodent cardiopulmonary disease models in the context of their potential application to susceptibility studies of air pollutants regardless of whether the models have been previously used for such studies. The pulmonary disease models include bronchitis, emphysema, asthma/allergy, chronic obstructive pulmonary disease, interstitial fibrosis, and infection. The models of systemic hypertension and congestive heart failure include: those derived by genetics (spontaneously hypertensive, Dahl S. renin transgenic, and other rodent models); congestive heart failure models derived by surgical manipulations; viral myocarditis; and cardiomyopathy induced by adriamycin. The characteristic pathogenic features critical to understanding the susceptibility to inhaled toxicants are described. It is anticipated that this review will provide a ready reference for the selection of appropriate rodent models of cardiopulmonary diseases and identify not only their pathobiologic similarities and/or differences to humans but also their potential usefulness in susceptibility studies. Images Figure 2 PMID:9539009

  8. Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy Characterize a Rodent Model of Covert Stroke

    NASA Astrophysics Data System (ADS)

    Herrera, Sheryl Lyn

    Covert stroke (CS) comprises lesions in the brain often associated by risk factors such as a diet high in fat, salt, cholesterol and sugar (HFSCS). Developing a rodent model for CS incorporating these characteristics is useful for developing and testing interventions. The purpose of this thesis was to determine if magnetic resonance (MR) can detect brain abnormalities to confirm this model will have the desired anatomical effects. Ex vivo MR showed brain abnormalities for rats with the induced lesions and fed the HFSCS diet. Spectra acquired on the fixed livers had an average percent area under the fat peak relative to the water peak of (20+/-4)% for HFSCS and (2+/-2)% for control. In vivo MR images had significant differences between surgeries to induce the lesions (p=0.04). These results show that applying MR identified abnormalities in the rat model and therefore is important in the development of this CS rodent model.

  9. Preclinical imaging and treatment of cancer: the use of animal models beyond rodents.

    PubMed

    Axiak-Bechtel, S M; Maitz, C A; Selting, K A; Bryan, J N

    2015-09-01

    The development of novel radiopharmaceutical agents for imaging and therapy of neoplastic diseases relies on accurate and reproducible animal models. Rodent models are often used to demonstrate the proof-of-principle tracer and therapeutic agent development, but their small size can make tissue sampling challenging. The dosimetry of decay emissions in the much smaller rodent tumors do not model dosimetry in human tumors well. In addition, rodent models of cancer represent a simplified version of a very complex process. Spontaneous tumors are heterogenous and the response to intervention can be unpredictable; tumor cells can adopt alternate signaling pathways and modify their interaction with the microenvironment. These inconsistencies, while present in humans, are difficult to fully reproduce in a genetically-engineered rodent model. Companion animals, primarily dogs and cats, offer translational models that more accurately reflect the intricate nature of spontaneous neoplasia in humans. Their larger size facilitates tissue and blood sampling when needed, and allows radiopharmaceutical tracers to be studied on human-scale imaging systems to better mimic the clinical application of the agent. This article will review the growing body of literature surrounding the use of radiopharmaceutical agents for both imaging and therapy in companion dogs and cats. Previous investigations have been performed both for the advancement of routine, high-level veterinary care, and in the context of translational research from which the results of imaging and treatment can be readily applied to people. Studies utilizing the spontaneously occurring cancer model in companion animals involving positron emission tomography, radiotracers, dosimetry, theranostics, targeted radiopharmaceuticals, brachytherapy, and boron neutron capture therapy are discussed. PMID:26200223

  10. Criteria for determining whether mismatch responses exist in animal models: Focus on rodents.

    PubMed

    Harms, Lauren; Michie, Patricia T; Näätänen, Risto

    2016-04-01

    The mismatch negativity (MMN) component of the auditory event-related potential, elicited in response to unexpected stimuli in the auditory environment, has great value for cognitive neuroscience research. It is changed in several neuropsychiatric disorders such as schizophrenia. The ability to measure and manipulate MMN-like responses in animal models, particularly rodents, would provide an enormous opportunity to learn more about the neurobiology underlying MMN. However, the MMN in humans is a very specific phenomenon: how do we decide which features we should focus on emulating in an animal model to achieve the highest level of translational validity? Here we discuss some of the key features of MMN in humans and summarise the success with which they have been translated into rodent models. Many studies from several different labs have successfully shown that the rat brain is capable of generating deviance detection responses that satisfy of the criteria for the human MMN. PMID:26196895

  11. 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

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

    PubMed

    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

  13. Rodent models for Alzheimer’s disease drug discovery

    PubMed Central

    Puzzo, Daniela; Gulisano, Walter; Palmeri, Agostino; Arancio, Ottavio

    2015-01-01

    Introduction Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histophatological hallmarks are represented by aggregates of beta-amyloid peptide (Aβ) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer's disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals. Area covered This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including: APP Tg2576, APP/PS1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of Aβ or tau, and models of physiological aging. Expert opinion Animal models of disease might be very useful for studying the pathophysiology of the disease and for testing new therapeutics in preclinical studies but they do not reproduce the entire clinical features of human AD. When selecting a model, researchers should consider the various factors that might influence the phenotype. They should also consider the timing of testing/treating animals since the age at which each model develops certain aspects of the AD pathology varies. PMID:25927677

  14. Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism.

    PubMed

    Stanton, Mark E; Peloso, Elizabeth; Brown, Kevin L; Rodier, Patricia

    2007-01-10

    Offspring of rats exposed to valproic acid (VPA) on gestational day (GD) 12 have been advocated as a rodent model of autism because they show neuron loss in brainstem nuclei and the cerebellum resembling that seen in human autistic cases . Studies of autistic children have reported alterations in acquisition of classical eyeblink conditioning and in reversal of instrumental discrimination learning . Acquisition of discriminative eyeblink conditioning depends on known brainstem-cerebellar circuitry whereas reversal depends on interactions of this circuitry with the hippocampus and prefrontal cortex. In order to explore behavioral parallels of the VPA rodent model with human autism, the present study exposed pregnant Long-Evans rats to 600 mg/kg VPA on GD12 and tested their offspring from Postnatal Day (PND26-31) on discriminative eyeblink conditioning and reversal. VPA rats showed faster eyeblink conditioning, consistent with studies in autistic children . This suggests that previously reported parallels between human autism and the VPA rodent model with respect to injury to brainstem-cerebellar circuitry are accompanied by behavioral parallels when a conditioning task engaging this circuitry is used. VPA rats also showed impaired reversal learning, but this likely reflected "carry-over" of enhanced conditioning during acquisition rather than a reversal learning deficit like that seen in human autism. Further studies of eyeblink conditioning in human autism and in various animal models may help to identify the etiology of this developmental disorder. PMID:17137645

  15. Discrimination Learning and Reversal of the Conditioned Eyeblink Reflex in a Rodent Model of Autism

    PubMed Central

    Stanton, Mark E.; Peloso, Elizabeth; Brown, Kevin L.; Rodier, Patricia

    2007-01-01

    Offspring of rats exposed to valproic acid (VPA) on Gestational Day (GD) 12 have been advocated as a rodent model of autism because they show neuron loss in brainstem nuclei and the cerebellum resembling that seen in human autistic cases [20, 37]. Studies of autistic children have reported alterations in acquisition of classical eyeblink conditioning [40] and in reversal of instrumental discrimination learning [9]. Acquisition of discriminative eyeblink conditioning depends on known brainstem-cerebellar circuitry whereas reversal depends on interactions of this circuitry with the hippocampus and prefrontal cortex. In order to explore behavioral parallels of the VPA rodent model with human autism, the present study exposed pregnant Long-Evans rats to 600 mg/kg VPA on GD12 [cf. 37] and tested their offspring from PND26-31 on discriminative eyeblink conditioning and reversal. VPA rats showed faster eyeblink conditioning, consistent with studies in autistic children [40]. This suggests that previously reported parallels between human autism and the VPA rodent model with respect to injury to brainstem-cerebellar circuitry [37] are accompanied by behavioral parallels when a conditioning task engaging this circuitry is used. VPA rats also showed impaired reversal learning, but this likely reflected “carry-over” of enhanced conditioning during acquisition rather than a reversal learning deficit like that seen in human autism. Further studies of eyeblink conditioning in human autism and in various animal models may help to identify the etiology of this developmental disorder. PMID:17137645

  16. Mainland size variation informs predictive models of exceptional insular body size change in rodents

    PubMed Central

    Durst, Paul A. P.; Roth, V. Louise

    2015-01-01

    The tendency for island populations of mammalian taxa to diverge in body size from their mainland counterparts consistently in particular directions is both impressive for its regularity and, especially among rodents, troublesome for its exceptions. However, previous studies have largely ignored mainland body size variation, treating size differences of any magnitude as equally noteworthy. Here, we use distributions of mainland population body sizes to identify island populations as ‘extremely’ big or small, and we compare traits of extreme populations and their islands with those of island populations more typical in body size. We find that although insular rodents vary in the directions of body size change, ‘extreme’ populations tend towards gigantism. With classification tree methods, we develop a predictive model, which points to resource limitations as major drivers in the few cases of insular dwarfism. Highly successful in classifying our dataset, our model also successfully predicts change in untested cases. PMID:26085585

  17. Insights revealed by rodent models of sugar binge eating.

    PubMed

    Murray, Susan M; Tulloch, Alastair J; Chen, Eunice Y; Avena, Nicole M

    2015-12-01

    Binge eating is seen across the spectrum of eating disorder diagnoses as well as among individuals who do not meet diagnostic criteria. Analyses of the specific types of foods that are frequently binged upon reveal that sugar-rich items feature prominently in binge-type meals, making the effects of binge consumption of sugar an important focus of study. One avenue to do this involves the use of animal models. Foundational and recent studies of animal models of sugar bingeing, both outlined here, lend insight into the various neurotransmitters and neuropeptides that may participate in or be altered by this behavior. Further, several preclinical studies incorporating sugar bingeing paradigms have explored the utility of pharmacological agents that target such neural systems for reducing sugar bingeing in an effort to enhance clinical treatment. Indeed, the translational implications of findings generated using animal models of sugar bingeing are considered here, along with potential avenues for further study. PMID:26510689

  18. Recent advances using rodent models for predicting human allergenicity

    SciTech Connect

    Knippels, Leon M.J. . E-mail: Knippels@voeding.tno.nl; Penninks, Andre H.

    2005-09-01

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

  19. Fatigue and Sleep during Cancer and Chemotherapy: Translational Rodent Models

    PubMed Central

    Ray, Maria; Rogers, Laura Q; Trammell, Rita A; Toth, Linda A

    2008-01-01

    The frequent occurrence of fatigue and disturbed sleep in cancer survivors and the negative effect of these symptoms on quality of life and clinical outcome underscore the need to identify mechanisms that cause cancer-related fatigue, with a view toward developing more effective treatments for this problem. Human studies of fatigue and disturbed sleep are limited by high inter-individual genetic and environmental variability, difficulties with behavioral or reporting compliance, and the subjective nature of the problems. Although animal models also must overcome the barrier of assessing fatigue and sleep disturbance in the absence of obvious objective clinical markers, animal studies are easier to control and standardize than are studies of people. Moreover, animal models are crucial to the identification and understanding of underlying disease mechanisms. This review describes the need for, the feasibility of, and several possible approaches to measuring fatigue in animal models of cancer and to relating such measures to disturbed sleep, immune function, and other potential mechanisms. Developing and using animal models to better understand fatigue and disturbed sleep related to cancer and its treatment has an enormous potential to expand the knowledge base and foster hypotheses necessary for the future development and testing of interventions. PMID:18589865

  20. Modeling autism-relevant behavioral phenotypes in rats and mice: Do 'autistic' rodents exist?

    PubMed

    Servadio, Michela; Vanderschuren, Louk J M J; Trezza, Viviana

    2015-09-01

    Autism spectrum disorders (ASD) are among the most severe developmental psychiatric disorders known today, characterized by impairments in communication and social interaction and stereotyped behaviors. However, no specific treatments for ASD are as yet available. By enabling selective genetic, neural, and pharmacological manipulations, animal studies are essential in ASD research. They make it possible to dissect the role of genetic and environmental factors in the pathogenesis of the disease, circumventing the many confounding variables present in human studies. Furthermore, they make it possible to unravel the relationships between altered brain function in ASD and behavior, and are essential to test new pharmacological options and their side-effects. Here, we first discuss the concepts of construct, face, and predictive validity in rodent models of ASD. Then, we discuss how ASD-relevant behavioral phenotypes can be mimicked in rodents. Finally, we provide examples of environmental and genetic rodent models widely used and validated in ASD research. We conclude that, although no animal model can capture, at once, all the molecular, cellular, and behavioral features of ASD, a useful approach is to focus on specific autism-relevant behavioral features to study their neural underpinnings. This approach has greatly contributed to our understanding of this disease, and is useful in identifying new therapeutic targets. PMID:26226143

  1. Traumatic Neuroma in Continuity Injury Model in Rodents

    PubMed Central

    Kemp, Stephen William Peter; Khu, Kathleen Joy Ong Lopez; Kumar, Ranjan; Webb, Aubrey A.; Midha, Rajiv

    2012-01-01

    Abstract Traumatic neuroma in continuity (NIC) results in profound neurological deficits, and its management poses the most challenging problem to peripheral nerve surgeons today. The absence of a clinically relevant experimental model continues to handicap our ability to investigate ways of better diagnosis and treatment for these disabling injuries. Various injury techniques were tested on Lewis rat sciatic nerves. Optimal experimental injuries that consistently resulted in NIC combined both intense focal compression and traction forces. Nerves were harvested at 0, 5, 13, 21, and 65 days for histological examination. Skilled locomotion and ground reaction force (GRF) analysis were performed up to 9 weeks on the experimental (n=6) and crush-control injuries (n=5). Focal widening, disruption of endoneurium and perineurium with aberrant intra- and extrafascicular axonal regeneration and progressive fibrosis was consistently demonstrated in 14 of 14 nerves with refined experimental injuries. At 8 weeks, experimental animals displayed a significantly greater slip ratio in both skilled locomotor assessments, compared to nerve crush animals (p<0.01). GRFs of the crush- injured animals showed earlier improvement compared to the experimental animals, whose overall GRF patterns failed to recover as well as the crush group. We have demonstrated histological features and poor functional recovery consistent with NIC formation in a rat model. The injury mechanism employed combines traction and compression forces akin to the physical forces at play in clinical nerve injuries. This model may serve as a tool to help diagnose this injury earlier and to develop intervention strategies to improve patient outcomes. PMID:22011082

  2. Two new rodent models for actinide toxicity studies. [/sup 237/Pu, /sup 241/Am

    SciTech Connect

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

    1981-04-01

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

  3. 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. PMID:22648774

  4. Predictive Modeling in Adult Education

    ERIC Educational Resources Information Center

    Lindner, Charles L.

    2011-01-01

    The current economic crisis, a growing workforce, the increasing lifespan of workers, and demanding, complex jobs have made organizations highly selective in employee recruitment and retention. It is therefore important, to the adult educator, to develop models of learning that better prepare adult learners for the workplace. The purpose of…

  5. A rodent model of mild traumatic brain blast injury.

    PubMed

    Perez-Polo, J R; Rea, H C; Johnson, K M; Parsley, M A; Unabia, G C; Xu, G-Y; Prough, D; DeWitt, D S; Spratt, H; Hulsebosch, C E

    2015-04-01

    One of the criteria defining mild traumatic brain injury (mTBI) in humans is a loss of consciousness lasting for less than 30 min. mTBI can result in long-term impairment of cognition and behavior. In rats, the length of time it takes a rat to right itself after injury is considered to be an analog for human return to consciousness. This study characterized a rat mild brain blast injury (mBBI) model defined by a righting response reflex time (RRRT) of more than 4 min but less than 10 min. Assessments of motor coordination relying on beam-balance and foot-fault assays and reference memory showed significant impairment in animals exposed to mBBI. This study's hypothesis is that there are inflammatory outcomes to mTBI over time that cause its deleterious effects. For example, mBBI significantly increased brain levels of interleukin (IL)-1β and tumor necrosis factor-α (TNFα) protein. There were significant inflammatory responses in the cortex, hippocampus, thalamus, and amygdala 6 hr after mBBI, as evidenced by increased levels of the inflammatory markers associated with activation of microglia and macrophages, ionized calcium binding adaptor 1 (IBA1), impairment of the blood-brain barrier, and significant neuronal losses. There were significant increases in phosphorylated Tau (p-Tau) levels, a putative precursor to the development of neuroencephalopathy, as early as 6 hr after mBBI in the cortex and the hippocampus but not in the thalamus or the amygdala. There was an apparent correlation between RRRTs and p-Tau protein levels but not IBA1. These results suggest potential therapies for mild blast injuries via blockade of the IL-1β and TNFα receptors. PMID:25410497

  6. 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

  7. Juvenile ferric iron prevents microbiota dysbiosis and colitis in adult rodents

    PubMed Central

    Ettreiki, Chourouk; Gadonna-Widehem, Pascale; Mangin, Irène; Coëffier, Moïse; Delayre-Orthez, Carine; Anton, Pauline M

    2012-01-01

    AIM: To assess whether juvenile chronic ferric iron ingestion limit colitis and dysbiosis at adulthood in rats and mice. METHODS: Two sets of experiments were designed. In the first set, recently weaned mice were either orally administered ferrous (Fe2+) iron salt or ferric (Fe3+) microencapsulated iron for 6 wk. The last week of experiments trinitrobenzene sulfonic acid (TNBS) colitis was induced. In the second set, juvenile rats received the microencapsulated ferric iron for 6 wk and were also submitted to TNBS colitis during the last week of experiments. In both sets of experiments, animals were sacrificed 7 d after TNBS instillation. Severity of the inflammation was assessed by scoring macroscopic lesions and quantifying colonic myeloperoxidase (MPO) activity. Alteration of the microflora profile was estimated using quantitative polymerase chain reaction (qPCR) by measuring the evolution of total caecal microflora, Bacteroidetes, Firmicutes and enterobacteria. RESULTS: Neither ferrous nor ferric iron daily exposures at the juvenile period result in any effect in control animals at adulthood although ferrous iron repeated administration in infancy limited weight gain. Ferrous iron was unable to limit the experimental colitis (1.71 ± 0.27 MPO U/mg protein vs 2.47 ± 0.22 MPO U/mg protein in colitic mice). In contrast, ferric iron significantly prevented the increase of MPO activity (1.64 ± 0.14 MPO U/mg protein) in TNBS-induced colitis. Moreover, this positive effect was observed at both the doses of ferric iron used (75 and 150 mg/kg per day po - 6 wk). In the study we also compared, in both rats and mice, the consequences of chronic repeated low level exposure to ferric iron (75 mg/kg per day po - 6 wk) on TNBS-induced colitis and its related dysbiosis. We confirmed that ferric iron limited the TNBS-induced increase of MPO activity in both the rodent species. Furthermore, we assessed the ferric iron incidence on TNBS-induced intestinal microbiota dysbiosis

  8. Computational models of adult neurogenesis

    NASA Astrophysics Data System (ADS)

    Cecchi, Guillermo A.; Magnasco, Marcelo O.

    2005-10-01

    Experimental results in recent years have shown that adult neurogenesis is a significant phenomenon in the mammalian brain. Little is known, however, about the functional role played by the generation and destruction of neurons in the context of an adult brain. Here, we propose two models where new projection neurons are incorporated. We show that in both models, using incorporation and removal of neurons as a computational tool, it is possible to achieve a higher computational efficiency that in purely static, synapse-learning-driven networks. We also discuss the implication for understanding the role of adult neurogenesis in specific brain areas like the olfactory bulb and the dentate gyrus.

  9. 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. PMID:27013283

  10. Mild Sensory Stimulation Completely Protects the Adult Rodent Cortex from Ischemic Stroke

    PubMed Central

    Chen-Bee, Cynthia H.; Frostig, Ron D.

    2010-01-01

    Despite progress in reducing ischemic stroke damage, complete protection remains elusive. Here we demonstrate that, after permanent occlusion of a major cortical artery (middle cerebral artery; MCA), single whisker stimulation can induce complete protection of the adult rat cortex, but only if administered within a critical time window. Animals that receive early treatment are histologically and behaviorally equivalent to healthy controls and have normal neuronal function. Protection of the cortex clearly requires reperfusion to the ischemic area despite permanent occlusion. Using blood flow imaging and other techniques we found evidence of reversed blood flow into MCA branches from an alternate arterial source via collateral vessels (inter-arterial connections), a potential mechanism for reperfusion. These findings suggest that the cortex is capable of extensive blood flow reorganization and more importantly that mild sensory stimulation can provide complete protection from impending stroke given early intervention. Such non-invasive, non-pharmacological intervention has clear translational potential. PMID:20585659

  11. Concise review: Preclinical studies on human cell-based therapy in rodent ischemic stroke models: where are we now after a decade?

    PubMed

    Leong, Wai Khay; Lewis, Martin D; Koblar, Simon A

    2013-06-01

    Stroke, a debilitating brain insult, afflicts millions of individuals globally each year. In the last decade, researchers have investigated cell-based therapy as an alternative strategy to improve neurological outcome following stroke. This concise review critically examines preclinical reports using human adult and fetal stem/progenitor cells in rodent models of ischemic stroke. As we enter the second decade of study, we should aim to optimize our collective likelihood to translational success for stroke victims worldwide. We advocate international consensus recommendations be developed for future preclinical research. PMID:23390084

  12. Rodent Control

    ERIC Educational Resources Information Center

    Indian Journal of Adult Education, 1975

    1975-01-01

    Strategies for rodent control in crop fields, threshing yards, and rural residential areas are presented together with an operational plan for implementing a program for rodent control at the national level. Training personnel in rodent control procedures and procedures for educating the public in the necessity for control are covered. (EC)

  13. 3D Segmentation of Rodent Brain Structures Using Hierarchical Shape Priors and Deformable Models

    PubMed Central

    Zhang, Shaoting; Huang, Junzhou; Uzunbas, Mustafa; Shen, Tian; Delis, Foteini; Huang, Xiaolei; Volkow, Nora; Thanos, Panayotis; Metaxas, Dimitris N.

    2016-01-01

    In this paper, we propose a method to segment multiple rodent brain structures simultaneously. This method combines deformable models and hierarchical shape priors within one framework. The deformation module employs both gradient and appearance information to generate image forces to deform the shape. The shape prior module uses Principal Component Analysis to hierarchically model the multiple structures at both global and local levels. At the global level, the statistics of relative positions among different structures are modeled. At the local level, the shape statistics within each structure is learned from training samples. Our segmentation method adaptively employs both priors to constrain the intermediate deformation result. This prior constraint improves the robustness of the model and benefits the segmentation accuracy. Another merit of our prior module is that the size of the training data can be small, because the shape prior module models each structure individually and combines them using global statistics. This scheme can preserve shape details better than directly applying PCA on all structures. We use this method to segment rodent brain structures, such as the cerebellum, the left and right striatum, and the left and right hippocampus. The experiments show that our method works effectively and this hierarchical prior improves the segmentation performance. PMID:22003750

  14. 3D segmentation of rodent brain structures using hierarchical shape priors and deformable models.

    PubMed

    Zhang, Shaoting; Huang, Junzhou; Uzunbas, Mustafa; Shen, Tian; Delis, Foteini; Huang, Xiaolei; Volkow, Nora; Thanos, Panayotis; Metaxas, Dimitris N

    2011-01-01

    In this paper, we propose a method to segment multiple rodent brain structures simultaneously. This method combines deformable models and hierarchical shape priors within one framework. The deformation module employs both gradient and appearance information to generate image forces to deform the shape. The shape prior module uses Principal Component Analysis to hierarchically model the multiple structures at both global and local levels. At the global level, the statistics of relative positions among different structures are modeled. At the local level, the shape statistics within each structure is learned from training samples. Our segmentation method adaptively employs both priors to constrain the intermediate deformation result. This prior constraint improves the robustness of the model and benefits the segmentation accuracy. Another merit of our prior module is that the size of the training data can be small, because the shape prior module models each structure individually and combines them using global statistics. This scheme can preserve shape details better than directly applying PCA on all structures. We use this method to segment rodent brain structures, such as the cerebellum, the left and right striatum, and the left and right hippocampus. The experiments show that our method works effectively and this hierarchical prior improves the segmentation performance. PMID:22003750

  15. Drugs, nutrients, and phytoactive principles improving the health span of rodent models of human age-related diseases.

    PubMed

    Lebel, Michel; Picard, Frédéric; Ferland, Guylaine; Gaudreau, Pierrette

    2012-02-01

    Rodents are often the species of choice to examine the effect of drugs on survival and on the progression of specific diseased tissues. This statement is also true for research laboratories working in the field of nutrition and aging. In addition to diets that can reduce the life expectancy of rodents, such as diabetogenic or high-fat diets, genetically modified rodents exhibiting different accelerated age-associated diseases also provide important biologic tools to decipher the impact of drugs, nutrients, or phytoactive compounds on their health and life span. This review covers some of the chemicals believed to decelerate the appearance of age-related diseases in different rodent models. Such chemicals include antioxidants, anti-inflammatory molecules, modulators of metabolic sensors, calorie restriction mimetics, and vegetal polyphenolic compounds that affect mitochondrial functions, cellular proliferation or differentiation as well as cell functionality. PMID:21393422

  16. 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.

  17. Magnetic resonance imaging of pathological processes in rodent models of amyotrophic lateral sclerosis.

    PubMed

    Evans, Matthew C; Modo, Michel; Talbot, Kevin; Sibson, Niki; Turner, Martin R

    2012-05-01

    Non-human models of neurodegenerative diseases have potential for the identification of key pathways in pathogenesis and for the more rapid assessment of therapeutic candidates. While there are legitimate concerns about the physiological differences between the rodent and human motor systems, mice expressing the 'G93A' superoxide dismutase-1 gene mutation are a predictable and robustly-characterized model for amyotrophic lateral sclerosis (ALS). This model has provided evidence for an important role of inflammatory processes during the pre-clinical phase, a stage currently inaccessible for human study in what is largely a sporadic disease. While magnetic resonance imaging is now an established and leading modality for the identification of ALS biomarkers in humans, it can also be increasingly applied to rodent models to probe structural, functional and biochemical changes throughout the course of the disease, with additional potential to generate surrogate markers for the efficacy of therapeutic interventions. Targeted MRI contrast agents, through tagging of various cell types and even individual molecules, will deliver an era of in vivo molecular neuroimaging, with greater specificity for the most relevant pathological processes. These are potentially important steps towards the ultimate goal of human therapeutic translation. PMID:22117132

  18. Nephrilin peptide modulates a neuroimmune stress response in rodent models of burn trauma and sepsis

    PubMed Central

    Mascarenhas, Desmond D; ElAyadi, Amina; Singh, Baljit K; Prasai, Anesh; Hegde, Sachin D; Herndon, David N; Finnerty, Celeste C

    2013-01-01

    Sepsis occurs three times more often in burns than in other types of trauma, suggesting an overlap or synergy between underlying immune mechanisms in burn trauma and sepsis. Nephrilin peptide, a designed inhibitor of mTORC2, has previously been shown to modulate a neuroimmune stress response in rodent models of xenobiotic and metabolic stress. Here we investigate the effect of nephrilin peptide administration in different rodent models of burn trauma and sepsis. In a rat scald burn model, daily subcutaneous bolus injection of 4 mg/kg nephrilin significantly reduced the elevation of kidney tissue substance P, S100A9 gene expression, PMN infiltration and plasma inflammatory markers in the acute phase, while suppressing plasma CCL2 and insulin C-peptide, kidney p66shc-S36 phosphorylation and PKC-beta and CGRP in dorsal root ganglia at 14 days (chronic phase). In the mouse cecal ligation and puncture model of sepsis, nephrilin fully protected mice from mortality between surgery and day 7, compared to 67% mortality in saline-treated animals, while significantly reducing elevated CCL2 in plasma. mTORC2 may modulate important neuroimmune responses in both burn trauma and sepsis. PMID:24273694

  19. The squirrel as a rodent model of the human visual system.

    PubMed

    Van Hooser, Stephen D; Nelson, Sacha B

    2006-01-01

    Over the last 50 years, studies of receptive fields in the early mammalian visual system have identified many classes of response properties in brain areas such as retina, lateral geniculate nucleus (LGN), and primary visual cortex (V1). Recently, there has been significant interest in understanding the cellular and network mechanisms that underlie these visual responses and their functional architecture. Small mammals like rodents offer many advantages for such studies, because they are appropriate for a wide variety of experimental techniques. However, the traditional rodent models, mice and rats, do not rely heavily on vision and have small visual brain areas. Squirrels are highly visual rodents that may be excellent model preparations for understanding mechanisms of function and disease in the human visual system. They use vision for navigating in their environment, predator avoidance, and foraging for food. Visual brain areas such as LGN, V1, superior colliculus, and pulvinar are particularly large and well elaborated in the squirrel, and the squirrel has several extrastriate cortical areas lateral to V1. Unlike many mammals, most squirrel species are diurnal with cone-dominated retinas, similar to the primate fovea, and have excellent dichromatic color vision that is mediated by green and blue cones. Owing to their larger size, squirrels are physiologically more robust than mice and rats under anesthesia, and some hibernating species are particularly tolerant of hypoxia that occurs during procedures such as brain slicing. Finally, many basic anatomical and physiological properties in the early visual system of squirrel have now been described, permitting investigations of cellular mechanisms. In this article, we review four decades of anatomical, behavioral, and physiological studies in squirrel and make comparisons with other species. PMID:17020632

  20. Behavioural methods used in rodent models of autism spectrum disorders: current standards and new developments.

    PubMed

    Wöhr, Markus; Scattoni, Maria Luisa

    2013-08-15

    Autism is a behaviourally defined disorder including attenuated or abnormal social interaction and communication, as well as aberrant repetitive behaviour, with symptoms emerging early in childhood. Although the cause of autism has not been discovered, several data strongly support the role of genetic factors in autism aetiology. For this reason, preclinical research is now focusing on generating transgenic and knockout mice, and more recently also rats, with mutations in genes identified in autistic children, with the main aim of understanding the role of those genes in autism aetiology, discovering the biological mechanisms underlying autistic behaviours detected in these mutant lines and evaluating potential treatments. Over the last years, a huge number of behavioural phenotyping assays for rodent models of autism and related disorders have been designed. In the first part of our review, we focus on current standards, i.e. state-of-the-art behavioural phenotyping tasks to assess autism core symptoms in rodent models. The second part is devoted to some few, in our view, very promising examples of new developments, namely an autism severity score, scent marking behaviour as an additional, ethologically valid measure for communication, plus a number of new developments in the behavioural domains of social facilitation, observational learning, and empathy. Finally, we will highlight the huge potential impact of newly generated rat knockout models of autism. PMID:23769995

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

    PubMed

    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

  2. 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

  3. Barriers to developing a valid rodent model of Alzheimer's disease: from behavioral analysis to etiological mechanisms

    PubMed Central

    Gidyk, Darryl C.; Deibel, Scott H.; Hong, Nancy S.; McDonald, Robert J.

    2015-01-01

    Sporadic Alzheimer's disease (AD) is the most prevalent form of age-related dementia. As such, great effort has been put forth to investigate the etiology, progression, and underlying mechanisms of the disease. Countless studies have been conducted, however, the details of this disease remain largely unknown. Rodent models provide opportunities to investigate certain aspects of AD that cannot be studied in humans. These animal models vary from study to study and have provided some insight, but no real advancements in the prevention or treatment of the disease. In this Hypothesis and Theory paper, we discuss what we perceive as barriers to impactful discovery in rodent AD research and we offer potential solutions for moving forward. Although no single model of AD is capable of providing the solution to the growing epidemic of the disease, we encourage a comprehensive approach that acknowledges the complex etiology of AD with the goal of enhancing the bidirectional translatability from bench to bedside and vice versa. PMID:26283893

  4. 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

  5. Factors affecting immigration of adults: experimental and theoretical observations with rodents

    NASA Astrophysics Data System (ADS)

    Seamon, Joshua; Adler, Gregory

    1997-11-01

    We examined immigration in populations of Peromyscus leucopus (white-footed mice) by 1) monitoring natural immigration at 10 sites, 2) introducing experimental immigrants into eight populations, and 3) constructing qualitative models of immigration. Density of natural immigrants covaried positively with resident density, and successful assimilation was lower at low resident and immigrant densities. Females and males did not differ in their chance of achieving residency. Year, sex, and number introduced were significant predictors of assimilation by individuals. Experimentally introduced individuals had no effect on densities of those mice resident before the introductions. Results obtained from studying natural immigration differed from those obtained from studying experimental immigration. Signed digraphs and time averaging were used to model the consequences of different resident-immigrant relationships and to suggest how different sources of variation may have affected assimilation and led to differences in natural and experimental immigration. Resident and immigrant densities could have been positively correlated even if residents actively inhibited immigration. Variation in immigrant density and survival rather than resident territorial activity apparently determined patterns of assimilation.

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

    PubMed Central

    Ghanian, Zahra; Sepehr, Reyhaneh; Schmitt, Heather; Eells, Janis; Ranji, Mahsa

    2013-01-01

    Abstract. 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. PMID:23291617

  7. 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.

  8. 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.

  9. Longitudinal in vivo monitoring of rodent glioma models through thinned skull using laser speckle contrast imaging

    NASA Astrophysics Data System (ADS)

    Rege, Abhishek; Seifert, Alan C.; Schlattman, Dan; Ouyang, Yu; Li, Khan W.; Basaldella, Luca; Brem, Henry; Tyler, Betty M.; Thakor, Nitish V.

    2012-12-01

    Laser speckle contrast imaging (LSCI) is a contrast agent free imaging technique suited for longitudinal assessment of vascular remodeling that accompanies brain tumor growth. We report the use of LSCI to monitor vascular changes in a rodent glioma model. Ten rats are inoculated with 9L gliosarcoma cells, and the angiogenic response is monitored five times over two weeks through a thinned skull imaging window. We are able to visualize neovascularization and measure the number of vessels per unit area to assess quantitatively the microvessel density (MVD). Spatial spread of MVD reveals regions of high MVD that may correspond to tumor location. Whole-field average MVD values increase with time in the tumor group but are fairly stable in the control groups. Statistical analysis shows significant differences in MVD values between the tumor group and both saline-receiving and unperturbed control groups over the two-week period (p<0.05). In conclusion, LSCI is suitable for investigation of tumor angiogenesis in rodent models. In addition, the statistical difference (p<0.02) between MVD values of the tumor (24.40±1.41) and control groups (15.40±1.60) on the 14th day after inoculation suggests a potential use of LSCI in the clinic in distinguishing tumor environments from normal vasculature.

  10. Skeletal changes associated with the onset of type 2 diabetes in the ZDF and ZDSD rodent models

    PubMed Central

    Reinwald, Susan; Peterson, Richard G.; Allen, Matt R.; Burr, David B.

    2009-01-01

    The incidence and prevalence of type 2 diabetes (T2D) continue to escalate at an unprecedented rate in the United States, particularly among populations with high rates of obesity. The impact of T2D on bone mass, geometry, architecture, strength, and resistance to fracture has yet to be incontrovertibly characterized because of the complex and heterogeneous nature of this disease. This study utilized skeletally mature male diabetic rats of the commonly used Zucker diabetic fatty (ZDF) and Zucker diabetic Sprague-Dawley (ZDSD) strains as surrogate models to assess alterations in bone attributable to T2D-like states. After the animals were euthanized, bone data were collected using dual-energy X-ray absorptiometry, peripheral quantitative tomography, and micro-CT imaging modalities and via three-point bending or compression mechanical testing methods. ZDF and ZDSD diabetic rats exhibited lower bone mineral densities, which coincided with declines in structural strength and increased fragility at the femoral midshaft and the L4 vertebral body in response to monotonic loading. Vertebral trabecular morphology was compromised in both diabetic rodent strains, and ZDSD diabetic rats exhibited additional phenotypic impairments to bone material properties at the spine. Because the metabolic origin of the T2D-like state that develops in the ZDSD rat strain is highly relevant to adult-onset diabetes, it is a particularly attractive novel model for future preclinical research. PMID:19158319

  11. Understanding selenoprotein function and regulation through the use of rodent models

    PubMed Central

    Kasaikina, Marina V.; Hatfield, Dolph L.; Gladyshev, Vadim N.

    2012-01-01

    Selenium (Se) is an essential micronutrient. Its biological functions are associated with selenoproteins, which contain this trace element in the form of the 21st amino acid, selenocysteine. Genetic defects in selenocysteine insertion into proteins are associated with severe health issues. The consequences of selenoprotein deficiency are more variable, with several selenoproteins being essential, and several showing no clear phenotypes. Much of these functional studies benefited from the use of rodent models and diets employing variable levels of Se. This review summarizes the data obtained with these models, focusing on mouse models with targeted expression of individual selenoproteins and removal of individual, subsets or all selenoproteins in a systemic or organ-specific manner. PMID:22440326

  12. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer's disease in rodent models

    PubMed Central

    Daniels, Michael J. D.; Rivers-Auty, Jack; Schilling, Tom; Spencer, Nicholas G.; Watremez, William; Fasolino, Victoria; Booth, Sophie J.; White, Claire S.; Baldwin, Alex G.; Freeman, Sally; Wong, Raymond; Latta, Clare; Yu, Shi; Jackson, Joshua; Fischer, Nicolas; Koziel, Violette; Pillot, Thierry; Bagnall, James; Allan, Stuart M.; Paszek, Pawel; Galea, James; Harte, Michael K.; Eder, Claudia; Lawrence, Catherine B.; Brough, David

    2016-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer's disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer's disease therapeutics. PMID:27509875

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

    PubMed

    Flôres, Danilo E F L; Tomotani, Barbara M; Tachinardi, Patricia; Oda, Gisele A; Valentinuzzi, Veronica S

    2013-01-01

    Subterranean rodents spend most of the day inside underground tunnels, where there is little daily change in environmental variables. Our observations of tuco-tucos (Ctenomys aff. knighti) in a field enclosure indicated that these animals perceive the aboveground light-dark cycle by several bouts of light-exposure at irregular times during the light hours of the day. To assess whether such light-dark pattern acts as an entraining agent of the circadian clock, we first constructed in laboratory the Phase Response Curve for 1 h light-pulses (1000lux). Its shape is qualitatively similar to other curves reported in the literature and to our knowledge it is the first Phase Response Curve of a subterranean rodent. Computer simulations were performed with a non-linear limit-cycle oscillator subjected to a simple model of the light regimen experienced by tuco-tucos. Results showed that synchronization is achieved even by a simple regimen of a single daily light pulse scattered uniformly along the light hours of the day. Natural entrainment studies benefit from integrated laboratory, field and computational approaches. PMID:23874562

  14. 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).

  15. Modeling Natural Photic Entrainment in a Subterranean Rodent (Ctenomys aff. knighti), the Tuco-Tuco

    PubMed Central

    Flôres, Danilo E. F. L.; Tomotani, Barbara M.; Tachinardi, Patricia; Oda, Gisele A.; Valentinuzzi, Veronica S.

    2013-01-01

    Subterranean rodents spend most of the day inside underground tunnels, where there is little daily change in environmental variables. Our observations of tuco-tucos (Ctenomys aff. knighti) in a field enclosure indicated that these animals perceive the aboveground light-dark cycle by several bouts of light-exposure at irregular times during the light hours of the day. To assess whether such light-dark pattern acts as an entraining agent of the circadian clock, we first constructed in laboratory the Phase Response Curve for 1 h light-pulses (1000lux). Its shape is qualitatively similar to other curves reported in the literature and to our knowledge it is the first Phase Response Curve of a subterranean rodent. Computer simulations were performed with a non-linear limit-cycle oscillator subjected to a simple model of the light regimen experienced by tuco-tucos. Results showed that synchronization is achieved even by a simple regimen of a single daily light pulse scattered uniformly along the light hours of the day. Natural entrainment studies benefit from integrated laboratory, field and computational approaches. PMID:23874562

  16. 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

  17. Rodents as pre-clinical models for predicting vaccine performance in humans.

    PubMed

    Riese, Peggy; Trittel, Stephanie; Schulze, Kai; Guzmán, Carlos A

    2015-01-01

    Vaccines represent a key building block for establishing a successful and sustainable control strategy against infectious diseases. Vaccine development often depends on the availability of correlates for protection and reliable animal models for the screening, selection and prioritization of potential vaccine candidates. This is performed according to their immunogenicity, efficacy and safety profiles in pre-clinical studies, which are also critical for identification of candidate antigens, selection of an optimal delivery system and design of appropriate vaccine formulations. Thus, pre-clinical studies in animal models are a prerequisite for addressing crucial issues and generating a solid pre-clinical package for the approval of clinical trials. This review addresses the strengths, limitations and perspectives of rodents as a vaccine development and pre-clinical validation tool. PMID:26268433

  18. Neuroplasticity and Repair in Rodent Neurotoxic Models of Spinal Motoneuron Disease

    PubMed Central

    Gulino, Rosario

    2016-01-01

    Retrogradely transported toxins are widely used to set up protocols for selective lesioning of the nervous system. These methods could be collectively named “molecular neurosurgery” because they are able to destroy specific types of neurons by using targeted neurotoxins. Lectins such as ricin, volkensin, or modeccin and neuropeptide- or antibody-conjugated saporin represent the most effective toxins used for neuronal lesioning. Some of these specific neurotoxins could be used to induce selective depletion of spinal motoneurons. In this review, we extensively describe two rodent models of motoneuron degeneration induced by volkensin or cholera toxin-B saporin. In particular, we focus on the possible experimental use of these models to mimic neurodegenerative diseases, to dissect the molecular mechanisms of neuroplastic changes underlying the spontaneous functional recovery after motoneuron death, and finally to test different strategies of neural repair. The potential clinical applications of these approaches are also discussed. PMID:26862439

  19. cAMP/PKA signaling inhibits osteogenic differentiation and bone formation in rodent models.

    PubMed

    Siddappa, Ramakrishnaiah; Mulder, Winfried; Steeghs, Ilse; van de Klundert, Christine; Fernandes, Hugo; Liu, Jun; Arends, Roel; van Blitterswijk, Clemens; de Boer, Jan

    2009-08-01

    We previously demonstrated that cAMP-mediated protein kinase A (PKA) activation induces in vitro osteogenesis and in vivo bone formation by human mesenchymal stem cells (hMSCs). To analyze the species-specific response of this phenomenon and to translate our findings into a clinical trial, suitable animal models and cell lines are desirable. In this report, we assessed whether PKA plays a similar proosteogenic role played by two commonly used PKA activators-N6,2'-O-dibutyryl-cAMP (db-cAMP) and 8-bromo cAMP (8b-cAMP)-in a number of model systems. To this end, we treated MC3T3-E1 cells, mouse calvarial osteoblasts, mouse MSCs, and rat MSCs with cAMP. We demonstrate that cAMP inhibits osteogenesis in rodent cell types, evidenced by inhibition of osteogenic markers such as alkaline phosphatase (ALP), osteocalcin (BGLAP), and collagen type 1 (COL1A1). In support of this, ex vivo-cultured mouse calvaria exposed to db-cAMP showed a reduction in bone volume. Interestingly, cAMP even stimulated adipogenic differentiation in rat MSCs. Taken together, our data demonstrate that cAMP inhibits osteogenesis in vitro and bone formation ex vivo in rodent models in contrast to our earlier findings in hMSCs. The species discrepancy in response to various osteogenic signals is a critical need to be tested in clinically relevant models to translate the fundamental findings in lower species level to clinical applications. PMID:19231969

  20. Enhancement of mammary carcinogenesis in two rodent models by silymarin dietary supplements.

    PubMed

    Malewicz, Barbara; Wang, Zaisen; Jiang, Cheng; Guo, Junming; Cleary, Margot P; Grande, Joseph P; Lü, Junxuan

    2006-09-01

    Silymarin is a mixture of polyphenolic flavonoids isolated from milk thistle (Silybum marianum) with anticancer activities reported for several organ sites. The present study tested the efficacy of dietary silymarin against mammary carcinogenesis in two rodent models. In the Sprague-Dawley rat model, female rats were fed a purified diet supplemented with none, 0.03, 0.1, 0.3 or 1% (w/w) of silymarin from 21 days of age (DOA) and carcinogenesis was initiated by a single i.p. injection of 1-methyl-1-nitrosourea (MNU) at 51 DOA. Mammary tumor (MT) development was followed till 110 days after carcinogen injection. In the MMTV-neu/HER2 transgenic mouse mammary carcinogenesis model, homozygous transgenic females were fed a purified diet supplemented with none or 0.3% silymarin, either from 28 or 120 DOA and MT development was followed to approximately 300 DOA. The results showed that dietary silymarin increased the plasma concentration of free and total silibinin, a major component of silymarin, in a dose-dependent manner in the rat, but did not decrease either MT incidence or number. Instead silymarin modestly increased the number of MNU-induced MTs in rats. Similarly, silymarin increased MT incidence and multiplicity and non-MTs in the neu-transgenic mice. In cell culture, treatment of human MCF-7 breast cancer cells with serum-achievable concentrations of silymarin in the rodent models stimulated their growth, in part through an estrogen-like activity. Because silymarin is being used in the treatment of liver cirrhosis and a variety of other human ailments, and is sold as a dietary supplement, our findings add a cautionary note to its application in breast cancer prevention. PMID:16597642

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

    NASA Astrophysics Data System (ADS)

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

    2015-09-01

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

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

    PubMed Central

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

    2015-01-01

    Anorexia nervosa (AN) is a psychiatric illness characterized by excessively restricted caloric intake and abnormally high levels of physical activity. A challenging illness to treat, due to the lack of understanding of the underlying neurobiology, AN has the highest mortality rate among psychiatric illnesses. To address this need, neuroscientists are using an animal model to study how neural circuits may contribute toward vulnerability to AN and may be affected by AN. Activity-based anorexia (ABA) is a bio-behavioral phenomenon described in rodents that models the key symptoms of anorexia nervosa. When rodents with free access to voluntary exercise on a running wheel experience food restriction, they become hyperactive – running more than animals with free access to food. Here, we describe the procedures by which ABA is induced in adolescent female C57BL/6 mice. On postnatal day 36 (P36), the animal is housed with access to voluntary exercise on a running wheel. After 4 days of acclimation to the running wheel, on P40, all food is removed from the cage. For the next 3 days, food is returned to the cage (allowing animals free food access) for 2 hr daily. After the fourth day of food restriction, free access to food is returned and the running wheel is removed from the cage to allow the animals to recover. Continuous multi-day analysis of running wheel activity shows that mice become hyperactive within 24 hr following the onset of food restriction. The mice run even during the limited time during which they have access to food. Additionally, the circadian pattern of wheel running becomes disrupted by the experience of food restriction. We have been able to correlate neurobiological changes with various aspects of the animals’ wheel running behavior to implicate particular brain regions and neurochemical changes with resilience and vulnerability to food-restriction induced hyperactivity. PMID:26555618

  3. Early maternal separation: a rodent model of depression and a prevailing human condition.

    PubMed

    Vetulani, Jerzy

    2013-01-01

    The early life of most mammals is spent in close contact with the mother, and for the neonate, early maternal separation is a traumatic event that, depending on various conditions, may shape its behavioral and neurochemical phenotype in adulthood. Studies on rodents demonstrated that a very brief separation followed by increased maternal care may positively affect the development of the offspring but that prolonged separation causes significant amounts of stress. The consequences of this stress (particularly the hyperreactivity of the HPA (hypothalamic-pituitary-adrenal) axis are expressed in adulthood and persist for life. Maternal separation in rodents, particularly rats, was used as a model for various psychotic conditions, especially depression. The most popular separation procedure of a 3-h daily separation from the second to the 12th postpartum day yields a depression model of high construct and predictive validity. The results of studies on maternal separation in rats and monkeys prompt a discussion of the consequences of traditional procedures in the maternity wards of developed countries where attention is focused on the hygiene of the neonates and not on their psychological needs. This alternate focus results in a drastic limitation of mother-infant contact and prolonged periods of separation. It is tempting to speculate that differences in the course and severity of various mental disorders, which are usually less prevalent in underdeveloped countries than in developed countries (as noted by Kraepelin), may be related to different modes of infant care. Only recently has so-called kangaroo mother care (establishing mother-infant skin-to-skin contact immediately after birth) become popular in developed countries. In addition to its instant benefits for the neonates, this procedure may also be beneficial for the mental health of the offspring in adulthood. PMID:24552992

  4. What can rodent models tell us about apathy and associated neuropsychiatric symptoms in Parkinson's disease?

    PubMed Central

    Magnard, R; Vachez, Y; Carcenac, C; Krack, P; David, O; Savasta, M; Boulet, S; Carnicella, S

    2016-01-01

    In addition to classical motor symptoms, Parkinson's disease (PD) patients display incapacitating neuropsychiatric manifestations, such as apathy, anhedonia, depression and anxiety. These hitherto generally neglected non-motor symptoms, have gained increasing interest in medical and scientific communities over the last decade because of the extent of their negative impact on PD patients' quality of life. Although recent clinical and functional imaging studies have provided useful information, the pathophysiology of apathy and associated affective impairments remains elusive. Our aim in this review is to summarize and discuss recent advances in the development of rodent models of PD-related neuropsychiatric symptoms using neurotoxin lesion-based approaches. The data collected suggest that bilateral and partial lesions of the nigrostriatal system aimed at inducing reliable neuropsychiatric-like deficits while avoiding severe motor impairments that may interfere with behavioral evaluation, is a more selective and efficient strategy than medial forebrain bundle lesions. Moreover, of all the different classes of pharmacological agents, D2/D3 receptor agonists such as pramipexole appear to be the most efficient treatment for the wide range of behavioral deficits induced by dopaminergic lesions. Lesion-based rodent models, therefore, appear to be relevant tools for studying the pathophysiology of the non-motor symptoms of PD. Data accumulated so far confirm the causative role of dopaminergic depletion, especially in the nigrostriatal system, in the development of behavioral impairments related to apathy, depression and anxiety. They also put forward D2/D3 receptors as potential targets for the treatment of such neuropsychiatric symptoms in PD. PMID:26954980

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

    PubMed

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

    2015-01-01

    Anorexia nervosa (AN) is a psychiatric illness characterized by excessively restricted caloric intake and abnormally high levels of physical activity. A challenging illness to treat, due to the lack of understanding of the underlying neurobiology, AN has the highest mortality rate among psychiatric illnesses. To address this need, neuroscientists are using an animal model to study how neural circuits may contribute toward vulnerability to AN and may be affected by AN. Activity-based anorexia (ABA) is a bio-behavioral phenomenon described in rodents that models the key symptoms of anorexia nervosa. When rodents with free access to voluntary exercise on a running wheel experience food restriction, they become hyperactive - running more than animals with free access to food. Here, we describe the procedures by which ABA is induced in adolescent female C57BL/6 mice. On postnatal day 36 (P36), the animal is housed with access to voluntary exercise on a running wheel. After 4 days of acclimation to the running wheel, on P40, all food is removed from the cage. For the next 3 days, food is returned to the cage (allowing animals free food access) for 2 hr daily. After the fourth day of food restriction, free access to food is returned and the running wheel is removed from the cage to allow the animals to recover. Continuous multi-day analysis of running wheel activity shows that mice become hyperactive within 24 hr following the onset of food restriction. The mice run even during the limited time during which they have access to food. Additionally, the circadian pattern of wheel running becomes disrupted by the experience of food restriction. We have been able to correlate neurobiological changes with various aspects of the animals' wheel running behavior to implicate particular brain regions and neurochemical changes with resilience and vulnerability to food-restriction induced hyperactivity. PMID:26555618

  6. A novel animal model for motion sickness and its first application in rodents.

    PubMed

    Yu, Xu-Hong; Cai, Guo-Jun; Liu, Ai-Jun; Chu, Zheng-Xu; Su, Ding-Feng

    2007-11-23

    The present work was designed to establish a novel animal model for motion sickness (MS) in rodents and to evaluate the effects of a combination of scopolamine and modafinil on MS with this novel method. It was found that the rats and mice presented several symptoms induced by rotation such as, piloerection, tremble, urinal and fecal incontinence. As the rats and mice are lack of emesis response to rotation, we used a score based on abovementioned symptoms as an index for the severity of MS in rodents. MS index was determined in 260 mice with this novel method. It was found that the distribution of MS index was normal (W=0.99; P=0.23. P>0.05 considered values' normal distribution). The effects of scopolamine on MS were studied in mice and rats. It was found that scopolamine significantly decreased MS index at the dose of 0.3 mg/kg in mice and 1.0 mg/kg in rats. Finally, the effects of a combination of scopolamine and modafinil were observed with this novel method in rats. It was found that the efficacy of the combination (5.0+5.0 mg/kg) was greater than the single drugs (10 mg/kg). Even the smallest dose of the combination (0.5+0.5 mg/kg) had a similar effect to large dose of scopolamine or modafinile when they were used alone. In conclusion, this animal model is suitable for MS study in rats and mice and the combination of scopolamine and modafinil might be a new method to treat or prevent MS. PMID:17612582

  7. 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

  8. 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. PMID:21459114

  9. Trans-sodium crocetinate improves outcomes in rodent models of occlusive and hemorrhagic stroke.

    PubMed

    Wang, Yi; Yoshimura, Ryo; Manabe, Hiroaki; Schretter, Catherine; Clarke, Ryon; Cai, Yu; Fitzgerald, Mark; Lee, Kevin S

    2014-10-01

    Trans-sodium crocetinate (TSC) is a novel carotenoid compound capable of enhancing the diffusion of small molecules in aqueous solutions. TSC improves the diffusion of oxygen and glucose, and increases oxygenation in ischemic brain tissue. TSC also dampens the intensity of an ischemic challenge during an ongoing ischemic event. The current study examined the impact of TSC in rat models of ischemic and hemorrhagic stroke. Rat three vessel occlusion (3VO), and combined 3VO and one vessel occlusion (3VO/1VO) models of ischemic stroke were evaluated for structural and behavioral outcomes. The effects of TSC were also tested in a rat model of intracerebral hemorrhage (ICH). Delayed treatment with TSC reduced infarct volume in a rodent model of transient focal ischemia involving either 2 or 6h of ischemia. Neurological outcomes, based on a multi-scale assessment and automated gait analysis, also were improved by TSC treatment. Additionally, TSC reduced edema and hemorrhagic volume in a rat model of ICH. An optimal therapeutic candidate for early intervention in ischemic stroke should be effective when administered on a delayed basis and should not aggravate outcomes associated with hemorrhagic stroke. The current findings demonstrate that delayed TSC treatment improves outcomes in experimental models of both ischemic and hemorrhagic stroke. Together, these findings suggest that TSC may be a safe and beneficial therapeutic modality for early stroke intervention, irrespective of the type of stroke involved. PMID:25128603

  10. Preliminary studies on model development for rodent toxicity and its interspecies correlation with aquatic toxicities of pharmaceuticals.

    PubMed

    Das, Rudra Narayan; Sanderson, Hans; Mwambo, Andrew E; Roy, Kunal

    2013-03-01

    Environmental toxicity due to pharmaceuticals has been an issue of serious concern for long time. Development of chemometric models with reliable predictive power has been considered as an effective tool for the design of new drug agents with reduced or without ecotoxic potential. Considering a higher degree of similarity in genetic homology towards drug receptor with mammals, we have used a dataset of 194 compounds with reported rodent, fish, daphnia and algae toxicity data for extrapolation of their toxicity towards humans. Allowing for rodents as the most surrogate to human physiology, attempts have also been made to develop interspecies correlation models keeping rodent toxicity as dependent variable so that any drug without reported rodent toxicity can be predicted using fish, daphnia or algae toxicity data which can be consequently extrapolated to human toxicity. The developed models have been subjected to multiple validation strategies. Acceptable results have been obtained in both cases of direct and interspecies extrapolation quantitative structure-activity relationship models. PMID:23238824

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

    PubMed

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

    2016-02-15

    Animal models of epilepsy and seizures, mostly involving mice and rats, are used to understand the pathophysiology of the different forms of epilepsy and their comorbidities, to identify biomarkers, and to discover new antiepileptic drugs and treatments for comorbidities. Such models represent an important area for application of the 3Rs (replacement, reduction and refinement of animal use). This report provides background information and recommendations aimed at minimising pain, suffering and distress in rodent models of epilepsy and seizures in order to improve animal welfare and optimise the quality of studies in this area. The report includes practical guidance on principles of choosing a model, induction procedures, in vivo recordings, perioperative care, welfare assessment, humane endpoints, social housing, environmental enrichment, reporting of studies and data sharing. In addition, some model-specific welfare considerations are discussed, and data gaps and areas for further research are identified. The guidance is based upon a systematic review of the scientific literature, survey of the international epilepsy research community, consultation with veterinarians and animal care and welfare officers, and the expert opinion and practical experience of the members of a Working Group convened by the United Kingdom's National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs). PMID:26376175

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

    SciTech Connect

    Valerio, Luis G. . E-mail: luis.valerio@FDA.HHS.gov; Arvidson, Kirk B.; Chanderbhan, Ronald F.; Contrera, Joseph F.

    2007-07-01

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

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

    PubMed

    Hu, Shaowen; Cucinotta, Francis A

    2011-02-01

    As significant ionising radiation exposure will occur during prolonged space travel in future, it is essential to understand their adverse effects on the radiosensitive organ systems that are important for immediate survival of humans, e.g. the haematopoietic system. In this paper, a biomathematical model of granulopoiesis is used to analyse the granulocyte changes seen in the blood of mammalians under acute and continuous radiation exposure. This is one of a set of haematopoietic models that have been successfully utilised to simulate and interpret the experimental data of acute and chronic radiation on rodents. Extension to canine and human systems indicates that the results of the model are consistent with the cumulative experimental and empirical data from various sources, implying the potential to integrate them into one united model system to monitor the haematopoietic response of various species under irradiation. The suppression of granulocytes' level of a space traveller under chronic stress of low-dose irradiation as well as the granulopoietic response when encountering a historically large solar particle event is also discussed. PMID:21196459

  14. Understanding and managing sanitary risks due to rodent zoonoses in an African city: beyond the Boston Model.

    PubMed

    Taylor, Peter J; Arntzen, Lorraine; Hayter, Mel; Iles, Malcolm; Frean, John; Belmain, Steven

    2008-03-01

    The Boston Model describes a successful rodent management plan that succeeded in a first-world city in the USA. In third-world cities, which often contain informal shack settlements, it is debatable whether the Boston Model would apply. In Durban, a major harbor city of three million people on the east coast of South Africa, we investigated the sanitary risks due to rodents in both formal (residential and commercial) and informal (shacks) sectors, and we evaluated the relative merits of different management interventions suggested by the Boston Model. Blood and tissue samples of six species (Rattus norvegicus, R. tanezumi, R. rattus, Mus musculus, Mastomys natalensis, Tatera brantsi) from 262 live-trapped rodents from 54 localities were tested for antibodies or DNA for plague (n= 193: antibody test), leptospirosis (n= 221 for antibody test; n= 69 for polymerase chain reaction test for DNA) and toxoplasmosis (n= 217: antibody test). We conducted a socioeconomic survey of 90 household to determine environmental and socioeconomic disease risk factors in the shack settlement of Cato Crest. No rodents were seropositive for plague, but nine Norway rats, R. norvegicus (4.1% of the sample tested) were seropositive for toxoplasmosis, and 22 R. norvegicus (10.0% of sample tested) were seropositive for leptospirosis. Disease endemic areas were concentrated in Cato Crest and the commercial district of Durban. Serology tests of humans living in Cato Crest (n= 219) showed 0% exposure to plague, 23% to leptospirosis and 35% to toxoplasmosis. Compared with shack-dwellers, the residents of brick houses had slightly lower levels of exposure to leptospirosis and toxoplasmosis. Based on our results, environmental hygiene and rodent-trapping campaigns were launched in Cato Crest. The initiative owes much of its current success to implementation of the principles inherent in the Boston Model, even though certain elements were lacking. PMID:21396050

  15. A Novel Rodent Model That Mimics the Metabolic Sequelae of Obese Craniopharyngioma Patients

    PubMed Central

    Roth, Christian L.; Blevins, James E.; Ralston, Melissa; Elfers, Clinton; Ogimoto, Kayoko; Kaiyala, Karl J.; Morton, Gregory J.

    2013-01-01

    Patients with craniopharyngioma (CP), a tumor located in the pituitary and/or hypothalamus, are susceptible to developing obesity and many metabolic complications. The study aim was to create a rodent model that mimics the complex neuroanatomical and metabolic disturbances commonly seen in obese CP patients. We compared the metabolic phenotype of animals with three distinct types of hypothalamic lesions: 1) destruction of the arcuate nucleus (ARC) induced by monosodium glutamate (MSG), 2) electrolytic lesion of the adjacent ventromedial nucleus (VMN) alone, 3) both the VMN and dorsomedial nucleus (DMN), or a 4) combined medial hypothalamic lesion (CMHL) affecting the VMN, DMN, and the ARC. Only the CMHL model exhibited all key features observed in patients with hypothalamic obesity induced by CP. These features included excessive weight gain due to increased adiposity, increased food intake, and pronounced hyperinsulinemia and hyperleptinemia. Similar to characteristics of patients with CP, CMHL animals exhibited reduced plasma levels of alpha-melanocyte stimulating hormone and reduced ambulatory activity compared with weight-matched controls. Therefore, the CMHL model best mimics the complex metabolic abnormalities observed in obese CP patients compared with lesions to other hypothalamic areas and provides a foundation for future pharmacological approaches to treat obesity in children with hypothalamic damage. PMID:21372758

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

    PubMed

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

    2012-06-01

    Investigation of the amnesic disorder Korsakoff Syndrome (KS) has been vital in elucidating the critical brain regions involved in learning and memory. Although the thalamus and mammillary bodies are the primary sites of neuropathology in KS, functional deactivation of the hippocampus and certain cortical regions also contributes to the chronic cognitive dysfunction reported in KS. The rodent pyrithiamine-induced thiamine deficiency (PTD) model has been used to study the extent of hippocampal and cortical neuroadaptations in KS. In the PTD model, the hippocampus, frontal and retrosplenial cortical regions display loss of cholinergic innervation, decreases in behaviorally stimulated acetylcholine release and reductions in neurotrophins. While PTD treatment results in significant impairment in measures of spatial learning and memory, other cognitive processes are left intact and may be recruited to improve cognitive outcome. In addition, behavioral recovery can be stimulated in the PTD model by increasing acetylcholine levels in the medial septum, hippocampus and frontal cortex, but not in the retrosplenial cortex. These data indicate that although the hippocampus and frontal cortex are involved in the pathogenesis of KS, these regions retain neuroplasticity and may be critical targets for improving cognitive outcome in KS. PMID:22528861

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

    PubMed

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

    2016-08-25

    Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor. PMID:27302204

  18. Pathophysiology of human glaucomatous optic nerve damage: insights from rodent models of glaucoma.

    PubMed

    Morrison, John C; Cepurna Ying Guo, William O; Johnson, Elaine C

    2011-08-01

    Understanding mechanisms of glaucomatous optic nerve damage is essential for developing effective therapies to augment conventional pressure-lowering treatments. This requires that we understand not only the physical forces in play, but the cellular responses that translate these forces into axonal injury. The former are best understood by using primate models, in which a well-developed lamina cribrosa, peripapillary sclera and blood supply are most like that of the human optic nerve head. However, determining cellular responses to elevated intraocular pressure (IOP) and relating their contribution to axonal injury require cell biology techniques, using animals in numbers sufficient to perform reliable statistical analyses and draw meaningful conclusions. Over the years, models of chronically elevated IOP in laboratory rats and mice have proven increasingly useful for these purposes. While lacking a distinct collagenous lamina cribrosa, the rodent optic nerve head (ONH) possesses a cellular arrangement of astrocytes, or glial lamina, that ultrastructurally closely resembles that of the primate. Using these tools, major insights have been gained into ONH and the retinal cellular responses to elevated IOP that, in time, can be applied to the primate model and, ultimately, human glaucoma. PMID:20708000

  19. Pathogenesis of FUS-associated ALS and FTD: insights from rodent models.

    PubMed

    Nolan, Matthew; Talbot, Kevin; Ansorge, Olaf

    2016-01-01

    Disruptions to genes linked to RNA processing and homeostasis are implicated in the pathogenesis of two pathologically related but clinically heterogeneous neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in the Fused-in-Sarcoma (FUS) gene encoding a 526 amino-acid RNA-binding protein are found in a small subset of ALS cases, but FUS mutations do not appear to be a direct cause of FTD. Structural and functional similarities between FUS and another ALS-related RNA-binding protein, TDP-43, highlight the potential importance of aberrant RNA processing in ALS/FTD, and this pathway is now a major focus of interest. Recently, several research groups have reported transgenic vertebrate models of FUSopathy, with varying results. Here, we discuss the evidence for FUS pathogenicity in ALS/FTD, review the experimental approaches used and phenotypic features of FUS rodent models reported to date, and outline their contribution to our understanding of pathogenic mechanisms. Further refinement of vertebrate models will likely aid our understanding of the role of FUS in both diseases. PMID:27600654

  20. Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain

    PubMed Central

    Zambelli, Vanessa O.; Gross, Eric R.; Chen, Che-Hong; Gutierrez, Vanessa P.; Cury, Yara; Mochly-Rosen, Daria

    2014-01-01

    Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase 2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2*2), which is also present in human ALDH2 of ~540 million East Asians. The ALDH2*1/*2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R2=0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde and formalin-induced nociceptive behavior was greater in the ALDH2*1/*2 mice than wild-type mice. Finally, Alda-1 treatment was also beneficial when given even after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians’ apparent lower pain tolerance. PMID:25163478

  1. About a Snail, a Toad, and Rodents: Animal Models for Adaptation Research

    PubMed Central

    Roubos, Eric W.; Jenks, Bruce G.; Xu, Lu; Kuribara, Miyuki; Scheenen, Wim J. J. M.; Kozicz, Tamás

    2010-01-01

    Neural adaptation mechanisms have many similarities throughout the animal kingdom, enabling to study fundamentals of human adaptation in selected animal models with experimental approaches that are impossible to apply in man. This will be illustrated by reviewing research on three of such animal models, viz. (1) the egg-laying behavior of a snail, Lymnaea stagnalis: how one neuron type controls behavior, (2) adaptation to the ambient light condition by a toad, Xenopus laevis: how a neuroendocrine cell integrates complex external and neural inputs, and (3) stress, feeding, and depression in rodents: how a neuronal network co-ordinates different but related complex behaviors. Special attention is being paid to the actions of neurochemical messengers, such as neuropeptide Y, urocortin 1, and brain-derived neurotrophic factor. While awaiting new technological developments to study the living human brain at the cellular and molecular levels, continuing progress in the insight in the functioning of human adaptation mechanisms may be expected from neuroendocrine research using invertebrate and vertebrate animal models. PMID:22649351

  2. Insignificant effect of secretin in rodent models of polycystic kidney and liver disease.

    PubMed

    Wang, Xiaofang; Ye, Hong; Ward, Christopher J; Chu, Jessica Y S; Masyuk, Tatyana V; Larusso, Nicholas F; Harris, Peter C; Chow, Billy K C; Torres, Vicente E

    2012-10-01

    Polycystic kidney (PKD) and liver (PLD) diseases cause significant morbidity and mortality. A large body of evidence indicates that cyclic AMP plays an important role in their pathogenesis. Clinical trials of drugs that reduce cyclic AMP levels in target tissues are now in progress. Secretin may contribute to adenylyl cyclase-dependent urinary concentration and is a major agonist of adenylyl cyclase in cholangiocytes. To investigate the role of secretin in PKD and PLD, we have studied the expression of secretin and the secretin receptor in rodent models orthologous to autosomal recessive (PCK rat) and dominant (Pkd2(-/WS25) mouse) PKD; the effects of exogenous secretin administration to PCK rats, PCK rats lacking circulating vasopressin (PCK(di/di)), and Pkd2(-/WS25) mice; and the impact of a nonfunctional secretin receptor on disease development in Pkd2(-/WS25):SCTR(-/-) double mutants. Renal and hepatic secretin and secretin receptor mRNA and plasma secretin were increased in both models, and secretin receptor protein was increased in the kidneys and liver of Pkd2(-/WS25) mice. However, exogenous secretin administered subcutaneously via osmotic pumps had minimal or negligible effects and the absence of a functional secretin receptor had no influence on the severity of PKD or PLD. Therefore, it is unlikely that by itself secretin plays a significant role in the pathogenesis of PKD and/or PLD. PMID:22811488

  3. Convergent pharmacological mechanisms in impulsivity and addiction: insights from rodent models

    PubMed Central

    Jupp, B; Dalley, J W

    2014-01-01

    Research over the last two decades has widely demonstrated that impulsivity, in its various forms, is antecedent to the development of drug addiction and an important behavioural trait underlying the inability of addicts to refrain from continued drug use. Impulsivity describes a variety of rapidly and prematurely expressed behaviours that span several domains from impaired response inhibition to an intolerance of delayed rewards, and is a core symptom of attention deficit hyperactivity disorder (ADHD) and other brain disorders. Various theories have been advanced to explain how impulsivity interacts with addiction both causally and as a consequence of chronic drug abuse; these acknowledge the strong overlaps in neural circuitry and mechanisms between impulsivity and addiction and the seemingly paradoxical treatment of ADHD with stimulant drugs with high abuse potential. Recent years have witnessed unprecedented progress in the elucidation of pharmacological mechanisms underpinning impulsivity. Collectively, this work has significantly improved the prospect for new therapies in ADHD as well as our understanding of the neural mechanisms underlying the shift from recreational drug use to addiction. In this review, we consider the extent to which pharmacological interventions that target impulsive behaviour are also effective in animal models of addiction. We highlight several promising examples of convergence based on empirical findings in rodent-based studies. 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:24866553

  4. Mild systemic thermal therapy ameliorates renal dysfunction in a rodent model of chronic kidney disease.

    PubMed

    Iwashita, Yoshihiro; Kuwabara, Takashige; Hayata, Manabu; Kakizoe, Yutaka; Izumi, Yuichiro; Iiyama, Junichi; Kitamura, Kenichiro; Mukoyama, Masashi

    2016-06-01

    Thermal therapy has become a nonpharmacological therapy in clinical settings, especially for cardiovascular diseases. However, the practical role of thermal therapy on chronic kidney disease remains elusive. We performed the present study to investigate whether a modified thermal protocol, repeated mild thermal stimulation (MTS), could affect renal damages in chronic kidney disease using a mouse renal ablation model. Mice were subjected to MTS or room temperature (RT) treatment once daily for 4 wk after subtotal nephrectomy (Nx) or sham operation (Sh). We revealed that MTS alleviated renal impairment as indicated by serum creatinine and albuminuria in Nx groups. In addition, the Nx + MTS group showed attenuated tubular histological changes and reduced urinary neutrophil gelatinase-associated lipocalin excretion approximately by half compared with the Nx + RT group. Increased apoptotic signaling, such as TUNEL-positive cell count and cleavage of caspase 3, as well as enhanced oxidative stress were significantly reduced in the Nx + MTS group compared with the Nx + RT group. These changes were accompanied with the restoration of kidney Mn-SOD levels by MTS. Heat shock protein 27, a key molecular chaperone, was phosphorylated by MTS only in Nx kidneys rather than in Sh kidneys. MTS also tended to increase the phosphorylation of p38 MAPK and Akt in Nx kidneys, possibly associated with the activation of heat shock protein 27. Taken together, these results suggest that modified MTS can protect against renal injury in a rodent model of chronic kidney disease. PMID:27029428

  5. A comparison of automated anatomical–behavioural mapping methods in a rodent model of stroke☆

    PubMed Central

    Crum, William R.; Giampietro, Vincent P.; Smith, Edward J.; Gorenkova, Natalia; Stroemer, R. Paul; Modo, Michel

    2013-01-01

    Neurological damage, due to conditions such as stroke, results in a complex pattern of structural changes and significant behavioural dysfunctions; the automated analysis of magnetic resonance imaging (MRI) and discovery of structural–behavioural correlates associated with these disorders remains challenging. Voxel lesion symptom mapping (VLSM) has been used to associate behaviour with lesion location in MRI, but this analysis requires the definition of lesion masks on each subject and does not exploit the rich structural information in the images. Tensor-based morphometry (TBM) has been used to perform voxel-wise structural analyses over the entire brain; however, a combination of lesion hyper-intensities and subtle structural remodelling away from the lesion might confound the interpretation of TBM. In this study, we compared and contrasted these techniques in a rodent model of stroke (n = 58) to assess the efficacy of these techniques in a challenging pre-clinical application. The results from the automated techniques were compared using manually derived region-of-interest measures of the lesion, cortex, striatum, ventricle and hippocampus, and considered against model power calculations. The automated TBM techniques successfully detect both lesion and non-lesion effects, consistent with manual measurements. These techniques do not require manual segmentation to the same extent as VLSM and should be considered part of the toolkit for the unbiased analysis of pre-clinical imaging-based studies. PMID:23727124

  6. The Neuroprotective Effects of Carnosine in Early Stage of Focal Ischemia Rodent Model

    PubMed Central

    Park, Hui-Seung; Han, Kyung-Hoon; Shin, Jeoung-A; Park, Joo-Hyun; Song, Kwan-Young

    2014-01-01

    Objective This study was conducted to elucidate neuroprotective effect of carnosine in early stage of stroke. Methods Early stage of rodent stroke model and neuroblastoma chemical hypoxia model was established by middle cerebral artery occlusion and antimycin A. Neuroprotective effect of carnosine was investigated with 100, 250, and 500 mg of carnosine treatment. And antioxidant expression was analyzed by enzyme linked immunosorbent assay (ELISA) and western blot in brain and blood. Results Intraperitoneal injection of 500 mg carnosine induced significant decrease of infarct volume and expansion of penumbra (p<0.05). The expression of superoxide dismutase (SOD) showed significant increase than in saline group in blood and brain (p<0.05). In the analysis of chemical hypoxia, carnosine induced increase of neuronal cell viability and decrease of reactive oxygen species (ROS) production. Conclusion Carnosine has neuroprotective property which was related to antioxidant capacity in early stage of stroke. And, the oxidative stress should be considered one of major factor in early ischemic stroke. PMID:24851146

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

    PubMed

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

    2014-01-01

    Epilepsy is a dynamical disease and its effects are evident in over fifty million people worldwide. This study focused on objective classification of the multiple states involved in the brain's epileptiform activity. Four datasets from three different rodent hippocampal preparations were explored, wherein seizure-like-events (SLE) were induced by the perfusion of a low - Mg(2+) /high-K(+) solution or 4-Aminopyridine. Local field potentials were recorded from CA3 pyramidal neurons and interneurons and modeled as Markov processes. Specifically, hidden Markov models (HMM) were used to determine the nature of the states present. Properties of the Hilbert transform were used to construct the feature spaces for HMM training. By sequentially applying the HMM training algorithm, multiple states were identified both in episodes of SLE and nonSLE activity. Specifically, preSLE and postSLE states were differentiated and multiple inner SLE states were identified. This was accomplished using features extracted from the lower frequencies (1-4 Hz, 4-8 Hz) alongside those of both the low- (40-100 Hz) and high-gamma (100-200 Hz) of the recorded electrical activity. The learning paradigm of this HMM-based system eliminates the inherent bias associated with other learning algorithms that depend on predetermined state segmentation and renders it an appropriate candidate for SLE classification. PMID:23771347

  8. Adipose-Derived Stromal Vascular Fraction Cell Effects on a Rodent Model of Thin Endometrium

    PubMed Central

    Hunter, Robert K.; Nevitt, Chris D.; Gaskins, Jeremy T.; Keller, Bradley B.; Bohler, Henry C. L.; LeBlanc, Amanda J.

    2015-01-01

    Endometrial dysfunction affects approximately 1% of infertile women, and there is currently no standard therapy for improving fertility treatment outcomes in these patients. In our study, we utilized a rodent model of thin endometrium to test whether intrauterine application of adipose-derived stromal vascular fraction cells (SVF) could improve morphological and physiological markers of endometrial receptivity. Using anhydrous ethanol, endometrial area and gland density were significantly reduced in our model of thin endometrium. Application of SVF was associated with a 29% reduction in endometrial vascular endothelial growth factor (VEGF) expression and significant increases in uterine artery systolic/diastolic velocity ratios and resistance index values, suggesting reduced diastolic microvascular tone. However, no significant improvements in endometrial area or gland density were observed following SVF treatment. 3D confocal imaging demonstrated poor engraftment of SVF cells into recipient tissue, which likely contributed to the negative results of this study. We suspect modified treatment protocols utilizing adjuvant estrogen and/or tail vein cell delivery may improve SVF retention and therapeutic response in subsequent studies. SVF is an easily-obtainable cell product with regenerative capability that may have a future role in the treatment of infertile women with endometrial dysfunction. PMID:26657744

  9. Gnotobiotic Rodents: An In Vivo Model for the Study of Microbe–Microbe Interactions

    PubMed Central

    Martín, Rebeca; Bermúdez-Humarán, Luis G.; Langella, Philippe

    2016-01-01

    Germ-free rodents have no microorganisms living in or on them, allowing researchers to specifically control an animal’s microbiota through the direct inoculation of bacteria of interest. This strategy has been widely used to decipher host–microbe interactions as well as the role of microorganisms in both (i) the development and function of the gut barrier (mainly the intestinal epithelium) and (ii) homeostasis and its effects on human health and disease. However, this in vivo model also offers a more realistic environment than an assay tube in which to study microbe–microbe interactions, without most of the confounding interactions present in the intestinal microbiota of conventionally raised mice. This review highlights the usefulness of controlled-microbiota mice in studying microbe–microbe interactions. To this end, we summarize current knowledge on germ-free animals as an experimental model for the study of the ecology and metabolism of intestinal bacteria as well as of microbe–microbe interactions. PMID:27065973

  10. Rodent models of HAND and drug abuse: exogenous administration of viral protein(s) and cocaine.

    PubMed

    Yao, Honghong; Buch, Shilpa

    2012-06-01

    Humans and chimpanzees are the natural hosts for HIV. Non-human primate models of SIV/SHIV infection in rhesus, cynomologus and pigtail macaques have been used extensively as excellent model systems for pathogenesis and vaccine studies. However, owing to the variability of disease progression in infected macaques, a phenomenon identical to humans, coupled with their prohibitive costs, there exists a critical need for the development of small-animal models in which to study the untoward effects of HIV-1 infection. Owing to the fact that rodents are not the natural permissive hosts for lentiviral infection, development of small animal models for studying virus infection has used strategies that circumvent the steps of viral entry and infection. Such strategies involve overexpression of toxic viral proteins, SCID mice engrafted with the human PBLs or macrophages, and EcoHIV chimeric virus wherein the gp120 of HIV-1 was replaced with the gp80 of the ecotropic murine leukemia virus. Additional strategy that is often used by investigators to study the toxic effect of viral proteins involves direct stereotactic injection of the viral protein(s) into specific brain regions. The present report is a compilation of the applications of direct administration of Tat into the striatum to mimic the effects of the viral neurotoxin in the CNS. Added advantage of this model is that it is also amenable to repeated intraperitoneal cocaine injections, thereby allowing the study of the additive/synergistic effects of both the viral protein and cocaine. Such a model system recapitulates aspects of HAND in the context of drug abuse. PMID:22447295

  11. Anatomical features for an adequate choice of experimental animal model in biomedicine: II. Small laboratory rodents, rabbit, and pig.

    PubMed

    Lossi, Laura; D'Angelo, Livia; De Girolamo, Paolo; Merighi, Adalberto

    2016-03-01

    The anatomical features distinctive to each of the very large array of species used in today's biomedical research must be born in mind when considering the correct choice of animal model(s), particularly when translational research is concerned. In this paper we take into consideration and discuss the most important anatomical and histological features of the commonest species of laboratory rodents (rat, mouse, guinea pig, hamster, and gerbil), rabbit, and pig related to their importance for applied research. PMID:26527557

  12. Critical thoughts on current rodent models for evaluating potential treatments of alcohol addiction and withdrawal

    PubMed Central

    Ripley, Tamzin L; Stephens, David N

    2011-01-01

    Despite years of neurobiological research that have helped to identify potential therapeutic targets, we do not have a reliable pharmacological treatment for alcoholism. There are a range of possible explanations for this failure, including arguments that alcoholism is a spectrum disorder and that different population subtypes may respond to different treatments. This view is supported by categorisations such as early- and late-onset alcoholism, whilst multifactorial genetic factors may also alter responsivity to pharmacological agents. Furthermore, experience of alcohol withdrawal may play a role in future drinking in a way that may distinguish alcoholism from other forms of addiction. Additionally, our neurobiological models, based largely upon results from rodent studies, may not mimic specific aspects of the human condition and may reflect different underlying phenomena and biological processes from the clinical pattern. As a result, potential treatments may be targeting inappropriate aspects of alcohol-related behaviours. Instead, we suggest a more profitable approach is (a) to identify well-defined intermediate behavioural phenotypes in human experimental models that reflect defined aspects of the human clinical disorder and (b) to develop animal models that are homologous with those phenotypes in terms of psychological processes and underlying neurobiological mechanisms. This review describes an array of animal models currently used in the addiction field and what they tell us about alcoholism. We will then examine how established pharmacological agents have been developed using only a limited number of these models, before describing some alternative novel approaches to achieving homology between animal and human experimental measures. 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:21470204

  13. Lactobacillus casei strain Shirota protects against nonalcoholic steatohepatitis development in a rodent model.

    PubMed

    Okubo, Hirofumi; Sakoda, Hideyuki; Kushiyama, Akifumi; Fujishiro, Midori; Nakatsu, Yusuke; Fukushima, Toshiaki; Matsunaga, Yasuka; Kamata, Hideaki; Asahara, Takashi; Yoshida, Yasuto; Chonan, Osamu; Iwashita, Misaki; Nishimura, Fusanori; Asano, Tomoichiro

    2013-12-01

    Gut microbiota alterations are associated with various disorders. In this study, gut microbiota changes were investigated in a methionine-choline-deficient (MCD) diet-induced nonalcoholic steatohepatitis (NASH) rodent model, and the effects of administering Lactobacillus casei strain Shirota (LcS) on the development of NASH were also investigated. Mice were divided into three groups, given the normal chow diet (NCD), MCD diet, or the MCD diet plus daily oral administration of LcS for 6 wk. Gut microbiota analyses for the three groups revealed that lactic acid bacteria such as Bifidobacterium and Lactobacillus in feces were markedly reduced by the MCD diet. Interestingly, oral administration of LcS to MCD diet-fed mice increased not only the L. casei subgroup but also other lactic acid bacteria. Subsequently, NASH development was evaluated based on hepatic histochemical findings, serum parameters, and various mRNA and/or protein expression levels. LcS intervention markedly suppressed MCD-diet-induced NASH development, with reduced serum lipopolysaccharide concentrations, suppression of inflammation and fibrosis in the liver, and reduced colon inflammation. Therefore, reduced populations of lactic acid bacteria in the colon may be involved in the pathogenesis of MCD diet-induced NASH, suggesting normalization of gut microbiota to be effective for treating NASH. PMID:24113768

  14. Exogenous erythropoietin provides neuroprotection of grafted dopamine neurons in a rodent model of Parkinson's disease.

    PubMed

    Kanaan, Nicholas M; Collier, Timothy J; Marchionini, Deanna M; McGuire, Susan O; Fleming, Matthew F; Sortwell, Caryl E

    2006-01-12

    Parkinson's disease (PD) is a neurodegenerative disease marked by severe loss of dopamine (DA) neurons in the nigrostriatal system, which results in depletion of striatal DA. Transplantation of embryonic ventral mesencephalic (VM) DA neurons into the striatum is a currently explored experimental treatment aimed at replacing lost DA in the nigrostriatal system, but is plagued with poor survival (5-20%) of implanted neurons. Here, we tested the ability of erythropoietin (Epo) to provide neuroprotection for embryonic day 14 (E14) VM DA neurons. Epo was tested in vitro for the ability to augment tyrosine hydroxylase-immunoreactive (TH-ir) neuron survival under normal cell culture conditions. In vitro, Epo did not increase the number of TH-ir neurons when administered at the time of plating the E14 VM cells in culture. We also tested the efficacy of Epo to enhance E14 VM transplants in vivo. Rats unilaterally lesioned with 6-hydroxydopamine received transplants that were incubated in Epo. Treatment with Epo produced significant increases in TH-ir neuron number, soma size, and staining intensity. Animals receiving Epo-treated grafts exhibited significantly accelerated functional improvements and significantly greater overall improvements from rotational asymmetry compared to control grafted rats. These data indicate that the survival of embryonic mesencephalic TH-ir neurons is increased when Epo is administered with grafted cells in a rodent model of PD. As direct neurotrophic effects of Epo were not observed in vitro, the mechanism of Epo neuroprotection remains to be elucidated. PMID:16368081

  15. Parental buffering of fear and stress neurobiology: Reviewing parallels across rodent, monkey, and human models.

    PubMed

    Gunnar, Megan R; Hostinar, Camelia E; Sanchez, Mar M; Tottenham, Nim; Sullivan, Regina M

    2015-01-01

    It has been long recognized that parents exert profound influences on child development. Dating back to at least the seventeenth-century Enlightenment, the ability for parents to shape child behavior in an enduring way has been noted. Twentieth-century scholars developed theories to explain how parenting histories influence psychological development, and since that time, the number of scientific publications on parenting influences in both human and nonhuman animal fields has grown at an exponential rate, reaching numbers in the thousands by 2015. This special issue describes a symposium delivered by Megan Gunnar, Regina Sullivan, Mar Sanchez, and Nim Tottenham in the Fall of 2014 at the Society for Social Neuroscience. The goal of the symposium was to describe the emerging knowledge on neurobiological mechanisms that mediate parent-offspring interactions across three different species: rodent, monkey, and human. The talks were aimed at designing testable models of parenting effects on the development of emotional and stress regulation. Specifically, the symposium aimed at characterizing the special modulatory (buffering) effects of parental cues on fear- and stress-relevant neurobiology and behaviors of the offspring and to discuss examples of impaired buffering when the parent-infant relationship is disrupted. PMID:26234160

  16. Exercise and Nutritional Benefits in PD: Rodent Models and Clinical Settings.

    PubMed

    Archer, Trevor; Kostrzewa, Richard M

    2016-01-01

    Physical exercise offers a highly effective health-endowering activity as has been evidence using rodent models of Parkinson's disease (PD). It is a particularly useful intervention in individuals employed in sedentary occupations or afflicted by a neurodegenerative disorder, such as PD. The several links between exercise and quality-of-life, disorder progression and staging, risk factors and symptoms-biomarkers in PD all endower a promise for improved prognosis. Nutrition provides a strong determinant for disorder vulnerability and prognosis with fish oils and vegetables with a mediterranean diet offering both protection and resistance. Three factors determining the effects of exercise on disorder severity of patients may be presented: (i) Exercise effects upon motor impairment, gait, posture and balance, (ii) Exercise reduction of oxidative stress, stimulation of mitochondrial biogenesis and up-regulation of autophagy, and (iii) Exercise stimulation of dopamine (DA) neurochemistry and trophic factors. Running-wheel performance, as measured by distance run by individual mice from different treatment groups, was related to DA-integrity, indexed by striatal DA levels. Finally, both nutrition and exercise may facilitate positive epigenetic outcomes, such as lowering the dosage of L-Dopa required for a therapeutic effect. PMID:26728168

  17. Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers

    PubMed Central

    Wang, I-Ming; Zhang, Bin; Yang, Xia; Zhu, Jun; Stepaniants, Serguei; Zhang, Chunsheng; Meng, Qingying; Peters, Mette; He, Yudong; Ni, Chester; Slipetz, Deborah; Crackower, Michael A; Houshyar, Hani; Tan, Christopher M; Asante-Appiah, Ernest; O'Neill, Gary; Jane Luo, Mingjuan; Thieringer, Rolf; Yuan, Jeffrey; Chiu, Chi-Sung; Yee Lum, Pek; Lamb, John; Boie, Yves; Wilkinson, Hilary A; Schadt, Eric E; Dai, Hongyue; Roberts, Christopher

    2012-01-01

    Common inflammatome gene signatures as well as disease-specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co-expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue-specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response-related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non-drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases. PMID:22806142

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

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

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

  19. Degenerative Tissue Responses to Space-like Radiation Doses in a Rodent Model of Simulated Microgravity.

    PubMed

    Chowdhury, Parimal; Akel, Nisreen; Jamshidi-Parsian, Azemat; Gaddy, Dana; Griffin, Robert J; Yadlapalli, Jai Shankar K; Dobretsov, Maxim

    2016-03-01

    This study examines acute and degenerative tissue responses to space-like radiation doses in a rodent model of simulated microgravity. We have studied four groups of rats, control (CON), irradiated (IR), irradiated and hindlimb suspended (IR-HLS), and suspended (HLS) that were maintained for two weeks. IR and IR+HLS groups were exposed to five sessions of X-ray irradiation (1.2 Gy each, at 3-4 days intervals). Body weights, soleus muscle weights, and hindlimb bone mineral density (BMD) were measured. Results show that compared to CON animals, IR, HLS, and IR+HLS group reduced the body weight gain significantly. IR-associated growth retardation appeared to be closely linked to acute and transient post-IR 'anorexia' (a decrease in food intake). HLS but not IR induced major changes in the musculoskeletal system, consisting in decreases in soleus muscle mass and bone mineral density of distal femur and proximal tibia. Additional dosimetric studies showed that the effect of IR on weight is detectable at 0.3 Gy X-ray doses, while no threshold dose for the IR-produced decrease in food intake could be observed. This study suggests that space flight-associated anorexia and musculoskeletal degenerative changes may be driven by different, radiation- and microgravity-associated (respectively) mechanisms. PMID:27098627

  20. Cortical Brain Mapping of Peripheral Nerves Using Functional Magnetic Resonance Imaging in a Rodent Model

    PubMed Central

    Cho, Younghoon R.; Jones, Seth R.; Pawela, Christopher P.; Li, Rupeng; Kao, Dennis S.; Schulte, Marie L.; Runquist, Matthew L.; Yan, Ji-Geng; Hudetz, Anthony G.; Jaradeh, Safwan S.; Hyde, James S.; Matloub, Hani S.

    2008-01-01

    The regions of the body have cortical and subcortical representation in proportion to their degree of innervation. The rat forepaw has been studied extensively in recent years using functional magnetic resonance imaging (fMRI)—typically by stimulation using electrodes directly inserted into the skin of the forepaw. Here, we stimulate using surgically implanted electrodes. A major distinction is that stimulation of the skin of the forepaw is mostly sensory, whereas direct nerve stimulation reveals not only the sensory system but also deep brain structures associated with motor activity. In this paper, we seek to define both the motor and sensory cortical and subcortical representations associated with the four major nerves of the rodent upper extremity. We electrically stimulated each nerve (median, ulnar, radial, and musculocutaneous) during fMRI acquisition using a 9.4T Bruker scanner. A current level of 0.5-1.0 mA and a frequency of 5 Hz were used while keeping the duration constant. A distinct pattern of cortical activation was found for each nerve that can be correlated with known sensorimotor afferent and efferent pathways to the rat forepaw. This direct nerve stimulation rat model can provide insight into peripheral nerve injury. PMID:18924070

  1. Gene delivery of Homer1c rescues spatial learning in a rodent model of cognitive aging.

    PubMed

    Gerstein, Hilary; Lindstrom, Mary J; Burger, Corinna

    2013-08-01

    Homer1c has been shown to play a role in learning and memory. Overexpression of Homer1c in the hippocampus can improve memory in normal rats and can also rescue spatial learning deficits in Homer1 knockout mice. In a previous study, we found that Homer1c mRNA is upregulated after a spatial learning paradigm in aged rats that successfully learn the task, when compared to aged rats that are learning-impaired (AI). This study was designed to validate the role of Homer1c in successful cognitive aging. In this article, we report that gene delivery of Homer1c into the hippocampus of aged learning-impaired rats significantly improves individual performance on an object location memory task. The learning ability of these rats on the Morris Water Maze was also superior to that of AI control rats. In summary, using 2 independent spatial memory tasks, we demonstrate that Homer1c is sufficient to improve the spatial learning deficits in a rodent model of cognitive aging. These results point to Homer1c as a potential therapeutic target for improving age-related cognitive impairment. PMID:23523268

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

    PubMed Central

    Karl, Tim

    2013-01-01

    Schizophrenia is a multi-factorial disease characterized by a high heritability and environmental risk factors. In recent years, an increasing number of researchers worldwide have started investigating the “two-hit hypothesis” of schizophrenia predicting that genetic and environmental risk factors (GxE) interactively cause the development of the disorder. This work is starting to produce valuable new animal models and reveal novel insights into the pathophysiology of schizophrenia. This mini review will focus on recent advancements in the field made by challenging mutant and transgenic rodent models for the schizophrenia candidate gene neuregulin 1 (NRG1) with particular environmental factors. It will outline results obtained from mouse and rat models for various Nrg1 isoforms/isoform types (e.g., transmembrane domain Nrg1, Type II Nrg1), which have been exposed to different forms of stress (acute versus chronic, restraint versus social) and housing conditions (standard laboratory versus minimally enriched housing). These studies suggest Nrg1 as a prime candidate for GxE interactions in schizophrenia rodent models and that the use of rodent models will enable a better understanding of GxE interactions and the underlying mechanisms. PMID:23966917

  3. Cross-species comparison of orthologous gene expression in human bladder cancer and carcinogen-induced rodent models

    PubMed Central

    Lu, Yan; Liu, Pengyuan; Wen, Weidong; Grubbs, Clinton J; Townsend, Reid R; Malone, James P; Lubet, Ronald A; You, Ming

    2011-01-01

    Genes differentially expressed by tumor cells represent promising drug targets for anti-cancer therapy. Such candidate genes need to be validated in appropriate animal models. This study examined the suitability of rodent models of bladder cancer in B6D2F1 mice and Fischer-344 rats to model clinical bladder cancer specimens in humans. Using a global gene expression approach cross-species analysis showed that 13-34% of total genes in the genome were differentially expressed between tumor and normal tissues in each of five datasets from humans, rats, and mice. About 20% of these differentially expressed genes overlapped among species, corresponding to 2.6 to 4.8% of total genes in the genome. Several genes were consistently dysregulated in bladder tumors in both humans and rodents. Notably, CNN1, MYL9, PDLIM3, ITIH5, MYH11, PCP4 and FM05 were found to commonly down-regulated; while T0P2A, CCNB2, KIF20A and RRM2 were up-regulated. These genes are likely to have conserved functions contributing to bladder carcinogenesis. Gene set enrichment analysis detected a number of molecular pathways commonly activated in both humans and rodent bladder cancer. These pathways affect the cell cycle, HIF-1 and MYC expression, and regulation of apoptosis. We also compared expression changes at mRNA and protein levels in the rat model and identified several genes/proteins exhibiting concordant changes in bladder tumors, including ANXA1, ANXA2, CA2, KRT14, LDHA, LGALS4, SERPINA1, KRT18 and LDHB. In general, rodent models of bladder cancer represent the clinical disease to an extent that will allow successful mining of target genes and permit studies on the molecular mechanisms of bladder carcinogenesis. PMID:21139803

  4. Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease

    PubMed Central

    2010-01-01

    Background Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T2 water 1H relaxation or 1H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin. Results Lactacystin induced parkinsonian-like behaviour, characterised by impaired contralateral forelimb grip strength and increased contralateral circling in response to apomorphine. T2-weighted MRI, 3-weeks post-lesion, revealed significant morphological changes in PD-relevant brain areas, including the striatum and ventral midbrain in addition to a decrease in T2 water 1H relaxation in the substantia nigra (SN), but not the striatum. Post-mortem histological analyses revealed extensive dopaminergic neuronal degeneration and α-synuclein aggregation in the SN. However, extensive neuronal loss could also be observed in extra-nigral areas, suggesting non-specific toxicity of lactacystin. Iron accumulation could also be observed throughout the midbrain reflecting changes in T2. Importantly, morphological, but not T2 relaxivity changes, were significantly associated with both behavioural and histological outcomes in this model. Conclusions A pattern of morphological changes in lactacystin-lesioned animals has been identified, as well as alterations in nigral T2 relaxivity. The significant relationship of morphological changes with behavioural and histological outcomes in this model raises the possibility that these may be useful non-invasive surrogate markers of nigrostriatal degeneration in vivo. PMID:20051106

  5. [Caucasian cryptic species of rodents as models for studying the problem of species and speciation].

    PubMed

    Baskevich, M I; Potapov, S G; Mironova, T A

    2015-01-01

    The problem of species and speciation is considered using as a model the cryptic species of rodents inhabiting the Caucasus, the mountain chain with prominent altitude environmental gradient and insular pattern of mountain habitats. These circumstances open additional possibilities for the choice of species conception (biological or phylogenetic), exploration of ancestry pathways (sympatric or allopatric speciation) of model cryptic species groups, and testing the 'refuge' hypothesis. As model species, sibling-species Sicista from the group 'caucasica' (a group of unstriped birch mice) and representatives of the vole subspecies Terricola (Microtus, Arvicolinae) were used. Based on the new data on karyology, nucleotide sequences of mitochondrial gene cytb, multivariate statistical analysis of odontologic traits, and biogeography of sibling-species Sicista from the group 'caucasica' and voles from subspecies Terricola (Microtus, Arvicolinae), their evolutionary history is reconstructed and applicable species concepts are examined. For the present sibling-species Sicista from the group 'caucasica' the allopatric dispersion is typical, which agrees with the hypothesis of speciation in refuges. The sympatry of Terricola sibling-species in the Caucasus is considered as being secondary, and their phenotypic likeness--as an adaptation to similar environmental conditions. Affirmed coexistence of sibling-species Microtus (Terricola) majori and Microtus (Terricola) daghestanicus in the Caucasus (without their hybridization) supports the biological conception of species. The existence of Sicista allospecies from the group of Caucasian unstriped birch mice is best conformed to the phylogenetic conception. However, the high level of chromosomal differences between sibling-species and, in particular, between extreme variants of common evolutionary line (Sicista kazbegica, Sicista kluchorica) does not contradict the biological conception of species. PMID:26353399

  6. A new exposure model to evaluate smoked illicit drugs in rodents: A study of crack cocaine.

    PubMed

    Hueza, Isis M; Ponce, Fernando; Garcia, Raphael C T; Marcourakis, Tânia; Yonamine, Maurício; Mantovani, Cínthia de C; Kirsten, Thiago B

    2016-01-01

    The use of smoked illicit drugs has spread dramatically, but few studies use proper devices to expose animals to inhalational abused drugs despite the availability of numerous smoking devices that mimic tobacco exposure in rodents. Therefore, the present study developed an inexpensive device to easily expose laboratory animals to smoked drugs. We used crack cocaine as the drug of abuse, and the cocaine plasma levels and the behaviors of animals intoxicated with the crack cocaine were evaluated to prove inhaled drug absorption and systemic activity. We developed an acrylic device with two chambers that were interconnected and separated by a hatch. Three doses of crack (100, 250, or 500 mg), which contained 63.7% cocaine, were burned in a pipe, and the rats were exposed to the smoke for 5 or 10 min (n=5/amount/period). Exposure to the 250-mg dose for 10 min achieved cocaine plasma levels that were similar to those of users (170 ng/mL). Behavioral evaluations were also performed to validate the methodology. Rats (n=10/group) for these evaluations were exposed to 250 mg of crack cocaine or air for 10 min, twice daily, for 28 consecutive days. Open-field evaluations were performed at three different periods throughout the experimental design. Exposed animals exhibited transient anorexia, increased motor activity, and shorter stays in central areas of the open field, which suggests reduced anxiety. Therefore, the developed model effectively exposed animals to crack cocaine, and this model may be useful for the investigation of other inhalational abused drugs. PMID:26391341

  7. Inflammatory cytokine receptor blockade in a rodent model of mild traumatic brain injury.

    PubMed

    Perez-Polo, J R; Rea, H C; Johnson, K M; Parsley, M A; Unabia, G C; Xu, G-Y; Prough, D; DeWitt, D S; Paulucci-Holthauzen, A A; Werrbach-Perez, K; Hulsebosch, C E

    2016-01-01

    In rodent models of traumatic brain injury (TBI), both Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) levels increase early after injury to return later to basal levels. We have developed and characterized a rat mild fluid percussion model of TBI (mLFP injury) that results in righting reflex response times (RRRTs) that are less than those characteristic of moderate to severe LFP injury and yet increase IL-1α/β and TNFα levels. Here we report that blockade of IL-1α/β and TNFα binding to IL-1R and TNFR1, respectively, reduced neuropathology in parietal cortex, hippocampus, and thalamus and improved outcome. IL-1β binding to the type I IL-1 receptor (IL-1R1) can be blocked by a recombinant form of the endogenous IL-1R antagonist IL-1Ra (Kineret). TNFα binding to the TNF receptor (TNFR) can be blocked by the recombinant fusion protein etanercept, made up of a TNFR2 peptide fused to an Fc portion of human IgG1. There was no benefit from the combined blockades compared with individual blockades or after repeated treatments for 11 days after injury compared with one treatment at 1 hr after injury, when measured at 6 hr or 18 days, based on changes in neuropathology. There was also no further enhancement of blockade benefits after 18 days. Given that both Kineret and etanercept given singly or in combination showed similar beneficial effects and that TNFα also has a gliotransmitter role regulating AMPA receptor traffic, thus confounding effects of a TNFα blockade, we chose to focus on a single treatment with Kineret. PMID:26172557

  8. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage

    PubMed Central

    Rolland, William B.; Lekic, Tim; Krafft, Paul R.; Hasegawa, Yu; Altay, Orhan; Hartman, Richard; Ostrowski, Robert; Manaenko, Anatol; Tang, Jiping; Zhang, John H.

    2013-01-01

    T-lymphocytes promote cerebral inflammation, thus aggravating neuronal injury after stroke. Fingolimod, a sphingosine 1-phosphate receptor analog, prevents the egress of lymphocytes from primary and secondary lymphoid organs. Based on these findings, we hypothesized fingolimod treatment would reduce the number of T-lymphocytes migrating into the brain, thereby ameliorating cerebral inflammation following experimental intracerebral hemorrhage (ICH). We investigated the effects of fingolimod in two well-established murine models of ICH, implementing intrastriatal infusions of either bacterial collagenase (cICH) or autologous blood (bICH). Furthermore, we tested the long term neurological improvements by Fingolimod in a collagenase-induced rat model of ICH. Fingolimod, in contrast to vehicle administration alone, improved neurological functions and reduced brain edema at 24 and 72 hours following experimental ICH in CD-1 mice (n=103; p<0.05). Significantly fewer lymphocytes were found in blood and brain samples of treated animals when compared to the vehicle group (p<0.05). Moreover, fingolimod treatment significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (INF-γ), and interleukin-17 (IL-17) in the mouse brain at 72 hours post-cICH (p<0.05 compared to vehicle). Long-term neurocognitive performance and histopathological analysis were evaluated in Sprague-Dawley rats between 8 and 10 weeks post-cICH (n=28). Treated rats showed reduced spatial and motor learning deficits, along with significantly reduced brain atrophy and neuronal cell loss within the basal ganglia (p<0.05 compared to vehicle). We conclude that fingolimod treatment ameliorated cerebral inflammation, at least to some extent, by reducing the availability and subsequent brain infiltration of T-lymphocytes, which improved the short and long-term sequelae after experimental ICH in rodents. PMID:23261767

  9. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage.

    PubMed

    Rolland, William B; Lekic, Tim; Krafft, Paul R; Hasegawa, Yu; Altay, Orhan; Hartman, Richard; Ostrowski, Robert; Manaenko, Anatol; Tang, Jiping; Zhang, John H

    2013-03-01

    T-lymphocytes promote cerebral inflammation, thus aggravating neuronal injury after stroke. Fingolimod, a sphingosine 1-phosphate receptor analog, prevents the egress of lymphocytes from primary and secondary lymphoid organs. Based on these findings, we hypothesized fingolimod treatment would reduce the number of T-lymphocytes migrating into the brain, thereby ameliorating cerebral inflammation following experimental intracerebral hemorrhage (ICH). We investigated the effects of fingolimod in two well-established murine models of ICH, implementing intrastriatal infusions of either bacterial collagenase (cICH) or autologous blood (bICH). Furthermore, we tested the long term neurological improvements by Fingolimod in a collagenase-induced rat model of ICH. Fingolimod, in contrast to vehicle administration alone, improved neurological functions and reduced brain edema at 24 and 72 h following experimental ICH in CD-1 mice (n=103; p<0.05). Significantly fewer lymphocytes were found in blood and brain samples of treated animals when compared to the vehicle group (p<0.05). Moreover, fingolimod treatment significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (INF-γ), and interleukin-17 (IL-17) in the mouse brain at 72 h post-cICH (p<0.05 compared to vehicle). Long-term neurocognitive performance and histopathological analysis were evaluated in Sprague-Dawley rats between 8 and 10 weeks post-cICH (n=28). Treated rats showed reduced spatial and motor learning deficits, along with significantly reduced brain atrophy and neuronal cell loss within the basal ganglia (p<0.05 compared to vehicle). We conclude that fingolimod treatment ameliorated cerebral inflammation, at least to some extent, by reducing the availability and subsequent brain infiltration of T-lymphocytes, which improved the short and long-term sequelae after experimental ICH in rodents. PMID:23261767

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

    PubMed Central

    2015-01-01

    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 substituents 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. PMID:26101573

  11. Isoflurane Suppresses Stress-Enhanced Fear Learning in a Rodent Model of Posttraumatic Stress Disorder

    PubMed Central

    Rau, Vinuta; Oh, Irene; Laster, Michael; Eger, Edmond I; Fanselow, Michael S.

    2009-01-01

    Background A minority of patients who experience awareness and/or pain during surgery subsequently develop posttraumatic stress disorder. In a rodent model of posttraumatic stress disorder, stress-enhanced fear learning (SEFL), rats are pre-exposed to a stressor of 15 footshocks. Subsequent exposure to a single footshock produces an enhanced fear response. This effect is akin to sensitized reactions shown by some posttraumatic stress disorder patients to cues previously associated with the traumatic event. Methods We studied the effect of isoflurane and nitrous oxide on SEFL. Rats were exposed to the inhaled anesthetic during or after a 15-footshock stressor. Then rats were given a single footshock in a different environment. Their fear response was quantified in response to the 15-footshock and single-footshock environments. SEFL longevity was tested by placing a 90-day period between the 15 footshocks and the single footshock. In addition, the intensity of the footshock was increased to evaluate treatment effectiveness. Results Increasing isoflurane concentrations decreased SEFL when given during, but not after, the stressor. At 0.40 minimum alveolar concentration, isoflurane given during the stressor blocked SEFL 90 days later. A three-fold increase in the stressor intensity increased the isoflurane concentration required to block SEFL to no more than 0.67 minimum alveolar concentration. As with isoflurane, nitrous oxide suppressed SEFL at a similar minimum alveolar concentration fraction. Conclusions These results suggest that sufficient concentrations (perhaps 0.67 minimum alveolar concentration or less) of an inhaled anesthetic may prevent SEFL. PMID:19212264

  12. Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models.

    PubMed

    Sasso, Oscar; Moreno-Sanz, Guillermo; Martucci, Cataldo; Realini, Natalia; Dionisi, Mauro; Mengatto, Luisa; Duranti, Andrea; Tarozzo, Glauco; Tarzia, Giorgio; Mor, Marco; Bertorelli, Rosalia; Reggiani, Angelo; Piomelli, Daniele

    2013-03-01

    Fatty acid ethanolamides (FAEs), which include palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), are endogenous agonists of peroxisome proliferator-activated receptor-α (PPAR-α) and important regulators of the inflammatory response. They are degraded in macrophages by the lysosomal cysteine amidase, N-acylethanolamine acid amidase (NAAA). Previous studies have shown that pharmacological inhibition of NAAA activity suppresses macrophage activation in vitro and causes marked anti-inflammatory effects in vivo, which is suggestive of a role for NAAA in the control of inflammation. It is still unknown, however, whether NAAA-mediated FAE deactivation might regulate pain signaling. The present study examined the effects of ARN077, a potent and selective NAAA inhibitor recently disclosed by our group, in rodent models of hyperalgesia and allodynia caused by inflammation or nerve damage. Topical administration of ARN077 attenuated, in a dose-dependent manner, heat hyperalgesia and mechanical allodynia elicited in mice by carrageenan injection or sciatic nerve ligation. The antinociceptive effects of ARN077 were prevented by the selective PPAR-α antagonist GW6471 and did not occur in PPAR-α-deficient mice. Furthermore, topical ARN077 reversed the allodynia caused by ultraviolet B radiation in rats, and this effect was blocked by pretreatment with GW6471. Sciatic nerve ligation or application of the proinflammatory phorbol ester 12-O-tetradecanoylphorbol 13-acetate decreased FAE levels in sciatic nerve and skin tissue, respectively. ARN077 reversed these biochemical effects. The results identify ARN077 as a potent inhibitor of intracellular NAAA activity, which is active in vivo by topical administration. The findings further suggest that NAAA regulates peripheral pain initiation by interrupting endogenous FAE signaling at PPAR-α. PMID:23218523

  13. ANTINOCICEPTIVE EFFECTS OF THE N-ACYLETHANOLAMINE ACID AMIDASE INHIBITOR ARN077 IN RODENT PAIN MODELS

    PubMed Central

    Sasso, Oscar; Moreno-Sanz, Guillermo; Martucci, Cataldo; Realini, Natalia; Dionisi, Mauro; Mengatto, Luisa; Duranti, Andrea; Tarozzo, Glauco; Tarzia, Giorgio; Mor, Marco; Bertorelli, Rosalia; Reggiani, Angelo; Piomelli, Daniele

    2013-01-01

    Fatty acid ethanolamides (FAEs), which include palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), are endogenous agonists of peroxisome proliferator-activated receptor-α (PPAR-α) and important regulators of the inflammatory response. They are degraded in macrophages by the lysosomal cysteine amidase, N-acylethanolamine acid amidase (NAAA). Previous studies have shown that pharmacological inhibition of NAAA activity suppresses macrophage activation in vitro and causes marked anti-inflammatory effects in vivo, which is suggestive of a role for NAAA in the control of inflammation. It is still unknown, however, whether NAAA-mediated FAE deactivation might regulate pain signaling. In the present study, we examined the effects of ARN077, a potent and selective NAAA inhibitor recently disclosed by our group, in rodent models of hyperalgesia and allodynia caused by inflammation or nerve damage. Topical administration of ARN077 attenuated, in a dose-dependent manner, heat hyperalgesia and mechanical allodynia elicited in mice by carrageenan injection or sciatic nerve ligation. The anti-nociceptive effects of ARN077 were prevented by the selective PPAR-α antagonist GW6471 and did not occur in PPAR-α-deficient mice. Furthermore, topical ARN077 reversed the allodynia caused by ultraviolet B-radiation in rats, and this effect was blocked by pretreatment with GW6471. Sciatic nerve ligation or application of the pro-inflammatory phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) decreased FAE levels in sciatic nerve and skin tissue, respectively. ARN077 reversed these biochemical effects. The results identify ARN077 as a potent inhibitor of intracellular NAAA activity, which is active in vivo by topical administration. The findings further suggest that NAAA regulates peripheral pain initiation by interrupting endogenous FAE signaling at PPAR-α. PMID:23218523

  14. A rodent model of rapid-onset diabetes induced by glucocorticoids and high-fat feeding.

    PubMed

    Shpilberg, Yaniv; Beaudry, Jacqueline L; D'Souza, Anna; Campbell, Jonathan E; Peckett, Ashley; Riddell, Michael C

    2012-09-01

    Glucocorticoids (GCs) are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone) produced in response to stressful conditions that are thought to increase the preference for calorie dense 'comfort' foods. If chronically elevated, GCs can contribute to the development of type 2 diabetes mellitus (T2DM), although the mechanisms for the diabetogenic effects are not entirely clear. The present study proposes a new rodent model to investigate the combined metabolic effects of elevated GCs and high-fat feeding on ectopic fat deposition and diabetes development. Male Sprague-Dawley rats (aged 7-8 weeks) received exogenous corticosterone or wax (placebo) pellets, implanted subcutaneously, and were fed either a standard chow diet (SD) or a 60% high-fat diet (HFD) for 16 days. Animals given corticosterone and a HFD (cort-HFD) had lower body weight and smaller relative glycolytic muscle mass, but increased relative epididymal mass, compared with controls (placebo-SD). Cort-HFD rats exhibited severe hepatic steatosis and increased muscle lipid deposition compared with placebo-SD animals. Moreover, cort-HFD animals were found to exhibit severe fasting hyperglycemia (60% increase), hyperinsulinemia (80% increase), insulin resistance (60% increase) and impaired β-cell response to oral glucose load (20% decrease) compared with placebo-SD animals. Thus, a metabolic syndrome or T2DM phenotype can be rapidly induced in young Sprague-Dawley rats by using exogenous GCs if a HFD is consumed. This finding might be valuable in examining the physiological and molecular mechanisms of GC-induced metabolic disease. PMID:22184636

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

    PubMed

    Andersen, Louise Bjørkholt; Golic, Michaela; Przybyl, Lukasz; Sorensen, Grith Lykke; Jørgensen, Jan Stener; Fruekilde, Palle; von Versen-Höynck, Frauke; Herse, Florian; Højskov, Carsten Schriver; Dechend, Ralf; Christesen, Henrik Thybo; Haase, Nadine

    2016-07-01

    Maternal vitamin D deficiency is proposed as a risk factor for preeclampsia in humans. We tested the hypothesis that vitamin D depletion aggravates and high supplementation ameliorates the preeclampsia phenotype in an established transgenic rat model of human renin-angiotensin system-mediated preeclampsia. Adult rat dams, transgenic for human angiotensinogen (hAGT) and mated with male rats transgenic for human renin (hREN), were fed either vitamin D-depleted chow (VDd) or enriched chow (VDh) 2 weeks before mating and during pregnancy. Mean blood pressure was recorded by tail-cuff, and 24-hour urine samples were collected in metabolic cages at days 6 and 18 of gestation. Rats were sacrificed at day 21 of gestation. Depleted dams (VDd) had negligible serum 25-hydroxyvitamin D2+3 levels (mean ± SEM; 2.95 ± 0.45 nmol/l vs. VDh 26.20 ± 2.88 nmol/l, P = .01), but in both groups, levels of 1,25(OH)2D3 remained below detection level of 25 pmol/l. Dietary vitamin D depletion did not aggravate hypertension (mean ± SEM BP, day 20 of gestation: 151.38 ± 5.65 mmHg VDd vs. 152.00 ± 4.10 mmHg VDh) or proteinuria. Fetal anthropometrics were similar between the groups, whereas VDd displayed lower placental:fetal weight ratios (0.15 vs. 0.16 g/g, P = .01) and increased sFlt-1/PlGF ratio. Expression of hREN was lower in placenta of VDd dams (0.82 ± 0.44 AU vs. 1.52 ± 0.15 AU, P = .04). Expression of key vitamin D metabolizing enzymes was unchanged. Dietary vitamin D intervention did not alter key aspects of the preeclampsia phenotype using the transgenic rodent model of human renin-angiotensin system-mediated pre-eclampsia, plausibly due to altered vitamin D metabolism or excretion in the transgenic rats. PMID:27450577

  16. Retinal Degeneration in a Rodent Model of Smith-Lemli-Opitz Syndrome

    PubMed Central

    Fliesler, Steven J.; Peachey, Neal S.; Richards, Michael J.; Nagel, Barbara A.; Vaughan, Dana K.

    2010-01-01

    Objective To assess the electrophysiologic, histologic, and biochemical features of an animal model of Smith-Lemli-Opitz syndrome (SLOS). Methods Sprague-Dawley rats were treated with AY9944, a selective inhibitor of 3β-hydroxysterol-Δ7-reductase (the affected enzyme in SLOS). Dark- and light-adapted electroretinograms were obtained from treated and control animals. From each animal, 1 retina was analyzed by microscopy, and the contralateral retina plus serum samples were analyzed for sterol composition. The main outcome measures were rod and cone electroretinographic amplitudes and implicit times, outer nuclear layer (ONL) thickness, rod outer segment length, pyknotic ONL nucleus counts, and the 7-dehydrocholesterol/ cholesterol mole ratio in the retina and serum. Results By 10 weeks’ postnatal age, rod and cone electroretinographic wave amplitudes in AY9944-treated animals were significantly reduced and implicit times were significantly increased relative to controls. Maximal rod photoresponse and gain values were reduced approximately 2-fold in treated animals relative to controls. The ONL thickness and average rod outer segment length were reduced by approximately 18% and 33%, respectively, and ONL pyknotic nucleus counts were approximately 4.5-fold greater in treated animals relative to controls. The retinal pigment epithelium of treated animals contained massive amounts of membranous/lipid inclusions not routinely observed in controls. The 7-dehydrocholesterol/cholesterol mole ratios in treated retinas and serum samples were approximately 5:1 and 9:1, respectively, whereas the ratios in control tissues were essentially zero. Conclusions This rodent model exhibits the key biochemical hallmarks associated with SLOS and displays electrophysiologic deficits comparable to or greater than those observed in the human disease. Clinical Relevance These results predict retinal degeneration in patients with SLOS, particularly those with the more severe (type II

  17. Between the primate and ‘reptilian’ brain: rodent models demonstrate the role of corticostriatal circuits in decision making

    PubMed Central

    Zador, Anthony; Wilbrecht, Linda

    2015-01-01

    Decision making can be defined as the flexible integration and transformation of information from the external world into action. Recently, the development of novel genetic tools and new behavioral paradigms has made it attractive to study behavior of all kinds in rodents. By some perspectives, rodents are not an acceptable model for the study of decision making due to their simpler behavior often attributed to their less extensive cortical development when compared to non-human primates. We argue that decision making can be approached with a common framework across species. We review insights from comparative anatomy that suggest the expansion of cortical-striatal connectivity is a key development in evolutionary increases in behavioral flexibility. We briefly review studies that establish a role for corticostriatal circuits in integrative decision making. Finally, we provide an overview of a few recent, highly complementary rodent decision making studies using genetic tools, revealing with new cellular and temporal resolution how, when and where information can be integrated and compared in striatal circuits to influence choice. PMID:25575943

  18. Multiple rodent models and behavioral measures reveal unexpected responses to FTY720 and DMF in experimental autoimmune encephalomyelitis.

    PubMed

    de Bruin, N M W J; Schmitz, K; Schiffmann, S; Tafferner, N; Schmidt, M; Jordan, H; Häußler, A; Tegeder, I; Geisslinger, G; Parnham, M J

    2016-03-01

    Experimental autoimmune encephalomyelitis (EAE) is a widely-used rodent model for multiple sclerosis (MS), but a single model can hardly capture all features of MS. We investigated whether behavioral parameters in addition to clinical motor function scores could be used to assess treatment efficacy during score-free intervals in the relapsing-remitting EAE model in SJL/J mice. We studied the effects of the clinical reference compounds FTY720 (fingolimod, 0.5mg/kg/day) and dimethyl fumarate (DMF, 20-30 mg/kg/day) on clinical scores in several rodent EAE models in order to generate efficacy profiles. SJL/J mice with relapsing-remitting EAE were studied using behavioral tests, including rotarod, gait analysis, locomotor activity and grip strength. SJL/J mice were also examined according to Crawley's sociability and preference for social novelty test. Prophylactic treatment with FTY720 prevented clinical scores in three of the four EAE rodent models: Dark Agouti (DA) and Lewis rats and C57BL/6J mice. Neither prophylactic nor late-therapeutic treatment with FTY720 reduced clinical scores or reversed deficits in the rotarod test in SJL/J mice, but we observed effects on motor functions and sociability in the absence of clinical scores. Prophylactic treatment with FTY720 improved the gait of SJL/J mice whereas late-therapeutic treatment improved manifestations of reduced social (re)cognition or preference for social novelty. DMF was tested in three EAE models and did not improve clinical scores at the dose used. These data indicate that improvements in behavioral deficits can occur in absence of clinical scores, which indicate subtle drug effects and may have translational value for human MS. PMID:26692368

  19. Surviving lethal septic shock without fluid resuscitation in a rodent model

    PubMed Central

    Li, Yongqing; Liu, Baoling; Fukudome, Eugene Y.; Kochanek, Ashley R.; Finkelstein, Robert A.; Chong, Wei; Jin, Guang; Lu, Jennifer; deMoya, Marc A.; Velmahos, George C.; Alam, Hasan B.

    2016-01-01

    Background We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, before a lethal dose of lipopolysaccharide (LPS) improves survival in mice. The purpose of the present study was to determine whether SAHA treatment would attenuate LPS-induced shock and improve survival when given postinsult in a rodent model. Methods C57BL/6J mice were intraperitoneally (IP) injected with LPS (30 mg/kg), and 2 hours later randomized into 2 groups: (1) vehicle animals (n = 10) received dimethyl sulfoxide (DMSO) solution only; and (2) SAHA animals (n = 10) were given SAHA (50 mg/kg, IP) in DMSO solution. Survival was monitored over the next 7 days. In a second study, LPS-injected mice were treated with either DMSO or SAHA as described, and normal (sham) animals served as controls. Lungs were harvested at 4, 6, and 8 hours after LPS injection for analysis of gene expression. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA post-treatment on LPS-induced inflammation using enzyme-linked immunosorbent assay. Results All LPS-injected mice that received the vehicle agent alone died within 24 hours, whereas the SAHA-treated animals displayed a significant improvement in 1 week survival (80% vs 0%; P < .001). LPS insult significantly enhanced gene expression of MyD88, tumor necrosis factor (TNF)-α and interleukin (IL)-6, and was associated with an increased protein secretion of TNF-α and IL-6 into the cell culture medium. In contrast, SAHA treatment significantly attenuated all of these LPS-related alterations. Conclusion We report for the first time that administration of SAHA (50 mg/kg IP) after a lethal dose of LPS significantly improves long-term survival, and attenuates expression of the proinflammatory mediators TNF-α and IL-6. Furthermore, our data suggest that the anti-inflammatory effects of SAHA may be due to downregulation of the MyD88-dependent pathway, and decreased

  20. Wireless control of intraspinal microstimulation in a rodent model of paralysis

    PubMed Central

    Kasasbeh, Aimen; Mallory, Grant W.; Hachmann, Jan T.; Dube, John R.; Kimble, Christopher J.; Lobel, Darlene A.; Bieber, Allan; Jeong, Ju Ho; Bennet, Kevin E.; Lujan, J. Luis

    2015-01-01

    OBJECT Despite a promising outlook, existing intraspinal microstimulation (ISMS) techniques for restoring functional motor control after spinal cord injury are not yet suitable for use outside a controlled laboratory environment. Thus, successful application of ISMS therapy in humans will require the use of versatile chronic neurostimulation systems. The objective of this study was to establish proof of principle for wireless control of ISMS to evoke controlled motor function in a rodent model of complete spinal cord injury. METHODS The lumbar spinal cord in each of 17 fully anesthetized Sprague-Dawley rats was stimulated via ISMS electrodes to evoke hindlimb function. Nine subjects underwent complete surgical transection of the spinal cord at the T-4 level 7 days before stimulation. Targeting for both groups (spinalized and control) was performed under visual inspection via dorsal spinal cord landmarks such as the dorsal root entry zone and the dorsal median fissure. Teflon-insulated stimulating platinum-iridium microwire electrodes (50 μm in diameter, with a 30- to 60-μm exposed tip) were implanted within the ventral gray matter to an approximate depth of 1.8 mm. Electrode implantation was performed using a free-hand delivery technique (n = 12) or a Kopf spinal frame system (n = 5) to compare the efficacy of these 2 commonly used targeting techniques. Stimulation was controlled remotely using a wireless neurostimulation control system. Hindlimb movements evoked by stimulation were tracked via kinematic markers placed on the hips, knees, ankles, and paws. Postmortem fixation and staining of the spinal cord tissue were conducted to determine the final positions of the stimulating electrodes within the spinal cord tissue. RESULTS The results show that wireless ISMS was capable of evoking controlled and sustained activation of ankle, knee, and hip muscles in 90% of the spinalized rats (n = 9) and 100% of the healthy control rats (n = 8). No functional differences

  1. Effects of AgRP inhibition on energy balance and metabolism in rodent models.

    PubMed

    Dutia, Roxanne; Kim, Andrea J; Modes, Matthew; Rothlein, Robert; Shen, Jane M; Tian, Ye Edward; Ihbais, Jumana; Victory, Sam F; Valcarce, Carmen; Wardlaw, Sharon L

    2013-01-01

    Activation of brain melanocortin-4 receptors (MC4-R) by α-melanocyte-stimulating hormone (MSH) or inhibition by agouti-related protein (AgRP) regulates food intake and energy expenditure and can modulate neuroendocrine responses to changes in energy balance. To examine the effects of AgRP inhibition on energy balance, a small molecule, non-peptide compound, TTP2515, developed by TransTech Pharma, Inc., was studied in vitro and in rodent models in vivo. TTP2515 prevented AgRP from antagonizing α-MSH-induced increases in cAMP in HEK 293 cells overexpressing the human MC4-R. When administered to rats by oral gavage TTP2515 blocked icv AgRP-induced increases in food intake, weight gain and adiposity and suppression of T4 levels. In both diet-induced obese (DIO) and leptin-deficient mice, TTP2515 decreased food intake, weight gain, adiposity and respiratory quotient. TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice. However, when tested in AgRP KO mice, TTP2515 also suppressed food intake and weight gain during HFD feeding. In several studies TTP2515 increased T4 but not T3 levels, however this was also observed in AgRP KO mice. TTP2515 also attenuated refeeding and weight gain after fasting, an effect not evident in AgRP KO mice when administered at moderate doses. This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug. TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding. Thus the usefulness of this drug in treating obesity deserves further exploration, to define the AgRP dependent and independent mechanisms by which TTP2515 exerts its effects on energy balance. PMID:23762342

  2. Developmental rodent models of fear and anxiety: from neurobiology to pharmacology

    PubMed Central

    Ganella, Despina E; Kim, Jee Hyun

    2014-01-01

    Anxiety disorders pose one of the biggest threats to mental health in the world, and they predominantly emerge early in life. However, research of anxiety disorders and fear-related memories during development has been largely neglected, and existing treatments have been developed based on adult models of anxiety. The present review describes animal models of anxiety disorders across development and what is currently known of their pharmacology. To summarize, the underlying mechanisms of intrinsic ‘unlearned’ fear are poorly understood, especially beyond the period of infancy. Models using ‘learned’ fear reveal that through development, rats exhibit a stress hyporesponsive period before postnatal day 10, where they paradoxically form odour-shock preferences, and then switch to more adult-like conditioned fear responses. Juvenile rats appear to forget these aversive associations more easily, as is observed with the phenomenon of infantile amnesia. Juvenile rats also undergo more robust extinction, until adolescence where they display increased resistance to extinction. Maturation of brain structures, such as the amygdala, prefrontal cortex and hippocampus, along with the different temporal recruitment and involvement of various neurotransmitter systems (including NMDA, GABA, corticosterone and opioids) are responsible for these developmental changes. Taken together, the studies described in this review highlight that there is a period early in development where rats appear to be more robust in overcoming adverse early life experience. We need to understand the fundamental pharmacological processes underlying anxiety early in life in order to take advantage of this period for the treatment of anxiety disorders. 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:24527726

  3. Rodent models in bone-related research: the relevance of calvarial defects in the assessment of bone regeneration strategies.

    PubMed

    Gomes, P S; Fernandes, M H

    2011-01-01

    In vivo research with animal models has been a preferred experimental system in bone-related biomedical research since, by approximation, it allows relevant data gathering regarding physiological and pathological conditions that could be of use to establish more effective clinical interventions. Animal models, and more specifically rodent models, have been extensively used and have contributed greatly to the development and establishment of a wide range of translational approaches aiming to regenerate the bone tissue. In this regard, the calvarial defect model has found great application in basic and applied research, nonetheless the controversial rationalization for the use of critical size defects - defects that are unable to report spontaneous healing - or subcritical size defects in the proposed applications. Accordingly, this work aims to review the advantages and limitations of the use of rodent models in biomedical bone-related research, emphasizing the problematic issues of the use of calvarial critical and subcritical size defects. Additionally, surgical protocols for the establishment of both defects in rat calvarial bone, as well as the description and exemplification of the most frequently used techniques to access the bone tissue repair, are portrayed. PMID:21156759

  4. A protocol for phenotypic detection and characterization of vascular cells of different origins in a lung neovascularization model in rodents

    PubMed Central

    Jones, Rosemary C; Capen, Diane E; Cohen, Kenneth S; Munn, Lance L; Jain, Rakesh K; Duda, Dan G

    2009-01-01

    The goal of many current studies of neovascularization is to define the phenotype of vascular cell populations of different origins and to determine how such cells promote assembly of vascular channel. Here, we describe a protocol to immunophenotype vascular cells by high-resolution imaging and by fluorescence-activated flow cytometry in an in vivo rodent model of pulmonary microvascular remodeling. Analysis of cells by this combined approach will characterize their phenotype, quantify their number and identify their role in the assembly of vascular channels. PMID:18323810

  5. Rodent repellency

    USGS Publications Warehouse

    DeWitt, J.B.; Welch, J.F.; Bellack, E.

    1950-01-01

    In the course of studies involving more than 2,500 chemical repellents, it has been found that certain groups of- compounds containing nitrogen or sulfur are repellent to rats under the , test conditions and it appears probable that some of these compounds might be used for the protection of packaged goods against rodent attacks. Additional tests to determine optimum methods of application will be necessary before final evaluation of these compounds will be possible and extensive field trials will be required to establish the degree of protection which may be afforded by the use of these materials. Pending such final evaluation, it may be assumed that the results,to date offer a means of selecting the most promising types of'materials for further trial....On the basis of the test data, it appears that some amine derivative, such as a salt of some organic, acid, or a complex with trinitrobenzene or with a metallic salt of a dialkyl dithiocarbamic acid might offer promise of protection of packaging materials against rodent attacks....Protection might be obtained through the use of certain 'physical deterrents' such as plastics, waxes or drying oils.

  6. Social isolation in prairie voles induces behaviors relevant to negative affect: toward the development of a rodent model focused on co-occurring depression and anxiety

    PubMed Central

    Grippo, Angela J.; Wu, Kevin D.; Hassan, Iman; Carter, C. Sue

    2008-01-01

    Recent evidence suggests substantial overlap between mood and anxiety disorders, both in clinical presentation and associated features. A theoretical framework to account for this overlap focuses on negative affectivity, defined as the disposition to experience negative emotional states, including fear, sadness and guilt. This model has been successful in explaining the co-occurrence of depressive and anxiety disorders in humans. As a next step, development of an animal model focused on both depression- and anxiety-relevant behaviors may advance understanding of depression-anxiety symptom overlap, relations of these disorders with associated medical conditions and responses to treatment. The current study was designed to investigate inducible and quantifiable depression- and anxiety-like behaviors in prairie voles (Microtus ochrogaster). Adult, female prairie voles were exposed to 4 weeks of social pairing (control) or isolation, an established stressor for socially monogamous mammals (including humans). Operational measures of depression (sucrose intake and behaviors in the forced swim test), anxiety (behaviors in the elevated plus maze) and aggression (responses to an unrelated prairie vole pup) were investigated. Social isolation induced a progressive decline in sucrose intake and increased immobility time during the forced swim test. Social isolation also decreased the amount of time spent in the open arms of the elevated plus maze, and increased pup-directed attack behavior. The current findings suggest that isolation induces behaviors reflecting elevated negative affect. These results may provide a foundation for creating a rodent model to examine the mechanisms underlying comorbid mood and anxiety disorders. PMID:17935206

  7. Air gun impactor--a novel model of graded white matter spinal cord injury in rodents.

    PubMed

    Marcol, Wiesław; Slusarczyk, Wojciech; Gzik, Marek; Larysz-Brysz, Magdalena; Bobrowski, Michał; Grynkiewicz-Bylina, Beata; Rosicka, Paulina; Kalita, Katarzyna; Węglarz, Władysław; Barski, Jarosław J; Kotulska, Katarzyna; Labuzek, Krzysztof; Lewin-Kowalik, Joanna

    2012-10-01

    Understanding mechanisms of spinal cord injury and repair requires a reliable experimental model. We have developed a new device that produces a partial damage of spinal cord white matter by means of a precisely adjusted stream of air applied under high pressure. This procedure is less invasive than standard contusion or compression models and does not require surgical removal of vertebral bones. We investigated the effects of spinal cord injury made with our device in 29 adult rats, applying different experimental parameters. The rats were divided into three groups in respect to the applied force of the blast wave. Functional outcome and histopathological effects of the injury were analyzed during 12-week follow-up. The lesions were also examined by means of magnetic resonance imaging (MRI) scans. The weakest stimulus produced transient hindlimb paresis with no cyst visible in spinal cord MRI scans, whereas the strongest was associated with permanent neurological deficit accompanied by pathological changes resembling posttraumatic syringomyelia. Obtained data revealed that our apparatus provided a spinal cord injury animal model with structural changes very similar to that present in patients after moderate spinal cord trauma. PMID:22711195

  8. An ex vivo rat eye model to aid development of high-resolution retina imaging devices for rodents

    NASA Astrophysics Data System (ADS)

    van Oterendorp, Christian; Martin, Keith R.; Zhong, Jiang Jian; Diaz-Santana, Luis

    2010-09-01

    High resolution in vivo retinal imaging in rodents is becoming increasingly important in eye research. Development of suitable imaging devices currently requires many lengthy animal procedures. We present an ex vivo rat model eye with fluorescently labelled retinal ganglion cells (RGC) and nerve fibre bundles that reduces the need for animal procedures while preserving key properties of the living rat eye. Optical aberrations and scattering of four model eyes and eight live rat eyes were quantified using a Shack-Hartmann sensor. Fluorescent images from RGCs were obtained using a prototype scanning laser ophthalmoscope. The wavefront aberration root mean square value without defocus did not significantly differ between model and living eyes. Higher order aberrations were slightly higher but RGC image quality was comparable to published in vivo work. Overall, the model allows a large reduction in number and duration of animal procedures required to develop new in vivo retinal imaging devices.

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

    SciTech Connect

    Schlosser, Paul M. Sasso, Alan F.

    2014-10-15

    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 of 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.

  10. Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice.

    PubMed

    Castagné, Vincent; Moser, Paul; Roux, Sylvain; Porsolt, Roger D

    2011-04-01

    The development of antidepressants requires simple rodent behavioral tests for initial screening before undertaking more complex preclinical tests and clinical evaluation. Presented in the unit are two widely used screening tests used for antidepressants, the forced swim (also termed behavioral despair) test in the rat and mouse, and the tail suspension test in the mouse. These tests have good predictive validity and allow rapid and economical detection of substances with potential antidepressant-like activity. The behavioral despair and the tail suspension tests are based on the same principle: measurement of the duration of immobility when rodents are exposed to an inescapable situation. The majority of clinically used antidepressants decrease the duration of immobility. Antidepressants also increase the latency to immobility, and this additional measure can increase the sensitivity of the behavioral despair test in the mouse for certain classes of antidepressant. Testing of new substances in the behavioral despair and tail suspension tests allows a simple assessment of their potential antidepressant activity by the measurement of their effect on immobility. PMID:21462162

  11. Factors influencing the cognitive and neural effects of hormone treatment during aging in a rodent model

    PubMed Central

    Chisholm, Nioka C.; Juraska, Janice M.

    2013-01-01

    Whether hormone treatment alters brain structure or has beneficial effects on cognition during aging has recently become a topic of debate. Although previous research has indicated that hormone treatment benefits memory in menopausal women, several newer studies have shown no effect or detrimental effects. These inconsistencies emphasize the need to evaluate the role of hormones in protecting against age-related cognitive decline in an animal model. Importantly, many studies investigating the effects of estrogen and progesterone on cognition and related brain regions have used young adult animals, which respond differently than aged animals. However, when only the studies that have examined the effects of hormone treatment in an aging model are reviewed, there are still varied behavioral and neural outcomes. This article reviews some of the important factors that can influence the behavioral and neural outcomes of hormone treatment including the type of estrogen administered, whether or not estrogen is combined with progesterone and if so, the type of progesterone used, as well as the route, mode, and length of treatment. How these factors influence cognitive outcomes highlights the importance of study design and avoiding generalizations from a small number of studies. PMID:23419893

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

    PubMed

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

    2015-06-01

    Panic attacks (PAs), the core feature of panic disorder, represent a common phenomenon in the general adult population and are associated with a considerable decrease in quality of life and high health care costs. To date, the underlying pathophysiology of PAs is not well understood. A unique feature of PAs is that they represent a rare example of a psychopathological phenomenon that can be reliably modeled in the laboratory in panic disorder patients and healthy volunteers. The most effective techniques to experimentally trigger PAs are those that acutely disturb the acid-base homeostasis in the brain: inhalation of carbon dioxide (CO2), hyperventilation, and lactate infusion. This review particularly focuses on the use of CO2 inhalation in humans and rodents as an experimental model of panic. Besides highlighting the different methodological approaches, the cardio-respiratory and the endocrine responses to CO2 inhalation are summarized. In addition, the relationships between CO2 level, changes in brain pH, the serotonergic system, and adaptive physiological and behavioral responses to CO2 exposure are presented. We aim to present an integrated psychological and neurobiological perspective. Remaining gaps in the literature and future perspectives are discussed. PMID:25930682

  13. A rapid and versatile method for the isolation, purification and cryogenic storage of Schwann cells from adult rodent nerves

    PubMed Central

    Andersen, Natalia D.; Srinivas, Shruthi; Piñero, Gonzalo; Monje, Paula V.

    2016-01-01

    We herein developed a protocol for the rapid procurement of adult nerve-derived Schwann cells (SCs) that was optimized to implement an immediate enzymatic dissociation of fresh nerve tissue while maintaining high cell viability, improving yields and minimizing fibroblast and myelin contamination. This protocol introduces: (1) an efficient method for enzymatic cell release immediately after removal of the epineurium and extensive teasing of the nerve fibers; (2) an adaptable drop-plating method for selective cell attachment, removal of myelin debris, and expansion of the initial SC population in chemically defined medium; (3) a magnetic-activated cell sorting purification protocol for rapid and effective fibroblast elimination; and (4) an optional step of cryopreservation for the storage of the excess of cells. Highly proliferative SC cultures devoid of myelin and fibroblast growth were obtained within three days of nerve processing. Characterization of the initial, expanded, and cryopreserved cell products confirmed maintenance of SC identity, viability and growth rates throughout the process. Most importantly, SCs retained their sensitivity to mitogens and potential for differentiation even after cryopreservation. To conclude, this easy-to-implement and clinically relevant protocol allows for the preparation of expandable homogeneous SC cultures while minimizing time, manipulation of the cells, and exposure to culture variables. PMID:27549422

  14. A rapid and versatile method for the isolation, purification and cryogenic storage of Schwann cells from adult rodent nerves.

    PubMed

    Andersen, Natalia D; Srinivas, Shruthi; Piñero, Gonzalo; Monje, Paula V

    2016-01-01

    We herein developed a protocol for the rapid procurement of adult nerve-derived Schwann cells (SCs) that was optimized to implement an immediate enzymatic dissociation of fresh nerve tissue while maintaining high cell viability, improving yields and minimizing fibroblast and myelin contamination. This protocol introduces: (1) an efficient method for enzymatic cell release immediately after removal of the epineurium and extensive teasing of the nerve fibers; (2) an adaptable drop-plating method for selective cell attachment, removal of myelin debris, and expansion of the initial SC population in chemically defined medium; (3) a magnetic-activated cell sorting purification protocol for rapid and effective fibroblast elimination; and (4) an optional step of cryopreservation for the storage of the excess of cells. Highly proliferative SC cultures devoid of myelin and fibroblast growth were obtained within three days of nerve processing. Characterization of the initial, expanded, and cryopreserved cell products confirmed maintenance of SC identity, viability and growth rates throughout the process. Most importantly, SCs retained their sensitivity to mitogens and potential for differentiation even after cryopreservation. To conclude, this easy-to-implement and clinically relevant protocol allows for the preparation of expandable homogeneous SC cultures while minimizing time, manipulation of the cells, and exposure to culture variables. PMID:27549422

  15. Transplantation of human neural stem cells restores cognition in an immunodeficient rodent model of traumatic brain injury.

    PubMed

    Haus, Daniel L; López-Velázquez, Luci; Gold, Eric M; Cunningham, Kelly M; Perez, Harvey; Anderson, Aileen J; Cummings, Brian J

    2016-07-01

    Traumatic brain injury (TBI) in humans can result in permanent tissue damage and has been linked to cognitive impairment that lasts years beyond the initial insult. Clinically effective treatment strategies have yet to be developed. Transplantation of human neural stem cells (hNSCs) has the potential to restore cognition lost due to injury, however, the vast majority of rodent TBI/hNSC studies to date have evaluated cognition only at early time points, typically <1month post-injury and cell transplantation. Additionally, human cell engraftment and long-term survival in rodent models of TBI has been difficult to achieve due to host immunorejection of the transplanted human cells, which confounds conclusions pertaining to transplant-mediated behavioral improvement. To overcome these shortfalls, we have developed a novel TBI xenotransplantation model that utilizes immunodeficient athymic nude (ATN) rats as the host recipient for the post-TBI transplantation of human embryonic stem cell (hESC) derived NSCs and have evaluated cognition in these animals at long-term (≥2months) time points post-injury. We report that immunodeficient ATN rats demonstrate hippocampal-dependent spatial memory deficits (Novel Place, Morris Water Maze), but not non-spatial (Novel Object) or emotional/anxiety-related (Elevated Plus Maze, Conditioned Taste Aversion) deficits, at 2-3months post-TBI, confirming that ATN rats recapitulate some of the cognitive deficits found in immunosufficient animal strains. Approximately 9-25% of transplanted hNSCs survived for at least 5months post-transplantation and differentiated into mature neurons (NeuN, 18-38%), astrocytes (GFAP, 13-16%), and oligodendrocytes (Olig2, 11-13%). Furthermore, while this model of TBI (cortical impact) targets primarily cortex and the underlying hippocampus and generates a large lesion cavity, hNSC transplantation facilitated cognitive recovery without affecting either lesion volume or total spared cortical or hippocampal

  16. Fear Extinction in Rodents

    PubMed Central

    Chang, Chun-hui; Knapska, Ewelina; Orsini, Caitlin A.; Rabinak, Christine A.; Zimmerman, Joshua M.; Maren, Stephen

    2009-01-01

    Pavlovian conditioning paradigms have become important model systems for understanding the neuroscience of behavior. In particular, studies of the extinction of Pavlovian fear responses are yielding important information about the neural substrates of anxiety disorders in humans. These studies are germane to understanding the neural mechanisms underlying behavioral interventions that suppress fear, including exposure therapy. This chapter described detailed behavioral protocols for examining the nature and properties of fear extinction in laboratory rodents. PMID:19340814

  17. Transitional versus surgical menopause in a rodent model: etiology of ovarian hormone loss impacts memory and the acetylcholine system.

    PubMed

    Acosta, Jazmin I; Mayer, Loretta; Talboom, Joshua S; Tsang, Candy Wing S; Smith, Constance J; Enders, Craig K; Bimonte-Nelson, Heather A

    2009-09-01

    Clinical research suggests that type of ovarian hormone loss at menopause influences cognition. Until recently ovariectomy (OVX) has been the primary rodent model to examine effects of ovarian hormone loss on cognition. This model limits evaluations to abrupt and complete ovarian hormone loss, modeling less than 13% of women who receive surgical menopause. The majority of women do not have their ovaries surgically removed and undergo transitional hormone loss via ovarian follicular depletion. 4-Vinylcyclohexene-diepoxide (VCD) produces gradual ovarian follicular depletion in the rodent, with hormone profiles more similar to naturally menopausal women vs. OVX. We directly compared VCD and OVX models to examine whether type of hormone loss (transitional vs. surgical) impacted cognition as assessed on a maze battery as well as the cholinergic system tested via scopolamine mnemonic challenge and brain acetylcholinesterase activity. Middle-aged rats received either sham surgery, OVX surgery, VCD, or VCD then OVX to assess effects of removal of residual ovarian output after transitional menopause and follicular depletion. VCD-induced transitional menopause impaired learning of a spatial recent memory task; surgical removal of residual ovarian hormones by OVX abolished this negative effect of transitional menopause. Furthermore, transitional menopause before OVX was better for memory than an abrupt loss of hormones via OVX only. Surgical ovarian hormone loss, regardless of menopause history, increased hippocampal acetylcholinesterase activity. Circulating gonadotropin and androstenedione levels were related to cognitive competence. Collectively, findings suggest that in the rat, initiation of transitional menopause before surgical ovary removal can benefit mnemonic function and could obviate some negative cognitive consequences of surgical menopause alone. PMID:19470706

  18. Deep brain stimulation improves behavior and modulates neural circuits in a rodent model of schizophrenia.

    PubMed

    Bikovsky, Lior; Hadar, Ravit; Soto-Montenegro, María Luisa; Klein, Julia; Weiner, Ina; Desco, Manuel; Pascau, Javier; Winter, Christine; Hamani, Clement

    2016-09-01

    Schizophrenia is a debilitating psychiatric disorder with a significant number of patients not adequately responding to treatment. Deep brain stimulation (DBS) is a surgical technique currently investigated for medically-refractory psychiatric disorders. Here, we use the poly I:C rat model of schizophrenia to study the effects of medial prefrontal cortex (mPFC) and nucleus accumbens (Nacc) DBS on two behavioral schizophrenia-like deficits, i.e. sensorimotor gating, as reflected by disrupted prepulse inhibition (PPI), and attentional selectivity, as reflected by disrupted latent inhibition (LI). In addition, the neurocircuitry influenced by DBS was studied using FDG PET. We found that mPFC- and Nacc-DBS alleviated PPI and LI abnormalities in poly I:C offspring, whereas Nacc- but not mPFC-DBS disrupted PPI and LI in saline offspring. In saline offspring, mPFC-DBS increased metabolism in the parietal cortex, striatum, ventral hippocampus and Nacc, while reducing it in the brainstem, cerebellum, hypothalamus and periaqueductal gray. Nacc-DBS, on the other hand, increased activity in the ventral hippocampus and olfactory bulb and reduced it in the septal area, brainstem, periaqueductal gray and hypothalamus. In poly I:C offspring changes in metabolism following mPFC-DBS were similar to those recorded in saline offspring, except for a reduced activity in the brainstem and hypothalamus. In contrast, Nacc-DBS did not induce any statistical changes in brain metabolism in poly I:C offspring. Our study shows that mPFC- or Nacc-DBS delivered to the adult progeny of poly I:C treated dams improves deficits in PPI and LI. Despite common behavioral responses, stimulation in the two targets induced different metabolic effects. PMID:27302677

  19. Synergistic effect of 5-hydroxytryptamine 3 and neurokinin 1 receptor antagonism in rodent models of somatic and visceral pain.

    PubMed

    Greenwood-Van Meerveld, Beverley; Mohammadi, Ehsan; Tyler, Karl; Pietra, Claudio; Bee, Lucy A; Dickenson, Anthony

    2014-10-01

    Synergistic activity has been observed between serotonergic 5-hydroxytryptamine 3 (5-HT3) and tachykinergic neurokinin 1 (NK1) receptor-mediated responses. This study investigated the efficacy of a 5-HT3 antagonist, palonosetron, and a NK1 antagonist, netupitant, alone or in combination in rodent models of somatic and visceral colonic hypersensitivity. In a rat model of experimental neuropathic pain, somatic hypersensitivity was quantified by the number of ipsilateral paw withdrawals to a von Frey filament (6g). Electrophysiologic responses were recorded in the dorsal horn neurons after mechanical or thermal stimuli. Acute colonic hypersensitivity was induced experimentally in rats by infusing dilute acetic acid (0.6%) directly into the colon. Colonic sensitivity was assessed by a visceromotor behavioral response quantified as the number of abdominal contractions in response to graded isobaric pressures (0-60 mm Hg) of colorectal distension. Palonosetron or netupitant was administered alone or in combination via oral gavage. When dosed alone, both significantly reduced somatic sensitivity, decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation, and caused significant (P < 0.05) inhibition of colonic hypersensitivity in a dose-dependent manner. The combined administration of palonosetron and netupitant at doses that were ineffective alone significantly reduced both somatic and visceral sensitivity and decreased the evoked response of spinal dorsal horn neurons to mechanical or thermal stimulation. In summary, the combination of palonosetron with a NK1 receptor antagonist showed synergistic analgesic activity in rodent models of somatic and visceral hypersensitivity, and may prove to be a useful therapeutic approach to treat pain associated with irritable bowel syndrome. PMID:25077526

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

    PubMed

    Schlosser, Paul M; Sasso, Alan F

    2014-10-15

    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 of 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. PMID:25151221

  1. Effects of Gaps Induced Into the ACL Tendon Graft on Tendon-Bone Healing in a Rodent ACL Reconstruction Model

    PubMed Central

    Lovric, Vedran; Kanazawa, Tomonoshin; Nakamura, Yoshinari; Oliver, Rema A.; Yu, Yan; Walsh, William Robert

    2011-01-01

    Summary Graft necrosis following ACL reconstruction is often associated with the use of autologous grafts. Host cells rather than graft cells contribute to the repair of the tendon-bone interface and the remodeling of the autologous graft. The native tendon-bone interface is not recreated and the biomechanical properties are not restored back to native values. We examined the effects of introducing gaps within the tendon graft prior to ACL reconstruction in a rodent model. We hypothesised that gaps will make physical way for host cells to infiltrate and repopulate the graft and thus enhance healing. Animals were sacrificed at seven, fourteen, and twenty-eight days for biomechanical testing and histology. Our findings indicate that graft necrosis, usually observed in the initial two weeks of the healing process, is averted. Histological observations showed that tendon-bone healing stages were hastened however this didn’t translate into improved biomechanical properties. PMID:23738254

  2. 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

  3. Microglia activation: one of the checkpoints in the CNS inflammation caused by Angiostrongylus cantonensis infection in rodent model.

    PubMed

    Wei, Jie; Wu, Feng; He, Ai; Zeng, Xin; Ouyang, Li-si; Liu, Ming-she; Zheng, Huan-qin; Lei, Wan-long; Wu, Zhong-dao; Lv, Zhi-yue

    2015-09-01

    Angiostrongylus cantonensis (A. cantonensis) is a rodent nematode. Adult worms of A. cantonensis live in the pulmonary arteries of rats; humans are non-permissive hosts like the mice. The larva cannot develop into an adult worm and only causes serious eosinophilic meningitis or meningo-encephalitis if humans or mice eat food containing larva of A. cantonensis in the third stage. The differing consequences largely depend on differing immune responses of hosts to parasite during A. cantonensis invasion and development. To further understand the reasons why mice and rats attain different outcomes in A. cantonensis infection, we used the HE staining to observe the pathological changes of infected mice and rats. In addition, we measured mRNA levels of some cytokines (IL-5, IL-6, IL-13, Eotaxin, IL-4, IL-10, TGF-β, IFN-γ, IL-17A, TNF-α, IL-1β, and iNOS) in brain tissues of mice and rats by real-time PCR. The result showed that brain inflammation in mice was more serious than in rats. Meanwhile, mRNA expression levels of IL-6, IL-1β, TNF-α, and iNOS increased after mice were infected. In contrast, mRNA levels of these cytokines in rats brain tissues decreased at post- infection 21 days. These cytokines mostly were secreted by activated microglia in central nervous system. Microglia of mice and rats were showed by Iba-1 (microglia marker) staining. In micee brains, microglia got together and had more significant activation than in rats brains. The results demonstrate that mice and rats have different CNS inflammation after infection by A. cantonensis, and it is in line with other researchers' reported findings. In conclusion, it is suggested that microglia activation is probably to be one of the most important factors in angiostrongyliasis from our study. PMID:26002828

  4. Adult Children of Alcoholics: A Counseling Model.

    ERIC Educational Resources Information Center

    Crawford, Robert L.; Phyfer, Ann Quinn

    1988-01-01

    Notes that adult children of alcoholics attending college present unique problems and opportunities to the college counselor. Presents a treatment model for serving such students which identifies four survivor roles and their manifestations, and suggests counseling techniques for each role. (Author/NB)

  5. Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring

    PubMed Central

    Irazabal, Maria V.; Mishra, Prasanna K.; Torres, Vicente E.; Macura, Slobodan I.

    2015-01-01

    Several in vivo pre-clinical studies in Polycystic Kidney Disease (PKD) utilize orthologous rodent models to identify and study the genetic and molecular mechanisms responsible for the disease, and are very convenient for rapid drug screening and testing of promising therapies. A limiting factor in these studies is often the lack of efficient non-invasive methods for sequentially analyzing the anatomical and functional changes in the kidney. Magnetic resonance imaging (MRI) is the current gold standard imaging technique to follow autosomal dominant polycystic kidney disease (ADPKD) patients, providing excellent soft tissue contrast and anatomic detail and allowing Total Kidney Volume (TKV) measurements.A major advantage of MRI in rodent models of PKD is the possibility for in vivo imaging allowing for longitudinal studies that use the same animal and therefore reducing the total number of animals required. In this manuscript, we will focus on using Ultra-high field (UHF) MRI to non-invasively acquire in vivo images of rodent models for PKD. The main goal of this work is to introduce the use of MRI as a tool for in vivo phenotypical characterization and drug monitoring in rodent models for PKD. PMID:26132821

  6. Use of Ultra-high Field MRI in Small Rodent Models of Polycystic Kidney Disease for In Vivo Phenotyping and Drug Monitoring.

    PubMed

    Irazabal, Maria V; Mishra, Prasanna K; Torres, Vicente E; Macura, Slobodan I

    2015-01-01

    Several in vivo pre-clinical studies in Polycystic Kidney Disease (PKD) utilize orthologous rodent models to identify and study the genetic and molecular mechanisms responsible for the disease, and are very convenient for rapid drug screening and testing of promising therapies. A limiting factor in these studies is often the lack of efficient non-invasive methods for sequentially analyzing the anatomical and functional changes in the kidney. Magnetic resonance imaging (MRI) is the current gold standard imaging technique to follow autosomal dominant polycystic kidney disease (ADPKD) patients, providing excellent soft tissue contrast and anatomic detail and allowing Total Kidney Volume (TKV) measurements.A major advantage of MRI in rodent models of PKD is the possibility for in vivo imaging allowing for longitudinal studies that use the same animal and therefore reducing the total number of animals required. In this manuscript, we will focus on using Ultra-high field (UHF) MRI to non-invasively acquire in vivo images of rodent models for PKD. The main goal of this work is to introduce the use of MRI as a tool for in vivo phenotypical characterization and drug monitoring in rodent models for PKD. PMID:26132821

  7. The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models.

    PubMed

    Shiraishi, Eri; Suzuki, Kazunori; Harada, Akina; Suzuki, Noriko; Kimura, Haruhide

    2016-03-01

    Cognitive deficits in various domains, including recognition memory, attention, impulsivity, working memory, and executive function, substantially affect functional outcomes in patients with schizophrenia. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a potent and selective phosphodiesterase 10A inhibitor that produces antipsychotic-like effects in rodent models of schizophrenia. We evaluated the effects of TAK-063 on multiple cognitive functions associated with schizophrenia using naïve and drug-perturbed rodents. TAK-063 at 0.1 and 0.3 mg/kg p.o. improved time-dependent memory decay in object recognition in naïve rats. TAK-063 at 0.1 and 0.3 mg/kg p.o. increased accuracy rate, and TAK-063 at 0.3 mg/kg p.o. reduced impulsivity in a five-choice serial reaction time task in naïve rats. N-methyl-d-aspartate receptor antagonists, such as phencyclidine and MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], were used to induce working memory deficits relevant to schizophrenia in animals. TAK-063 at 0.3 mg/kg p.o. attenuated both phencyclidine-induced working memory deficits in a Y-maze test in mice and MK-801-induced working memory deficits in an eight-arm radial maze task in rats. An attentional set-shifting task using subchronic phencyclidine-treated rats was used to assess the executive function. TAK-063 at 0.3 mg/kg p.o. reversed cognitive deficits in extradimensional shifts. These findings suggest that TAK-063 has a potential to ameliorate deficits in multiple cognitive domains impaired in schizophrenia. PMID:26675680

  8. Monocarboxylate Transporter 2 and Stroke Severity in a Rodent Model of Sleep Apnea

    PubMed Central

    Wang, Yang; Guo, Shang-Z; Bonen, Arend; Li, Richard C.; Kheirandish-Gozal, Leila; Zhang, Shelley X.L.; Brittian, Kenneth R.; Gozal, David

    2011-01-01

    Stroke is not only more prevalent but is also associated with more severe adverse functional outcomes among patients with sleep apnea. Monocarboxylate transporters (MCT) are important regulators of cellular bioenergetics, have been implicated in brain susceptibility to acute severe hypoxia (ASH), and could underlie the unfavorable prognosis of cerebrovascular accidents in sleep apnea patients. Rodents were exposed to either intermittent hypoxia (IH) during sleep, a characteristic feature of sleep apnea, or to sustained hypoxia (SH), and expression of MCT1 and MCT2 was assessed. In addition, the functional recovery to MCAO in rats and hMCT2 transgenic mice and of hippocampal slices subjected to ASH was assessed, as well as the effects of MCT blocker and MCT2 antisense oligonucleotides and siRNAs. IH, but not SH, induced significant reductions in MCT2 expression over time at both the mRNA and protein levels, and in the functional recovery of hippocampal slices subjected to ASH. Similarly, MCAO-induced infarcts were significantly greater in IH-exposed rats and mice, and over-expression of hMCT2 in mice markedly attenuated the adverse effects of IH. Exogenous pyruvate treatment reduced infarct volumes in normoxic rats but not in IH-exposed rats. Administration of he MCT2 blocker 4CN, but not the MCT1 antagonist pCMBS, increased infarct size. Thus, prolonged exposures to IH mimicking sleep apnea are associated with increased CNS vulnerability to ischemia that is mediated, at least in part, by concomitant decreases in the expression and function of MCT2. Efforts to develop agonists of MCT2 should provide opportunities to ameliorate the overall outcome of stroke. PMID:21753001

  9. Age Progression of Neuropathological Markers in the Brain of the Chilean Rodent Octodon degus, a Natural Model of Alzheimer's Disease.

    PubMed

    Inestrosa, Nibaldo C; Ríos, Juvenal A; Cisternas, Pedro; Tapia-Rojas, Cheril; Rivera, Daniela S; Braidy, Nady; Zolezzi, Juan M; Godoy, Juan A; Carvajal, Francisco J; Ardiles, Alvaro O; Bozinovic, Francisco; Palacios, Adrián G; Sachdev, Perminder S

    2015-11-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of age-related dementia worldwide. Several models for AD have been developed to provide information regarding the initial changes that lead to degeneration. Transgenic mouse models recapitulate many, but not all, of the features of AD, most likely because of the high complexity of the pathology. In this context, the validation of a wild-type animal model of AD that mimics the neuropathological and behavioral abnormalities is necessary. In previous studies, we have reported that the Chilean rodent Octodon degus could represent a natural model for AD. In the present work, we further describe the age-related neurodegeneration observed in the O. degus brain. We report some histopathological markers associated with the onset progression of AD, such as glial activation, increase in oxidative stress markers, neuronal apoptosis and the expression of the peroxisome proliferative-activated receptor γ coactivator-1α (PGC-1α). With these results, we suggest that the O. degus could represent a new model for AD research and a powerful tool in the search for therapeutic strategies against AD. PMID:25351914

  10. Exendin-4 reverts behavioural and neurochemical dysfunction in a pre-motor rodent model of Parkinson's disease with noradrenergic deficit.

    PubMed

    Rampersaud, N; Harkavyi, A; Giordano, G; Lever, R; Whitton, J; Whitton, Ps

    2012-12-01

    BACKGROUND AND PURPOSE Parkinson's disease (PD) is characterized by progressive dopaminergic cell loss; however, the noradrenergic system exhibits degeneration as well. Noradrenergic deficit in PD may be responsible for certain non-motor symptoms of the pathology, including psychiatric disorders and cognitive decline. The aim of this study was to generate a pre-motor rodent model of PD with noradrenergic denervation, and to assess whether treatment with exendin-4 (EX-4), a glucagon-like peptide 1 receptor agonist, could reverse impairment exhibited by our model. EXPERIMENTAL APPROACH We generated a model of PD utilizing N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine and 6-hydroxydopamine to create partial lesions of both the noradrenergic and dopaminergic systems respectively. We then assessed the validity of our model using an array of behavioural paradigms and biochemical techniques. Finally, we administered EX-4 over a 1 week period to determine therapeutic efficacy. KEY RESULTS Our model exhibits anhedonia and decreased object recognition as indicated by a decrease in sucrose preference, increased immobility in the forced swim test and reduced novel object exploration. Tissue and extracellular dopamine and noradrenaline were reduced in the frontal cortex and striatum. TH+ cell counts decreased in the locus coeruleus and substantia nigra. Treatment with EX-4 reversed behavioural impairment and restored extracellular/tissue levels of both dopamine and noradrenaline and TH+ cell counts. CONCLUSION AND IMPLICATIONS We conclude that early treatment with EX-4 may reverse certain neuropsychiatric dysfunction and restore dopamine and noradrenaline content. PMID:22774922

  11. Investigating the underlying mechanisms of aberrant behaviors in bipolar disorder from patients to models: Rodent and human studies.

    PubMed

    van Enkhuizen, Jordy; Geyer, Mark A; Minassian, Arpi; Perry, William; Henry, Brook L; Young, Jared W

    2015-11-01

    Psychiatric patients with bipolar disorder suffer from states of depression and mania, during which a variety of symptoms are present. Current treatments are limited and neurocognitive deficits in particular often remain untreated. Targeted therapies based on the biological mechanisms of bipolar disorder could fill this gap and benefit patients and their families. Developing targeted therapies would benefit from appropriate animal models which are challenging to establish, but remain a vital tool. In this review, we summarize approaches to create a valid model relevant to bipolar disorder. We focus on studies that use translational tests of multivariate exploratory behavior, sensorimotor gating, decision-making under risk, and attentional functioning to discover profiles that are consistent between patients and rodent models. Using this battery of translational tests, similar behavior profiles in bipolar mania patients and mice with reduced dopamine transporter activity have been identified. Future investigations should combine other animal models that are biologically relevant to the neuropsychiatric disorder with translational behavioral assessment as outlined here. This methodology can be utilized to develop novel targeted therapies that relieve symptoms for more patients without common side effects caused by current treatments. PMID:26297513

  12. Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction.

    PubMed

    Noonan, Michele A; Bulin, Sarah E; Fuller, Dwain C; Eisch, Amelia J

    2010-01-01

    Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis, the hippocampus, is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat intravenous cocaine self-administration in rodents, a clinically relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation, or locomotion, because sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Furthermore, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse. PMID:20053911

  13. Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction

    PubMed Central

    Noonan, Michele A.; Bulin, Sarah; Fuller, Dwain C.; Eisch, Amelia J.

    2010-01-01

    Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis - the hippocampus - is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat i.v. cocaine self-administration in rodents, a clinicall-relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation or locomotion, as sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Further, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse. PMID:20053911

  14. Multi-Object Model-based Multi-Atlas Segmentation for Rodent Brains using Dense Discrete Correspondences

    PubMed Central

    Lee, Joohwi; Kim, Sun Hyung; Styner, Martin

    2016-01-01

    The delineation of rodent brain structures is challenging due to low-contrast multiple cortical and subcortical organs that are closely interfacing to each other. Atlas-based segmentation has been widely employed due to its ability to delineate multiple organs at the same time via image registration. The use of multiple atlases and subsequent label fusion techniques has further improved the robustness and accuracy of atlas-based segmentation. However, the accuracy of atlas-based segmentation is still prone to registration errors; for example, the segmentation of in vivo MR images can be less accurate and robust against image artifacts than the segmentation of post mortem images. In order to improve the accuracy and robustness of atlas-based segmentation, we propose a multi-object, model-based, multi-atlas segmentation method. We first establish spatial correspondences across atlases using a set of dense pseudo-landmark particles. We build a multi-object point distribution model using those particles in order to capture inter- and intra-subject variation among brain structures. The segmentation is obtained by fitting the model into a subject image, followed by label fusion process. Our result shows that the proposed method resulted in greater accuracy than comparable segmentation methods, including a widely used ANTs registration tool. PMID:27065200

  15. Multi-object model-based multi-atlas segmentation for rodent brains using dense discrete correspondences

    NASA Astrophysics Data System (ADS)

    Lee, Joohwi; Kim, Sun Hyung; Styner, Martin

    2016-03-01

    The delineation of rodent brain structures is challenging due to low-contrast multiple cortical and subcortical organs that are closely interfacing to each other. Atlas-based segmentation has been widely employed due to its ability to delineate multiple organs at the same time via image registration. The use of multiple atlases and subsequent label fusion techniques has further improved the robustness and accuracy of atlas-based segmentation. However, the accuracy of atlas-based segmentation is still prone to registration errors; for example, the segmentation of in vivo MR images can be less accurate and robust against image artifacts than the segmentation of post mortem images. In order to improve the accuracy and robustness of atlas-based segmentation, we propose a multi-object, model-based, multi-atlas segmentation method. We first establish spatial correspondences across atlases using a set of dense pseudo-landmark particles. We build a multi-object point distribution model using those particles in order to capture inter- and intra- subject variation among brain structures. The segmentation is obtained by fitting the model into a subject image, followed by label fusion process. Our result shows that the proposed method resulted in greater accuracy than comparable segmentation methods, including a widely used ANTs registration tool.

  16. The impact of prenatal alcohol exposure on social, cognitive and affective behavioral domains: Insights from rodent models.

    PubMed

    Marquardt, Kristin; Brigman, Jonathan L

    2016-03-01

    Fetal Alcohol Spectrum Disorders (FASD) are characterized by deficits in working memory, response inhibition, and behavioral flexibility. However, the combination and severity of impairments are highly dependent upon maternal ethanol consumption patterns, which creates a complex variety of manifestations. Rodent models have been essential in identifying behavioral endpoints of prenatal alcohol exposure (PAE). However, experimental model outcomes are extremely diverse based on level, pattern, timing, and method of ethanol exposure, as well as the behavioral domain assayed and paradigm used. Therefore, comparisons across studies are difficult and there is currently no clear comprehensive behavioral phenotype of PAE. This lack of defined cognitive and behavioral phenotype is a contributing factor to the difficulty in identifying FASD individuals. The current review aims to critically examine preclinical behavioral outcomes in the social, cognitive, and affective domains in terms of the PAE paradigm, with a special emphasis on dose, timing, and delivery, to establish a working model of behavioral impairment. In addition, this review identifies gaps in our current knowledge and proposes future areas of research that will advance knowledge in the field of PAE outcomes. Understanding the complex behavioral phenotype, which results from diverse ethanol consumption will allow for development of better diagnostic tools and more critical evaluation of potential treatments for FASD. PMID:26992695

  17. Rodents And Other Gnawers.

    ERIC Educational Resources Information Center

    Naturescope, 1986

    1986-01-01

    Presents information about rodents and lagomorphs, including definitions and the characteristics of these animals. Contains teaching activities such as "Habitats for Hoppers,""Cartoon Gnawers," and "The Great Rodent Expedition." Reproducible handouts for two of the activities are provided. (TW)

  18. Zebrafish assessment of cognitive improvement and anxiolysis: Filling the gap between in vitro and rodent models for drug development

    PubMed Central

    Levin, Edward D.

    2015-01-01

    Zebrafish can provide a valuable animal model to screen potential cognitive enhancing and anxiolytic drugs. They are economical and can provide a relatively quick indication of possible functional efficacy. In as much as they have a complex nervous system and elaborate behavioral repertoire, zebrafish can provide a good intermediate model between in vitro receptor and cell-based assays and classic mammalian models for drug screening. In addition, the variety of molecular tools available in zebrafish makes them outstanding models for helping to determine the neuromolecular mechanisms for psychoactive drugs. However, to use zebrafish as a translational model we must have validated, sensitive and efficient behavioral tests. In a series of studies, our lab has developed tests of cognitive function and stress response, which are sensitive to drug effects in a similar manner as rodent models and humans for cognitive enhancement and alleviating stress response. In particular, the three-chamber task for learning and memory was shown to be sensitive to the cognitive enhancing effects of nicotine and has been useful in helping to determine neural mechanisms crucial for nicotinic-induced cognitive enhancement. The novel tank diving test was shown to be a valid and efficient test of stress response. It is sensitive to the reduction of stress-related behaviors of the anxiolytic drugs diazepam and buspirone but not chlordiazepoxide. Nicotine also causes stress alleviating effects which can be interpreted as anxiolytic effects. Zebrafish models of behavioral pharmacology can be useful to efficiently screen test compounds for drug development and can be useful for helping to determine the mechanisms crucial for new therapeutic treatments of neurobehavioral impairments. PMID:21615262

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

    PubMed

    Fernandes, Hélio B; Silva, Francilene V; Passos, Flávia Franceli B; Bezerra, Roosevelt D S; Chaves, Mariana H; Oliveira, Francisco A; Oliveira, Rita C Meneses

    2010-01-01

    Parkia platycephala Benth. (Leguminosae--Mimosoideae), popularly known as "visgueira", fava bean tree or "fava-de-bolota", is widely found in the Northern and Northeastern regions of Brazil. Its pods are used as cattle food supplement in the drought period. Compounds with a gastroprotective activity were obtained from the genus Parkia. Therefore, this study aimed at investigating the gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves (Pp-EtOH), as well as evaluating its possible mechanisms of action in experimental ulcer induction models. Lesions were induced by absolute ethanol, ethanol-HCl, ischemia-reperfusion and indomethacin in rodents. Pp-EtOH showed a protective effect in the lesion models (66, 48 and 52%, respectively), but it was not able to protect gastric mucosa against indomethacin-induced lesions. Results show a possible participation of the NO-synthase pathway in the gastroprotection and an antioxidant activity, by the increase of the catalase activity. The participation of prostaglandins and potassium channels sensitive to ATP in the gastroprotective effect of Pp-EtOH seems less likely to occur. More comprehensive studies, therefore, should be carried out to elucidate the antiulcerative effects of this promising natural product against this gastrointestinal disorder. PMID:21526272

  20. Early adverse experience as a developmental risk factor for later psychopathology: evidence from rodent and primate models.

    PubMed

    Sánchez, M M; Ladd, C O; Plotsky, P M

    2001-01-01

    Increasing evidence supports the view that the interaction of perinatal exposure to adversity with individual genetic liabilities may increase an individual's vulnerability to the expression of psycho- and physiopathology throughout life. The early environment appears to program some aspects of neurobiological development and, in turn, behavioral, emotional, cognitive, and physiological development. Several rodent and primate models of early adverse experience have been analyzed in this review, including those that "model" maternal separation or loss, abuse or neglect, and social deprivation. Accumulating evidence shows that these early traumatic experiences are associated with long-term alterations in coping style, emotional and behavioral regulation. neuroendocrine responsiveness to stress, social "fitness,' cognitive function, brain morphology, neurochemistry, and expression levels of central nervous system genes that have been related to anxiety and mood disorders. Studies are underway to identify important aspects of adverse early experience, such as (a) the existence of "sensitive periods" during development associated with alterations in particular output systems. (b) the presence of "windows of opportunity" during which targeted interventions (e.g., nurturant parenting or supportive-enriching environment) may prevent or reverse dysfunction, (c) the identity of gene polymorphisms contributing to the individual's variability in vulnerability, and (d) a means to translate the timing of these developmental "sensitive periods" across species. PMID:11523842

  1. Long-term vascular access ports as a means of sedative administration in a rodent fMRI survival model

    PubMed Central

    Hettinger, Patrick C.; Li, Rupeng; Yan, Ji-Geng; Matloub, Hani S.; Cho, Younghoon R.; Pawela, Christopher P.; Rowe, Daniel B.; Hyde, James S.

    2011-01-01

    The purpose of this study is to develop a rodent functional magnetic resonance imaging (fMRI) survival model with the use of heparin-coated vascular access devices. Such a model would ease the administration of sedative agents, reduce the number of animals required in a survival experiment, and eliminate animal-to-animal variability seen in previous designs. Seven male Sprague-Dawley rats underwent surgical placement of an MRI-compatible vascular access port, followed by implantable electrode placement on the right median nerve. Functional MRI during nerve stimulation and resting-state functional connectivity MRI (fcMRI) were performed at times 0, 2, 4, 8, and 12 weeks postoperatively using a 9.4 T scanner. Anesthesia was maintained using intravenous dexmedetomidine and reversed using atipamezole. There were no fatalities or infectious complications during this study. All vascular access ports remained patent. Blood oxygen level dependent (BOLD) activation by electrical stimulation of the median nerve using implanted electrodes was seen within the forelimb sensory region (S1FL) for all animals at all time points. The number of activated voxels decreased at time points 4 and 8 weeks, returning to a normal level at 12 weeks, which is attributed to scar tissue formation and resolution around the embedded electrode. The applications of this experiment extend far beyond the scope of peripheral nerve experimentation. These vascular access ports can be applied to any survival MRI study requiring repeated medication administration, intravenous contrast, or blood sampling. PMID:21726581

  2. H2S production by reactive oxygen species in the carotid body triggers hypertension in a rodent model of sleep apnea.

    PubMed

    Yuan, Guoxiang; Peng, Ying-Jie; Khan, Shakil A; Nanduri, Jayasri; Singh, Amritha; Vasavda, Chirag; Semenza, Gregg L; Kumar, Ganesh K; Snyder, Solomon H; Prabhakar, Nanduri R

    2016-01-01

    Sleep apnea is a prevalent respiratory disease in which episodic cessation of breathing causes intermittent hypoxia. Patients with sleep apnea and rodents exposed to intermittent hypoxia exhibit hypertension. The carotid body senses changes in blood O2 concentrations, and an enhanced carotid body chemosensory reflex contributes to hypertension in sleep apnea patients. A rodent model of intermittent hypoxia that mimics blood O2 saturation profiles of patients with sleep apnea has shown that increased generation of reactive oxygen species (ROS) in the carotid body enhances the chemosensory reflex and triggers hypertension. CO generated by heme oxygenase-2 (HO-2) induces a signaling pathway that inhibits hydrogen sulfide (H2S) production by cystathionine γ-lyase (CSE), leading to suppression of carotid body activity. We found that ROS inhibited CO generation by HO-2 in the carotid body and liver through a mechanism that required Cys(265) in the heme regulatory motif of heterologously expressed HO-2. We showed that ROS induced by intermittent hypoxia inhibited CO production and increased H2S concentrations in the carotid body, which stimulated its neural activity. In rodents, blockade of H2S synthesis by CSE, by either pharmacologic or genetic approaches, inhibited carotid body activation and hypertension induced by intermittent hypoxia. Thus, our results indicate that oxidant-induced inactivation of HO-2, which leads to increased CSE-dependent H2S production in the carotid body, is a critical trigger of hypertension in rodents exposed to intermittent hypoxia. PMID:27531649

  3. Multivariate models of adult Pacific salmon returns.

    PubMed

    Burke, Brian J; Peterson, William T; Beckman, Brian R; Morgan, Cheryl; Daly, Elizabeth A; Litz, Marisa

    2013-01-01

    Most modeling and statistical approaches encourage simplicity, yet ecological processes are often complex, as they are influenced by numerous dynamic environmental and biological factors. Pacific salmon abundance has been highly variable over the last few decades and most forecasting models have proven inadequate, primarily because of a lack of understanding of the processes affecting variability in survival. Better methods and data for predicting the abundance of returning adults are therefore required to effectively manage the species. We combined 31 distinct indicators of the marine environment collected over an 11-year period into a multivariate analysis to summarize and predict adult spring Chinook salmon returns to the Columbia River in 2012. In addition to forecasts, this tool quantifies the strength of the relationship between various ecological indicators and salmon returns, allowing interpretation of ecosystem processes. The relative importance of indicators varied, but a few trends emerged. Adult returns of spring Chinook salmon were best described using indicators of bottom-up ecological processes such as composition and abundance of zooplankton and fish prey as well as measures of individual fish, such as growth and condition. Local indicators of temperature or coastal upwelling did not contribute as much as large-scale indicators of temperature variability, matching the spatial scale over which salmon spend the majority of their ocean residence. Results suggest that effective management of Pacific salmon requires multiple types of data and that no single indicator can represent the complex early-ocean ecology of salmon. PMID:23326586

  4. Multivariate Models of Adult Pacific Salmon Returns

    PubMed Central

    Burke, Brian J.; Peterson, William T.; Beckman, Brian R.; Morgan, Cheryl; Daly, Elizabeth A.; Litz, Marisa

    2013-01-01

    Most modeling and statistical approaches encourage simplicity, yet ecological processes are often complex, as they are influenced by numerous dynamic environmental and biological factors. Pacific salmon abundance has been highly variable over the last few decades and most forecasting models have proven inadequate, primarily because of a lack of understanding of the processes affecting variability in survival. Better methods and data for predicting the abundance of returning adults are therefore required to effectively manage the species. We combined 31 distinct indicators of the marine environment collected over an 11-year period into a multivariate analysis to summarize and predict adult spring Chinook salmon returns to the Columbia River in 2012. In addition to forecasts, this tool quantifies the strength of the relationship between various ecological indicators and salmon returns, allowing interpretation of ecosystem processes. The relative importance of indicators varied, but a few trends emerged. Adult returns of spring Chinook salmon were best described using indicators of bottom-up ecological processes such as composition and abundance of zooplankton and fish prey as well as measures of individual fish, such as growth and condition. Local indicators of temperature or coastal upwelling did not contribute as much as large-scale indicators of temperature variability, matching the spatial scale over which salmon spend the majority of their ocean residence. Results suggest that effective management of Pacific salmon requires multiple types of data and that no single indicator can represent the complex early-ocean ecology of salmon. PMID:23326586

  5. Salubrinal reduces oxidative stress, neuroinflammation and impulsive-like behavior in a rodent model of traumatic brain injury.

    PubMed

    Logsdon, Aric F; Lucke-Wold, Brandon P; Nguyen, Linda; Matsumoto, Rae R; Turner, Ryan C; Rosen, Charles L; Huber, Jason D

    2016-07-15

    Traumatic brain injury (TBI) is the leading cause of trauma related morbidity in the developed world. TBI has been shown to trigger secondary injury cascades including endoplasmic reticulum (ER) stress, oxidative stress, and neuroinflammation. The link between secondary injury cascades and behavioral outcome following TBI is poorly understood warranting further investigation. Using our validated rodent blast TBI model, we examined the interaction of secondary injury cascades following single injury and how these interactions may contribute to impulsive-like behavior after a clinically relevant repetitive TBI paradigm. We targeted these secondary pathways acutely following single injury with the cellular stress modulator, salubrinal (SAL). We examined the neuroprotective effects of SAL administration on significantly reducing ER stress: janus-N-terminal kinase (JNK) phosphorylation and C/EBP homology protein (CHOP), oxidative stress: superoxide and carbonyls, and neuroinflammation: nuclear factor kappa beta (NFκB) activity, inducible nitric oxide synthase (iNOS) protein expression, and pro-inflammatory cytokines at 24h post-TBI. We then used the more clinically relevant repeat injury paradigm and observed elevated NFκB and iNOS activity. These injury cascades were associated with impulsive-like behavior measured on the elevated plus maze. SAL administration attenuated secondary iNOS activity at 72h following repetitive TBI, and most importantly prevented impulsive-like behavior. Overall, these results suggest a link between secondary injury cascades and impulsive-like behavior that can be modulated by SAL administration. PMID:27131989

  6. Sleep alterations following exposure to stress predict fear-associated memory impairments in a rodent model of PTSD.

    PubMed

    Vanderheyden, William M; George, Sophie A; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R

    2015-08-01

    Sleep abnormalities, such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of posttraumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stressor exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops. SPS resulted in acute increases in REM sleep and transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. Reductions in theta (4-10 Hz) and sigma (10-15 Hz) band power during transition to REM sleep also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008

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

    PubMed

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

    2015-06-15

    Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Although a comorbidity of PCOS is obesity, many are lean. We hypothesized that increased saturated fat consumption and obesity would exacerbate metabolic and stress indices in a rodent model of PCOS. Female rats were implanted with the nonaromatizable androgen dihydrotestosterone (DHT) or placebo pellets prior to puberty. Half of each group was maintained ad libitum on either a high-fat diet (HFD; 40% butter fat calories) or nutrient-matched low-fat diet (LFD). Irrespective of diet, DHT-treated animals gained more body weight, had irregular cycles, and were glucose intolerant compared with controls on both diets. HFD/DHT animals had the highest levels of fat mass and insulin resistance. DHT animals demonstrated increased anxiety-related behavior in the elevated plus maze by decreased distance traveled and time in the open arms. HFD consumption increased immobility during the forced-swim test. DHT treatment suppressed diurnal corticosterone measurements in both diet groups. In parallel, DHT treatment significantly dampened stress responsivity to a mild stressor. Brains of DHT animals showed attenuated c-Fos activation in the ventromedial hypothalamus and arcuate nucleus; irrespective of DHT-treatment, however, all HFD animals had elevated hypothalamic paraventricular nucleus c-Fos activation. Whereas hyperandrogenism drives overall body weight gain, glucose intolerance, anxiety behaviors, and stress responsivity, HFD consumption exacerbates the effect of androgens on adiposity, insulin resistance, and depressive behaviors. PMID:26078189

  8. Expression of galanin and its receptors are perturbed in a rodent model of mild, blast-induced traumatic brain injury.

    PubMed

    Kawa, Lizan; Barde, Swapnali; Arborelius, Ulf P; Theodorsson, Elvar; Agoston, Denes; Risling, Mårten; Hökfelt, Tomas

    2016-05-01

    The symptomatology, mood and cognitive disturbances seen in post-traumatic stress disorder (PTSD) and mild blast-induced traumatic brain injury (mbTBI) overlap considerably. However the pathological mechanisms underlying the two conditions are currently unknown. The neuropeptide galanin has been suggested to play a role in the development of stress and mood disorders. Here we applied bio- and histochemical methods with the aim to elucidate the nature of any changes in the expression of galanin and its receptors in a rodent model of mbTBI. In situ hybridization and quantitative polymerase chain reaction studies revealed significant, injury-induced changes, in some cases lasting at least for one week, in the mRNA levels of galanin and/or its three receptors, galanin receptor 1-3 (GalR1-3). Such changes were seen in several forebrain regions, and the locus coeruleus. In the ventral periaqueductal gray GalR1 mRNA levels were increased, while GalR2 were decreased. Analysis of galanin peptide levels using radioimmunoassay demonstrated an increase in several brain regions including the locus coeruleus, dorsal hippocampal formation and amygdala. These findings suggest a role for the galanin system in the endogenous response to mbTBI, and that pharmacological studies of the effects of activation or inhibition of different galanin receptors in combination with functional assays of behavioral recovery may reveal promising targets for new therapeutic strategies in mbTBI. PMID:26928087

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

    PubMed Central

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

    2015-01-01

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

  10. Sleep Alterations Following Exposure to Stress Predict Fear-Associated Memory Impairments in a Rodent Model of PTSD

    PubMed Central

    Vanderheyden, William M.; George, Sophie A.; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R.

    2015-01-01

    Sleep abnormalities such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of post-traumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating these sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stress exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops in rats. SPS resulted in acutely increased REM sleep, transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. We also report reductions in theta (4–10 Hz) and sigma (10–15 Hz) band power during transition to REM sleep which also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008

  11. A Review on Chemical-Induced Inflammatory Bowel Disease Models in Rodents

    PubMed Central

    Randhawa, Puneet Kaur; Singh, Kavinder; Singh, Nirmal

    2014-01-01

    Ulcerative colitis and Crohn's disease are a set of chronic, idiopathic, immunological and relapsing inflammatory disorders of the gastrointestinal tract referred to as inflammatory bowel disorder (IBD). Although the etiological factors involved in the perpetuation of IBD remain uncertain, development of various animal models provides new insights to unveil the onset and the progression of IBD. Various chemical-induced colitis models are widely used on laboratory scale. Furthermore, these models closely mimic morphological, histopathological and symptomatical features of human IBD. Among the chemical-induced colitis models, trinitrobenzene sulfonic acid (TNBS)-induced colitis, oxazolone induced-colitis and dextran sulphate sodium (DSS)-induced colitis models are most widely used. TNBS elicits Th-1 driven immune response, whereas oxazolone predominantly exhibits immune response of Th-2 phenotype. DSS-induced colitis model also induces changes in Th-1/Th-2 cytokine profile. The present review discusses the methodology and rationale of using various chemical-induced colitis models for evaluating the pathogenesis of IBD. PMID:25177159

  12. Retinal Ganglion Cell Damage in an Experimental Rodent Model of Blast-Mediated Traumatic Brain Injury

    PubMed Central

    Mohan, Kabhilan; Kecova, Helga; Hernandez-Merino, Elena; Kardon, Randy H.; Harper, Matthew M.

    2013-01-01

    Purpose. To evaluate retina and optic nerve damage following experimental blast injury. Methods. Healthy adult mice were exposed to an overpressure blast wave using a custom-built blast chamber. The effects of blast exposure on retina and optic nerve function and structure were evaluated using the pattern electroretinogram (pERG), spectral domain optical coherence tomography (OCT), and the chromatic pupil light reflex. Results. Assessment of the pupil response to light demonstrated decreased maximum pupil constriction diameter in blast-injured mice using red light or blue light stimuli 24 hours after injury compared with baseline in the eye exposed to direct blast injury. A decrease in the pupil light reflex was not observed chronically following blast exposure. We observed a biphasic pERG decrease with the acute injury recovering by 24 hours postblast and the chronic injury appearing at 4 months postblast injury. Furthermore, at 3 months following injury, a significant decrease in the retinal nerve fiber layer was observed using OCT compared with controls. Histologic analysis of the retina and optic nerve revealed punctate regions of reduced cellularity in the ganglion cell layer and damage to optic nerves. Additionally, a significant upregulation of proteins associated with oxidative stress was observed acutely following blast exposure compared with control mice. Conclusions. Our study demonstrates that decrements in retinal ganglion cell responses can be detected after blast injury using noninvasive functional and structural tests. These objective responses may serve as surrogate tests for higher CNS functions following traumatic brain injury that are difficult to quantify. PMID:23620426

  13. Tempol ameliorates pharyngeal dilator muscle dysfunction in a rodent model of chronic intermittent hypoxia.

    PubMed

    Skelly, J Richard; Edge, Deirdre; Shortt, Christine M; Jones, James F X; Bradford, Aidan; O'Halloran, Ken D

    2012-02-01

    Respiratory muscle dysfunction is implicated in the pathophysiology of obstructive sleep apnea syndrome (OSAS), an oxidative stress disorder prevalent in men. Pharmacotherapy for OSAS is an attractive option, and antioxidant treatments may prove beneficial. We examined the effects of chronic intermittent hypoxia (CIH) on breathing and pharyngeal dilator muscle structure and function in male and female rats. Additionally, we tested the efficacy of antioxidant treatment in preventing (chronic administration) or reversing (acute administration) CIH-induced effects in male rats. Adult male and female Wistar rats were exposed to alternating cycles of normoxia and hypoxia (90 s each; Fi(O(2)) = 5% O(2) at nadir; Sa(O(2)) ∼ 80%) or sham treatment for 8 h/d for 9 days. Tempol (1 mM, superoxide dismutase mimetic) was administered to subgroups of sham- and CIH-treated animals. Breathing was assessed by whole-body plethysmography. Sternohyoid muscle contractile and endurance properties were examined in vitro. Muscle fiber type and cross-sectional area and the activity of key metabolic enzymes were determined. CIH decreased sternohyoid muscle force in male rats only. This was not attributable to fiber transitions or alterations in oxidative or glycolytic enzyme activity. Muscle weakness after CIH was prevented by chronic Tempol supplementation and was reversed by acute antioxidant treatment in vitro. CIH increased normoxic ventilation in male rats only. Sex differences exist in the effects of CIH on the respiratory system, which may contribute to the higher prevalence of OSAS in male subjects. Antioxidant treatment may be beneficial as an adjunct OSAS therapy. PMID:21868712

  14. In Vivo Rodent Models of Skeletal Muscle Adaptation to Decreased Use

    PubMed Central

    Cho, Su Han; Kim, Jang Hoe

    2016-01-01

    Skeletal muscle possesses plasticity and adaptability to external and internal physiological changes. Due to these characteristics, skeletal muscle shows dramatic changes depending on its response to stimuli such as physical activity, nutritional changes, disease status, and environmental changes. Modulation of the rate of protein synthesis/degradation plays an important role in atrophic responses. The purpose of this review is to describe different features of skeletal muscle adaptation with various models of deceased use. In this review, four models were addressed: immobilization, spinal cord transection, hindlimb unloading, and aging. Immobilization is a form of decreased use in which skeletal muscle shows electrical activity, tension development, and motion. These results differ by muscle group. Spinal cord transection was selected to simulate spinal cord injury. Similar to the immobilization model, dramatic atrophy occurs in addition to fiber type conversion in this model. Despite the fact that electromyography shows unremarkable changes in muscle after hindlimb unloading, decreased muscle mass and contractile force are observed. Lastly, aging significantly decreases the numbers of muscle fibers and motor units. Skeletal muscle responses to decreased use include decreased strength, decreased fiber numbers, and fiber type transformation. These four models demonstrated different changes in the skeletal muscle. This review elucidates the different skeletal muscle adaptations in these four decreased use animal models and encourages further studies. PMID:26996420

  15. In Vivo Rodent Models of Skeletal Muscle Adaptation to Decreased Use.

    PubMed

    Cho, Su Han; Kim, Jang Hoe; Song, Wook

    2016-03-01

    Skeletal muscle possesses plasticity and adaptability to external and internal physiological changes. Due to these characteristics, skeletal muscle shows dramatic changes depending on its response to stimuli such as physical activity, nutritional changes, disease status, and environmental changes. Modulation of the rate of protein synthesis/degradation plays an important role in atrophic responses. The purpose of this review is to describe different features of skeletal muscle adaptation with various models of deceased use. In this review, four models were addressed: immobilization, spinal cord transection, hindlimb unloading, and aging. Immobilization is a form of decreased use in which skeletal muscle shows electrical activity, tension development, and motion. These results differ by muscle group. Spinal cord transection was selected to simulate spinal cord injury. Similar to the immobilization model, dramatic atrophy occurs in addition to fiber type conversion in this model. Despite the fact that electromyography shows unremarkable changes in muscle after hindlimb unloading, decreased muscle mass and contractile force are observed. Lastly, aging significantly decreases the numbers of muscle fibers and motor units. Skeletal muscle responses to decreased use include decreased strength, decreased fiber numbers, and fiber type transformation. These four models demonstrated different changes in the skeletal muscle. This review elucidates the different skeletal muscle adaptations in these four decreased use animal models and encourages further studies. PMID:26996420

  16. Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models.

    PubMed

    Anderson, Rachel I; Becker, Howard C; Adams, Benjamin L; Jesudason, Cynthia D; Rorick-Kehn, Linda M

    2014-01-01

    To examine the role of orexin-1 and orexin-2 receptor activity on ethanol self-administration, compounds that differentially target orexin (OX) receptor subtypes were assessed in various self-administration paradigms using high-drinking rodent models. Effects of the OX1 antagonist SB334867, the OX2 antagonist LSN2424100, and the mixed OX1/2 antagonist almorexant (ACT-078573) on home cage ethanol consumption were tested in ethanol-preferring (P) rats using a 2-bottle choice procedure. In separate experiments, effects of SB334867, LSN2424100, and almorexant on operant ethanol self-administration were assessed in P rats maintained on a progressive ratio operant schedule of reinforcement. In a third series of experiments, SB334867, LSN2424100, and almorexant were administered to ethanol-preferring C57BL/6J mice to examine effects of OX receptor blockade on ethanol intake in a binge-like drinking (drinking-in-the-dark) model. In P rats with chronic home cage free-choice ethanol access, SB334867 and almorexant significantly reduced ethanol intake, but almorexant also reduced water intake, suggesting non-specific effects on consummatory behavior. In the progressive ratio operant experiments, LSN2424100 and almorexant reduced breakpoints and ethanol consumption in P rats, whereas the almorexant inactive enantiomer and SB334867 did not significantly affect the motivation to consume ethanol. As expected, vehicle-injected mice exhibited binge-like drinking patterns in the drinking-in-the-dark model. All three OX antagonists reduced both ethanol intake and resulting blood ethanol concentrations relative to vehicle-injected controls, but SB334867 and LSN2424100 also reduced sucrose consumption in a different cohort of mice, suggesting non-specific effects. Collectively, these results contribute to a growing body of evidence indicating that OX1 and OX2 receptor activity influences ethanol self-administration, although the effects may not be selective for ethanol consumption

  17. Orexin-1 and orexin-2 receptor antagonists reduce ethanol self-administration in high-drinking rodent models

    PubMed Central

    Anderson, Rachel I.; Becker, Howard C.; Adams, Benjamin L.; Jesudason, Cynthia D.; Rorick-Kehn, Linda M.

    2014-01-01

    To examine the role of orexin-1 and orexin-2 receptor activity on ethanol self-administration, compounds that differentially target orexin (OX) receptor subtypes were assessed in various self-administration paradigms using high-drinking rodent models. Effects of the OX1 antagonist SB334867, the OX2 antagonist LSN2424100, and the mixed OX1/2 antagonist almorexant (ACT-078573) on home cage ethanol consumption were tested in ethanol-preferring (P) rats using a 2-bottle choice procedure. In separate experiments, effects of SB334867, LSN2424100, and almorexant on operant ethanol self-administration were assessed in P rats maintained on a progressive ratio operant schedule of reinforcement. In a third series of experiments, SB334867, LSN2424100, and almorexant were administered to ethanol-preferring C57BL/6J mice to examine effects of OX receptor blockade on ethanol intake in a binge-like drinking (drinking-in-the-dark) model. In P rats with chronic home cage free-choice ethanol access, SB334867 and almorexant significantly reduced ethanol intake, but almorexant also reduced water intake, suggesting non-specific effects on consummatory behavior. In the progressive ratio operant experiments, LSN2424100 and almorexant reduced breakpoints and ethanol consumption in P rats, whereas the almorexant inactive enantiomer and SB334867 did not significantly affect the motivation to consume ethanol. As expected, vehicle-injected mice exhibited binge-like drinking patterns in the drinking-in-the-dark model. All three OX antagonists reduced both ethanol intake and resulting blood ethanol concentrations relative to vehicle-injected controls, but SB334867 and LSN2424100 also reduced sucrose consumption in a different cohort of mice, suggesting non-specific effects. Collectively, these results contribute to a growing body of evidence indicating that OX1 and OX2 receptor activity influences ethanol self-administration, although the effects may not be selective for ethanol consumption

  18. Using chronic social stress to model postpartum depression in lactating rodents.

    PubMed

    Carini, Lindsay M; Murgatroyd, Christopher A; Nephew, Benjamin C

    2013-01-01

    Exposure to chronic stress is a reliable predictor of depressive disorders, and social stress is a common ethologically relevant stressor in both animals and humans. However, many animal models of depression were developed in males and are not applicable or effective in studies of postpartum females. Recent studies have reported significant effects of chronic social stress during lactation, an ethologically relevant and effective stressor, on maternal behavior, growth, and behavioral neuroendocrinology. This manuscript will describe this chronic social stress paradigm using repeated exposure of a lactating dam to a novel male intruder, and the assessment of the behavioral, physiological, and neuroendocrine effects of this model. Chronic social stress (CSS) is a valuable model for studying the effects of stress on the behavior and physiology of the dam as well as her offspring and future generations. The exposure of pups to CSS can also be used as an early life stress that has long term effects on behavior, physiology, and neuroendocrinology. PMID:23792810

  19. Rodent models to study the metabolic effects of shiftwork in humans

    PubMed Central

    Opperhuizen, Anne-Loes; van Kerkhof, Linda W. M.; Proper, Karin I.; Rodenburg, Wendy; Kalsbeek, Andries

    2015-01-01

    Our current 24-h society requires an increasing number of employees to work nightshifts with millions of people worldwide working during the evening or night. Clear associations have been found between shiftwork and the risk to develop metabolic health problems, such as obesity. An increasing number of studies suggest that the underlying mechanism includes disruption of the rhythmically organized body physiology. Normally, daily 24-h rhythms in physiological processes are controlled by the central clock in the brain in close collaboration with peripheral clocks present throughout the body. Working schedules of shiftworkers greatly interfere with these normal daily rhythms by exposing the individual to contrasting inputs, i.e., at the one hand (dim)light exposure at night, nightly activity and eating and at the other hand daytime sleep and reduced light exposure. Several different animal models are being used to mimic shiftwork and study the mechanism responsible for the observed correlation between shiftwork and metabolic diseases. In this review we aim to provide an overview of the available animal studies with a focus on the four most relevant models that are being used to mimic human shiftwork: altered timing of (1) food intake, (2) activity, (3) sleep, or (4) light exposure. For all studies we scored whether and how relevant metabolic parameters, such as bodyweight, adiposity and plasma glucose were affected by the manipulation. In the discussion, we focus on differences between shiftwork models and animal species (i.e., rat and mouse). In addition, we comment on the complexity of shiftwork as an exposure and the subsequent difficulties when using animal models to investigate this condition. In view of the added value of animal models over human cohorts to study the effects and mechanisms of shiftwork, we conclude with recommendations to improve future research protocols to study the causality between shiftwork and metabolic health problems using animal models

  20. Rodent models to study the metabolic effects of shiftwork in humans.

    PubMed

    Opperhuizen, Anne-Loes; van Kerkhof, Linda W M; Proper, Karin I; Rodenburg, Wendy; Kalsbeek, Andries

    2015-01-01

    Our current 24-h society requires an increasing number of employees to work nightshifts with millions of people worldwide working during the evening or night. Clear associations have been found between shiftwork and the risk to develop metabolic health problems, such as obesity. An increasing number of studies suggest that the underlying mechanism includes disruption of the rhythmically organized body physiology. Normally, daily 24-h rhythms in physiological processes are controlled by the central clock in the brain in close collaboration with peripheral clocks present throughout the body. Working schedules of shiftworkers greatly interfere with these normal daily rhythms by exposing the individual to contrasting inputs, i.e., at the one hand (dim)light exposure at night, nightly activity and eating and at the other hand daytime sleep and reduced light exposure. Several different animal models are being used to mimic shiftwork and study the mechanism responsible for the observed correlation between shiftwork and metabolic diseases. In this review we aim to provide an overview of the available animal studies with a focus on the four most relevant models that are being used to mimic human shiftwork: altered timing of (1) food intake, (2) activity, (3) sleep, or (4) light exposure. For all studies we scored whether and how relevant metabolic parameters, such as bodyweight, adiposity and plasma glucose were affected by the manipulation. In the discussion, we focus on differences between shiftwork models and animal species (i.e., rat and mouse). In addition, we comment on the complexity of shiftwork as an exposure and the subsequent difficulties when using animal models to investigate this condition. In view of the added value of animal models over human cohorts to study the effects and mechanisms of shiftwork, we conclude with recommendations to improve future research protocols to study the causality between shiftwork and metabolic health problems using animal models

  1. Rodent Hypoxia–Ischemia Models for Cerebral Palsy Research: A Systematic Review

    PubMed Central

    Rumajogee, Prakasham; Bregman, Tatiana; Miller, Steven P.; Yager, Jerome Y.; Fehlings, Michael G.

    2016-01-01

    Cerebral palsy (CP) is a complex multifactorial disorder, affecting approximately 2.5–3/1000 live term births, and up to 22/1000 prematurely born babies. CP results from injury to the developing brain incurred before, during, or after birth. The most common form of this condition, spastic CP, is primarily associated with injury to the cerebral cortex and subcortical white matter as well as the deep gray matter. The major etiological factors of spastic CP are hypoxia/ischemia (HI), occurring during the last third of pregnancy and around birth age. In addition, inflammation has been found to be an important factor contributing to brain injury, especially in term infants. Other factors, including genetics, are gaining importance. The classic Rice–Vannucci HI model (in which 7-day-old rat pups undergo unilateral ligation of the common carotid artery followed by exposure to 8% oxygen hypoxic air) is a model of neonatal stroke that has greatly contributed to CP research. In this model, brain damage resembles that observed in severe CP cases. This model, and its numerous adaptations, allows one to finely tune the injury parameters to mimic, and therefore study, many of the pathophysiological processes and conditions observed in human patients. Investigators can recreate the HI and inflammation, which cause brain damage and subsequent motor and cognitive deficits. This model further enables the examination of potential approaches to achieve neural repair and regeneration. In the present review, we compare and discuss the advantages, limitations, and the translational value for CP research of HI models of perinatal brain injury. PMID:27199883

  2. A dynamic model of circadian rhythms in rodent tail skin temperature for comparison of drug effects

    PubMed Central

    2012-01-01

    Menopause-associated thermoregulatory dysfunction can lead to symptoms such as hot flushes severely impairing quality of life of affected women. Treatment effects are often assessed by the ovariectomized rat model providing time series of tail skin temperature measurements in which circadian rhythms are a fundamental ingredient. In this work, a new statistical strategy is presented for analyzing such stochastic-dynamic data with the aim of detecting successful drugs in hot flush treatment. The circadian component is represented by a nonlinear dynamical system which is defined by the van der Pol equation and provides well-interpretable model parameters. Results regarding the statistical evaluation of these parameters are presented. PMID:22221596

  3. Rodent Research-1 Validation of Rodent Hardware

    NASA Technical Reports Server (NTRS)

    Globus, Ruth; Beegle, Janet

    2013-01-01

    To achieve novel science objectives, validation of a rodent habitat on ISS will enable - In-flight analyses during long duration spaceflight- Use of genetically altered animals- Application of modern analytical techniques (e.g. genomics, proteomics, and metabolomics)

  4. Maternal separation with early weaning: A rodent model providing novel insights into neglect associated developmental deficits

    PubMed Central

    CARLYLE, BECKY C.; DUQUE, ALVARO; KITCHEN, ROBERT R.; BORDNER, KELLY A.; COMAN, DANIEL; DOOLITTLE, ELIZA; PAPADEMETRIS, XENOPHONIOS; HYDER, FAHMEED; TAYLOR, JANE R.; SIMEN, ARTHUR A.

    2013-01-01

    Child neglect is the most prevalent form of child maltreatment in the United States, and poses a serious public health concern. Children who survive such episodes go on to experience long-lasting psychological and behavioral problems, including higher rates of post-traumatic stress disorder symptoms, depression, alcohol and drug abuse, attention-deficit/hyperactivity disorder, and cognitive deficits. To date, most research into the causes of these life-long problems has focused on well-established targets such as stress responsive systems, including the hypothalamus–pituitary–adrenal axis. Using the maternal separation and early weaning model, we have attempted to provide comprehensive molecular profiling of a model of early-life neglect in an organism amenable to genomic manipulation: the mouse. In this article, we report new findings generated with this model using chromatin immunoprecipitation sequencing, diffuse tensor magnetic resonance imaging, and behavioral analyses. We also review the validity of the maternal separation and early weaning model, which reflects behavioral deficits observed in neglected humans including hyperactivity, anxiety, and attentional deficits. Finally, we summarize the molecular characterization of these animals, including RNA profiling and label-free proteomics, which highlight protein translation and myelination as novel pathways of interest. PMID:23062306

  5. Maternal separation with early weaning: a rodent model providing novel insights into neglect associated developmental deficits.

    PubMed

    Carlyle, Becky C; Duque, Alvaro; Kitchen, Robert R; Bordner, Kelly A; Coman, Daniel; Doolittle, Eliza; Papademetris, Xenophonios; Hyder, Fahmeed; Taylor, Jane R; Simen, Arthur A

    2012-11-01

    Child neglect is the most prevalent form of child maltreatment in the United States, and poses a serious public health concern. Children who survive such episodes go on to experience long-lasting psychological and behavioral problems, including higher rates of post-traumatic stress disorder symptoms, depression, alcohol and drug abuse, attention-deficit/hyperactivity disorder, and cognitive deficits. To date, most research into the causes of these life-long problems has focused on well-established targets such as stress responsive systems, including the hypothalamus-pituitary-adrenal axis. Using the maternal separation and early weaning model, we have attempted to provide comprehensive molecular profiling of a model of early-life neglect in an organism amenable to genomic manipulation: the mouse. In this article, we report new findings generated with this model using chromatin immunoprecipitation sequencing, diffuse tensor magnetic resonance imaging, and behavioral analyses. We also review the validity of the maternal separation and early weaning model, which reflects behavioral deficits observed in neglected humans including hyperactivity, anxiety, and attentional deficits. Finally, we summarize the molecular characterization of these animals, including RNA profiling and label-free proteomics, which highlight protein translation and myelination as novel pathways of interest. PMID:23062306

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

    PubMed Central

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

    2014-01-01

    Traditionally bacteria have been considered as either pathogens, commensals or symbionts. The mammal gut harbors 1014 organisms dispersed on approximately 1000 different species. Today, diagnostics, in contrast to previous cultivation techniques, allow the identification of close to 100% of bacterial species. This has revealed that a range of animal models within different research areas, such as diabetes, obesity, cancer, allergy, behavior and colitis, are affected by their gut microbiota. Correlation studies may for some diseases show correlation between gut microbiota composition and disease parameters higher than 70%. Some disease phenotypes may be transferred when recolonizing germ free mice. The mechanistic aspects are not clear, but some examples on how gut bacteria stimulate receptors, metabolism, and immune responses are discussed. A more deeper understanding of the impact of microbiota has its origin in the overall composition of the microbiota and in some newly recognized species, such as Akkermansia muciniphila, Segmented filamentous bacteria and Faecalibacterium prausnitzii, which seem to have an impact on more or less severe disease in specific models. Thus, the impact of the microbiota on animal models is of a magnitude that cannot be ignored in future research. Therefore, either models with specific microbiota must be developed, or the microbiota must be characterized in individual studies and incorporated into data evaluation. PMID:25548471

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

    ERIC Educational Resources Information Center

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

    2010-01-01

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

  8. Rodent Working Heart Model for the Study of Myocardial Performance and Oxygen Consumption.

    PubMed

    DeWitt, Elizabeth S; Black, Katherine J; Kheir, John N

    2016-01-01

    Isolated working heart models have been used to understand the effects of loading conditions, heart rate and medications on myocardial performance in ways that cannot be accomplished in vivo. For example, inotropic medications commonly also affect preload and afterload, precluding load-independent assessments of their myocardial effects in vivo. Additionally, this model allows for sampling of coronary sinus effluent without contamination from systemic venous return, permitting assessment of myocardial oxygen consumption. Further, the advent of miniaturized pressure-volume catheters has allowed for the precise quantification of markers of both systolic and diastolic performance. We describe a model in which the left ventricle can be studied while performing both volume and pressure work under controlled conditions. In this technique, the heart and lungs of a Sprague-Dawley rat (weight 300-500 g) are removed en bloc under general anesthesia. The aorta is dissected free and cannulated for retrograde perfusion with oxygenated Krebs buffer. The pulmonary arteries and veins are ligated and the lungs removed from the preparation. The left atrium is then incised and cannulated using a separate venous cannula, attached to a preload block. Once this is determined to be leak-free, the left heart is loaded and retrograde perfusion stopped, creating the working heart model. The pulmonary artery is incised and cannulated for collection of coronary effluent and determination of myocardial oxygen consumption. A pressure-volume catheter is placed into the left ventricle either retrograde or through apical puncture. If desired, atrial pacing wires can be placed for more precise control of heart rate. This model allows for precise control of preload (using a left atrial pressure block), afterload (using an afterload block), heart rate (using pacing wires) and oxygen tension (using oxygen mixtures within the perfusate). PMID:27584550

  9. A Novel Model of Surgical Injury in Adult Rat Kidney: A “Pouch Model”

    PubMed Central

    Litbarg, Natalia O.; Vujicic, Snezana; Setty, Suman; Sethupathi, Periannan; Dunea, George; Arruda, Jose A.; Singh, Ashok K.

    2013-01-01

    Regenerative mechanisms after surgical injury have been studied in many organs but not in the kidney. Studying surgical injury may provide new insights into mechanisms of kidney regeneration. In rodent models, extrarenal tissues adhere to surgical kidney wound and interfere with healing. We hypothesized that this can be prevented by wrapping injured kidney in a plastic pouch. Adult rats tolerated 5/6 nephrectomy with pouch application well. Histological analysis demonstrates that application of the pouch effectively prevented formation of adhesions and induced characteristic wound healing manifested by formation of granulation tissue. Additionally, selected tubules of the wounded kidney extended into the granulation tissue forming branching tubular epithelial outgrowths (TEOs) without terminal differentiation. Tubular regeneration outside of renal parenchyma was not previously observed, and suggests previously unrecognized capacity for regeneration. Our model provides a novel approach to study kidney wound healing. PMID:24100472

  10. Reduced linoleic acid intake in early postnatal life improves metabolic outcomes in adult rodents following a Western-style diet challenge.

    PubMed

    Oosting, Annemarie; Kegler, Diane; van de Heijning, Bert J M; Verkade, Henkjan J; van der Beek, Eline M

    2015-09-01

    The global increase in dietary n-6 polyunsaturated fatty acid (PUFA) intake has been suggested to contribute to the rise in obesity incidence. We hypothesized that reduced n-6 PUFA intake during early postnatal life improves adult body composition and metabolic phenotype upon a Western diet challenge. Male offspring of C57Bl/6j mice and Wistar rats were subjected to a control diet (CTRL; 3.16 En% linoleic acid [LA]) or a low n-6 PUFA diet (low LA; 1.36 En% LA) from postnatal days (PNs) 2 to 42. Subsequently, all animals were switched to a Western-style diet (2.54 En% LA) until PN98. We monitored body composition by dual-energy x-ray absorptiometry and glucose homeostasis by an intravenous glucose and insulin tolerance test in rats and by the homeostasis model assessment of insulin resistance (HOMA-IR) in mice. At PN98, plasma lipids, glucose, insulin, and adipokines were measured and adipocyte number and size were analyzed. In mice, the postnatal low-LA diet decreased fat accumulation during the adult Western-style diet challenge (-27% compared with CTRL, P < .001). Simultaneously, it reduced fasting triglyceride levels and lowered fasting resistin and leptin levels. In rats, the low-LA diet did not affect adult body composition, but decreased the number of retroperitoneal adipocytes and increased the number of large adipocytes. In conclusion, lowering dietary n-6 PUFA intake in early life protected against detrimental effects of an obesogenic diet in adulthood on metabolic homeostasis and fat mass accumulation. PMID:26239950

  11. Patterns of Behavioral Deficits in Rodents Following Brain Injury Across Species, Gender, and Experimental Model.

    PubMed

    Hartman, Richard E; Thorndyke, Earl C

    2016-01-01

    Behavioral data were collected from several hundred mice and rats using a variety of experimental models of brain injury. The use of consistent protocols allowed compilation of these data, facilitating analyses of animal behaviors across experimental models, species, and gender. Spatial learning and sensorimotor/coordination data are presented, suggesting that, in general, rats performed better than mice both in the water maze and on the rotarod. Compared with females, males performed slightly better in the water maze and slightly worse on the rotarod. However, gender by species interactions accounted for both of these differences. Male rats performed better in the water maze than female rats, male mice, and female mice, which did not differ. Male mice performed worse on the rotarod than female mice, male rats, and female rats, which performed similarly. Furthermore, animals with subcortical injury were impaired in the water maze, but performed better than animals with cortical injuries. However, only animals with cortical injuries were impaired on the rotarod. Additional covariates, such as edema and lesion size, may further clarify these phenotypes. Overall, we provide evidence that abbreviated test batteries can be specifically designed to test deficits, depending on the species, gender, and model. PMID:26463925

  12. Inhalation Exposure Systems for the Development of Rodent Models of Sulfur Mustard-Induced Pulmonary Injury

    PubMed Central

    Weber, Waylon M.; Kracko, Dean A.; Lehman, Mericka R.; Irvin, Clinton M.; Blair, Lee F.; White, Richard K.; Benson, Janet M.; Grotendorst, Gary R.; Cheng, Yung-Sung; McDonald, Jacob D.

    2011-01-01

    Sulfur mustard (SM) is a chemical threat agent for which its effects have no current treatment. Due to the ease of synthesis and dispersal of this material, the need to develop therapeutics is evident. The present manuscript details the techniques used to develop SM laboratory exposure systems for the development of animal models of pulmonary injury. These models are critical for evaluating SM injury and developing therapeutics against that injury. Iterative trials were conducted to optimize a lung injury model. The resulting pathology was used as a guide, with a goal of effecting homogeneous and diffuse lung injury comparable to that of human injury. Inhalation exposures were conducted by either nose-only inhalation or intubated inhalation. The exposures were conducted to either directly vaporized SM or SM that was nebulized from an ethanol solution. Inhalation of SM by nose-only inhalation resulted in severe nasal epithelial degeneration and minimal lung injury. The reactivity of SM did not permit it to transit past the upper airways to promote lower airway injury. Intratracheal inhalation of SM vapors at a concentration of 5400 mg · min/m3 resulted in homogeneous lung injury with no nasal degeneration. PMID:20025432

  13. Assessment of an experimental rodent model of pediatric mild traumatic brain injury.

    PubMed

    Mychasiuk, Richelle; Farran, Allyson; Esser, Michael J

    2014-04-15

    Childhood is one the highest risk periods for experiencing a mild traumatic brain injury (mTBI) from sports-related concussions, motor vehicle accidents, and falls. In addition, many children experience lingering symptomology (post-concussion syndrome) from these closed head injuries. Although the negative sequel of mTBI has been described, a clinically reliable animal model of mild pediatric brain injury has not. The purpose of this study was to examine the validity of a modified weight-drop technique as a model for the induction of mTBI/concussion in juvenile rats following a single impact. Male and female rats (P30) were exposed to a single mTBI or a sham injury followed by a behavioral test battery. Juvenile rats who experienced a single mTBI displayed significant motor/balance impairments when tested on the beam walking task and in the open field, as well as deficits of executive functioning as measured with the novel context mismatch task and the probe trial of the Morris water task. In addition, both male and female rats showed depression-like behavior in the forced swim task, with male rats also exhibiting decreased anxiety-related behaviors in the elevated plus maze. The results from this study suggest that the modified weight-drop technique induces a clinically relevant behavioral phenotype in juvenile rats, and may provide researchers with a reliable animal model of mTBI/concussion from which clinical therapeutic strategies could be developed. PMID:24283269

  14. Extinction learning deficit in a rodent model of attention-deficit hyperactivity disorder

    PubMed Central

    2012-01-01

    Background Deficient operant extinction has been hypothesized to be constitutive of ADHD dysfunction. In order to elucidate the behavioral mechanisms underlying this deficit, the performance of an animal model of ADHD, the spontaneously hypertensive rat (SHR), was compared against the performance of a control strain, the Wistar-Kyoto rat (WKY) during extinction. Method Following extensive training of lever pressing under variable interval schedules of food reinforcement (reported previously), SHR and WKY rats were exposed to two sessions of extinction training. Extinction data was analyzed using the Dynamic Bi-Exponential Refractory Model (DBERM) of operant performance. DBERM assumes that operant responses are organized in bouts separated by pauses; during extinction, bouts may decline across multiple dimensions, including frequency and length. DBERM parameters were estimated using hierarchical Bayesian modeling. Results SHR responded more than WKY during the first extinction session. DBERM parameter estimates revealed that, at the onset of extinction, SHR produced more response bouts than WKY. Over the course of extinction, response bouts progressively shortened for WKY but not for SHR. Conclusions Based on prior findings on the sensitivity of DBERM parameters to motivational and schedule manipulations, present data suggests that (1) more frequent response bouts in SHR are likely related to greater incentive motivation, and (2) the persistent length of bouts in SHR are likely related to a slower updating of the response-outcome association. Overall, these findings suggest specific motivational and learning deficits that may explain ADHD-related impairments in operant performance. PMID:23237608

  15. Physiologically based pharmacokinetic modeling of ethyl acetate and ethanol in rodents and humans.

    PubMed

    Crowell, S R; Smith, J N; Creim, J A; Faber, W; Teeguarden, J G

    2015-10-01

    A physiologically based pharmacokinetic (PBPK) model was developed and applied to a metabolic series approach for the ethyl series (i.e., ethyl acetate, ethanol, acetaldehyde, and acetate). This approach bases toxicity information on dosimetry analyses for metabolically linked compounds using pharmacokinetic data for each compound and toxicity data for parent or individual compounds. In vivo pharmacokinetic studies of ethyl acetate and ethanol were conducted in rats following IV and inhalation exposure. Regardless of route, ethyl acetate was rapidly converted to ethanol. Blood concentrations of ethyl acetate and ethanol following both IV bolus and infusion suggested linear kinetics across blood concentrations from 0.1 to 10 mM ethyl acetate and 0.01-0.8 mM ethanol. Metabolic parameters were optimized and evaluated based on available pharmacokinetic data. The respiratory bioavailability of ethyl acetate and ethanol were estimated from closed chamber inhalation studies and measured ventilation rates. The resulting ethyl series model successfully reproduces blood ethyl acetate and ethanol kinetics following IV administration and inhalation exposure in rats, and blood ethanol kinetics following inhalation exposure to ethanol in humans. The extrapolated human model was used to derive human equivalent concentrations for the occupational setting of 257-2120 ppm ethyl acetate and 72-517 ppm ethyl acetate for continuous exposure, corresponding to rat LOAELs of 350 and 1500 ppm. PMID:26297692

  16. The rodent endovascular puncture model of subarachnoid hemorrhage: mechanisms of brain damage and therapeutic strategies

    PubMed Central

    2014-01-01

    Subarachnoid hemorrhage (SAH) represents a considerable health problem. To date, limited therapeutic options are available. In order to develop effective therapeutic strategies for SAH, the mechanisms involved in SAH brain damage should be fully explored. Here we review the mechanisms of SAH brain damage induced by the experimental endovascular puncture model. We have included a description of similarities and distinctions between experimental SAH in animals and human SAH pathology. Moreover, several novel treatment options to diminish SAH brain damage are discussed. SAH is accompanied by cerebral inflammation as demonstrated by an influx of inflammatory cells into the cerebral parenchyma, upregulation of inflammatory transcriptional pathways and increased expression of cytokines and chemokines. Additionally, various cell death pathways including cerebral apoptosis, necrosis, necroptosis and autophagy are involved in neuronal damage caused by SAH. Treatment strategies aiming at inhibition of inflammatory or cell death pathways demonstrate the importance of these mechanisms for survival after experimental SAH. Moreover, neuroregenerative therapies using stem cells are discussed as a possible strategy to repair the brain after SAH since this therapy may extend the window of treatment considerably. We propose the endovascular puncture model as a suitable animal model which resembles the human pathology of SAH and which could be applied to investigate novel therapeutic therapies to combat this debilitating insult. PMID:24386932

  17. Long-term effects of early-life environmental manipulations in rodents and primates: Potential animal models in depression research.

    PubMed

    Pryce, Christopher R; Rüedi-Bettschen, Daniela; Dettling, Andrea C; Weston, Anna; Russig, Holger; Ferger, Boris; Feldon, Joram

    2005-01-01

    Depression is one of the most common human illnesses and is of immense clinical and economic significance. Knowledge of the neuro-psychology, -biology and -pharmacology of depression is limited, as is the efficacy of antidepressant treatment. In terms of depression aetiology, whilst the evidence for causal mechanisms is sparse, some genomic and environmental factors associated with increased vulnerability have been identified. With regards to the latter, the environments in which human infants and children develop are fundamental to how they develop, and parental loss, emotional and physical neglect, and abuse have been shown to be associated with: traits of depression, traits of predisposition to depression triggered by subsequent life events, and associated physiological abnormalities, across the life span. Studies of postnatal environmental manipulations in rodents and primates can potentially yield evidence that abnormal early-life experience leading to dysfunction of the neurobiology, physiology and behaviour of emotion is a general mammalian characteristic, and therefore, that this approach can be used to develop animal models for depression research, with aetiological, face, construct and predictive validity. The establishment of models with such validity, if at all achievable, will require a sophisticated combination of (1) appropriate postnatal manipulations that induce acute stress responses in the infant brain which in turn lead to long-term neurobiological consequences, and (2) appropriate behavioural and physiological assays to identify and quantify any depression-like phenotypes resulting from these long-term neurobiological phenotypes. Here, we review some of the evidence-positive and negative-that neglect-like environments in rat pups and monkey infants lead to long-term, depression-like behavioural traits of reduced motivation for reward and impaired coping with adversity, and to altered activity in relevant physiological homeostatic systems. PMID

  18. Further observations on the behavioral and neural effects of bone marrow stromal cells in rodent pain models

    PubMed Central

    Guo, Wei; Chu, Yu-Xia; Imai, Satoshi; Yang, Jia-Le; Zou, Shiping; Mohammad, Zaid; Wei, Feng; Dubner, Ronald

    2016-01-01

    Background Bone marrow stromal cells (BMSCs) have shown potential to treat chronic pain, although much still needs to be learned about their efficacy and mechanisms of action under different pain conditions. Here, we provide further convergent evidence on the effects of BMSCs in rodent pain models. Results In an orofacial pain model involving injury of a tendon of the masseter muscle, BMSCs attenuated behavioral pain conditions assessed by von Frey filaments and a conditioned place avoidance test in female Sprague-Dawley rats. The antihyperalgesia of BMSCs in females lasted for <8 weeks, which is shorter than that seen in males. To relate preclinical findings to human clinical conditions, we used human BMSCs. Human BMSCs (1.5 M cells, i.v.) attenuated mechanical and thermal hyperalgesia induced by spinal nerve ligation and suppressed spinal nerve ligation-induced aversive behavior, and the effect persisted through the 8-week observation period. In a trigeminal slice preparation, BMSC-treated and nerve-injured C57B/L mice showed reduced amplitude and frequency of spontaneous excitatory postsynaptic currents, as well as excitatory synaptic currents evoked by electrical stimulation of the trigeminal nerve root, suggesting inhibition of trigeminal neuronal hyperexcitability and primary afferent input by BMSCs. Finally, we observed that GluN2A (N-methyl-D-aspartate receptor subunit 2A) tyrosine phosphorylation and protein kinase Cgamma (PKCγ) immunoreactivity in rostral ventromedial medulla was suppressed at 8 weeks after BMSC in tendon-injured rats. Conclusions Collectively, the present work adds convergent evidence supporting the use of BMSCs in pain control. As PKCγ activity related to N-methyl-D-aspartate receptor activation is critical in opioid tolerance, these results help to understand the mechanisms of BMSC-produced long-term antihyperalgesia, which requires opioid receptors in rostral ventromedial medulla and apparently lacks the development of tolerance

  19. BDNF signaling contributes to oral cancer pain in a preclinical orthotopic rodent model

    PubMed Central

    Chodroff, Leah; Bendele, Michelle; Valenzuela, Vanessa; Henry, Michael

    2016-01-01

    The majority of patients with oral cancer report intense pain that is only partially managed by current analgesics. Thus, there is a strong need to study mechanisms as well as develop novel analgesics for oral cancer pain. Current study employed an orthotopic tongue cancer model with molecular and non-reflexive behavioral assays to determine possible mechanisms of oral cancer pain. Human oral squamous cell carcinoma cells line, HSC2, was injected into the tongue of male athymic mice and tumor growth was observed by day 6. Immunohistological analyses revealed a well-differentiated tumor with a localized immune response and pronounced sensory and sympathetic innervation and vascularization. The tumor expressed TMPRSS2, a protein previously reported with oral squamous cell carcinoma. ATF3 expression in trigeminal ganglia was not altered by tumor growth. Molecular characterization of the model demonstrated altered expression of several pain-related genes, out of which up-regulation of BDNF was most striking. Moreover, BDNF protein expression in trigeminal ganglia neurons was increased and inhibition of BDNF signaling with a tyrosine kinase B antagonist, ANA-12, reversed pain-like behaviors induced by the oral tumor. Oral squamous cell carcinoma tumor growth was also associated with a reduction in feeding, mechanical hypersensitivity in the face, as well as spontaneous pain behaviors as measured by the conditioned place preference test, all of which were reversed by analgesics. Interestingly, injection of HSC2 into the hindpaw did not reproduce this spectrum of pain behaviors; nor did injection of a colonic cancer cell line into the tongue. Taken together, this orthotopic oral cancer pain model reproduces the spectrum of pain reported by oral cancer patients, including higher order cognitive changes, and demonstrates that BDNF signaling constitutes a novel mechanism by which oral squamous cell carcinoma induces pain. Identification of the key role of tyrosine kinase B

  20. Quantitative Relationship between Axonal Injury and Mechanical Response in a Rodent Head Impact Acceleration Model

    PubMed Central

    Li, Yan; Kallakuri, Srinivasu; Zhou, Runzhou; Cavanaugh, John M.

    2011-01-01

    Abstract A modified Marmarou impact acceleration model was developed to study the mechanical responses induced by this model and their correlation to traumatic axonal injury (TAI). Traumatic brain injury (TBI) was induced in 31 anesthetized male Sprague-Dawley rats (392±13 g) by a custom-made 450-g impactor from heights of 1.25 m or 2.25 m. An accelerometer and angular rate sensor measured the linear and angular responses of the head, while the impact event was captured by a high-speed video camera. TAI distribution along the rostro-caudal direction, as well as across the left and right hemispheres, was determined using β-amyloid precursor protein (β-APP) immunocytochemistry, and detailed TAI injury maps were constructed for the entire corpus callosum. Peak linear acceleration 1.25 m and 2.25 m impacts were 666±165 g and 907±501 g, respectively. Peak angular velocities were 95±24 rad/sec and 124±48 rad/sec, respectively. Compared to the 2.25-m group, the observed TAI counts in the 1.25-m impact group were significantly lower. Average linear acceleration, peak angular velocity, average angular acceleration, and surface righting time were also significantly different between the two groups. A positive correlation was observed between normalized total TAI counts and average linear acceleration (R2=0.612, p<0.05), and time to surface right (R2=0.545, p<0.05). Our study suggested that a 2.25-m drop in the Marmarou model may not always result in a severe injury, and TAI level is related to the linear and angular acceleration response of the rat head during impact, not necessarily the drop height. PMID:21895482

  1. Trauma exposure and sleep: using a rodent model to understand sleep function in PTSD.

    PubMed

    Vanderheyden, William M; Poe, Gina R; Liberzon, Israel

    2014-05-01

    Post-traumatic stress disorder (PTSD) is characterized by intrusive memories of a traumatic event, avoidance behavior related to cues of the trauma, emotional numbing, and hyper-arousal. Sleep abnormalities and nightmares are core symptoms of this disorder. In this review, we propose a model which implicates abnormal activity in the locus coeruleus (LC), an important modifier of sleep-wake regulation, as the source of sleep abnormalities and memory abnormalities seen in PTSD. Abnormal LC activity may be playing a key role in symptom formation in PTSD via sleep dysregulation and suppression of hippocampal bidirectional plasticity. PMID:24623353

  2. Electroporation-mediated Delivery of Genes in Rodent Models of Lung Contusion

    PubMed Central

    Machado-Aranda, David; Raghavendran, Krishnan

    2015-01-01

    Several of the biological processes involved in the pathogenesis of acute lung injury and acute respiratory distress syndrome after lung contusion are regulated at a genetic and epigenetic level. Thus, strategies to manipulate gene expression in this context are highly desirable not only to elucidate the mechanisms involved but also to look for potential therapies. In the present chapter, we describe mouse and rat models of inducing blunt thoracic injury followed by electroporation-mediated gene delivery to the lung. Electroporation is a highly efficient and easily reproducible technique that allows circumvention of several of lung gene delivery challenges and safety issues present with other forms of lung gene therapy. PMID:24510825

  3. Conditioned Inhibition in a Rodent Model of Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Green, John T.; Chess, Amy C.; Conquest, Cynthia J.; Yegla, Brittney A.

    2011-01-01

    A deficit in inhibition may underlie some of the symptoms of Attention-deficit/hyperactivity disorder (ADHD), particularly impulsivity. However, the data on inhibitory deficits in children with ADHD are mixed. Moreover, there has been little characterization of inhibitory processes in animal models of ADHD. Pavlov’s conditioned inhibition procedure allows a direct assessment of the inhibitory status of a stimulus via summation and retardation tests. Therefore, in the current study we examined conditioned inhibition in spontaneously hypertensive rats (SHRs), the most well-validated animal model of ADHD. SHRs and Wistar rats were trained in a simultaneous feature-negative discrimination in eyeblink conditioning. Each session consisted of a mixture of two trial types: a tone paired with a periocular stimulation (A+) or a tone and light presented simultaneously without a periocular stimulation (XA−). Both SHRs and Wistars were able to discriminate A+ from XA− trials. In subsequent summation (X presented simultaneously with a different conditioned excitor, B) and retardation (X paired with the periocular stimulation) tests, the presence of inhibition to X was confirmed in both SHRs and Wistars: X reduced responding to B and X was slow to develop excitation when paired with periocular stimulation. These results are the first to demonstrate Pavlovian conditioned inhibition in SHRs and to use a summation and a retardation test to confirm X as a conditioned inhibitor. The data indicate that conditioned inhibition is intact in SHRs, thus inhibitory processes that do not require prefrontal cortex or cerebellum may be normal in this strain. PMID:22004263

  4. Rodent models of TDP-43 proteinopathy: investigating the mechanisms of TDP-43-mediated neurodegeneration.

    PubMed

    Gendron, Tania F; Petrucelli, Leonard

    2011-11-01

    Since the identification of phosphorylated and truncated transactive response DNA-binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions, much effort has been directed towards ascertaining how TDP-43 contributes to the pathogenesis of disease. As with other protein misfolding disorders, TDP-43-mediated neuronal death is likely caused by both a toxic gain and loss of TDP-43 function. Indeed, the presence of cytoplasmic TDP-43 inclusions is associated with loss of nuclear TDP-43. Moreover, post-translational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage into C-terminal fragments, may bestow toxic properties upon TDP-43 and cause TDP-43 dysfunction. However, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neurotoxicity. Additionally, given our incomplete understanding of the roles of TDP-43, both in the nucleus and the cytoplasm, it is difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. The development of TDP-43 transgenic animal models is expected to narrow these gaps in our knowledge. The aim of this review is to highlight the key findings emerging from TDP-43 transgenic animal models and the insight they provide into the mechanisms driving TDP-43-mediated neurodegeneration. PMID:21811811

  5. Dorsal MPFC circuitry in rodent models of cocaine use: Implications for drug-addiction therapies

    PubMed Central

    Jasinska, Agnes J.; Chen, Billy T.; Bonci, Antonello; Stein, Elliot A.

    2014-01-01

    While the importance of the medial prefrontal cortex (MPFC) in cocaine addiction is well established, its precise contribution to cocaine seeking, taking, and relapse remains incompletely understood. In particular, across two different models of cocaine self-administration, pharmacological or optogenetic activation of the dorsal MPFC has been reported to sometimes promote and sometimes inhibit cocaine seeking. We highlight important methodological differences between the two experimental paradigms, and propose a framework to potentially reconcile the apparent discrepancy. We also draw parallels between these preclinical models of cocaine self-administration and human neuroimaging studies in cocaine users, and argue that both lines of evidence point to dynamic interactions between cue-reactivity processes and control processes within the dorsal MPFC circuitry. From a translational perspective, these findings underscore the importance of interventions and therapeutics targeting not just a brain region, but a specific computational process within that brain region, and may have implications for the design and implementation of more effective treatments for human cocaine addiction. PMID:24620898

  6. Biomaterial-based interventions for neuronal regeneration and functional recovery in rodent model of spinal cord injury: A systematic review

    PubMed Central

    Krishna, Vibhor; Konakondla, Sanjay; Nicholas, Joyce; Varma, Abhay; Kindy, Mark; Wen, Xuejun

    2013-01-01

    Context There is considerable interest in translating laboratory advances in neuronal regeneration following spinal cord injury (SCI). A multimodality approach has been advocated for successful functional neuronal regeneration. With this goal in mind several biomaterials have been employed as neuronal bridges either to support cellular transplants, to release neurotrophic factors, or to do both. A systematic review of this literature is lacking. Such a review may provide insight to strategies with a high potential for further investigation and potential clinical application. Objective To systematically review the design strategies and outcomes after biomaterial-based multimodal interventions for neuronal regeneration in rodent SCI model. To analyse functional outcomes after implantation of biomaterial-based multimodal interventions and to identify predictors of functional outcomes. Methods A broad PubMed, CINHAL, and a manual search of relevant literature databases yielded data from 24 publications; 14 of these articles included functional outcome information. Studies reporting behavioral data in rat model of SCI and employing biodegradable polymer-based multimodal intervention were included. For behavioral recovery, studies using severe injury models (transection or severe clip compression (>16.9 g) or contusion (50 g/cm)) were categorized separately from those investigating partial injury models (hemisection or moderate-to-severe clip compression or contusion). Results The cumulative mean improvements in Basso, Beattie, and Bresnahan scores after biomaterial-based interventions are 5.93 (95% CI = 2.41 − 9.45) and 4.44 (95% CI = 2.65 – 6.24) for transection and hemisection models, respectively. Factors associated with improved outcomes include the type of polymer used and a follow-up period greater than 6 weeks. Conclusion The functional improvement after implantation of biopolymer-based multimodal implants is modest. The relationship with neuronal

  7. Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

    PubMed Central

    2012-01-01

    Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications. PMID:24900443

  8. Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models.

    PubMed

    Albaugh, Pam; Fan, Yi; Mi, Yuan; Sun, Fangxian; Adrian, Francisco; Li, Nanxin; Jia, Yong; Sarkisova, Yelena; Kreusch, Andreas; Hood, Tami; Lu, Min; Liu, Guoxun; Huang, Shenlin; Liu, Zuosheng; Loren, Jon; Tuntland, Tove; Karanewsky, Donald S; Seidel, H Martin; Molteni, Valentina

    2012-02-01

    Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (22), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of 22 make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications. PMID:24900443

  9. Environment-contact administration of rotenone: A new rodent model of Parkinson's disease.

    PubMed

    Liu, Yan; Sun, Jian-Dong; Song, Lian-Kun; Li, Jing; Chu, Shi-Feng; Yuan, Yu-He; Chen, Nai-Hong

    2015-11-01

    Epidemiological studies suggest an association between pesticides and the incidence of Parkinson's disease (PD). Individuals are likely to be exposed to numerous natural or synthetic environmental agents by ingestion, inhalation, or skin contact. Here, we describe a novel environment-contact administration of rotenone model, in which male C57BL/6 mice (15 per group per time-point) were placed in one bedding-free, rotenone-applied cage for 2h every day over a period of 2-6 weeks, mimicking the common ways a person may be exposed to pesticides. Our results showed that rotenone exposure had no detrimental effect on body weights of mice during 6 weeks, nor did it cause systemic toxicity (HPLC analysis of rotenone in blood and brain, as well as complex I activity measurements in brain and muscle), but it caused significant impairments in motor function (open field test, pole test, and rotarod test) from 4 weeks that were responsive to apomorphine. Accordingly, rotenone caused significant dopamine depletion from the striatum (HPLC analysis), nigrostriatal degeneration (quantitative tyrosine hydroxylase immunohistochemistry and western blot), and accumulation of α-synuclein in the substantia nigra and striatum (α-synuclein immunohistochemistry) in a time-dependent manner. In addition, rotenone-exposed mice also developed deficits in gastrointestinal and olfactory function (fecal pellet output and buried food pellet test) prior to the motor dysfunction. Furthermore, we observed that α-synuclein accumulated in the anterior olfactory nucleus and the enteric nervous system at 2 weeks. In summary, this novel rotenone model was able to reproduce many key aspects of PD progression. Therefore, it provides new insight into how environmental factors could trigger PD and provides a useful tool for studying PD pathogenesis and testing neuroprotective strategies. PMID:26239001

  10. Maturation of the developing human fetal prostate in a rodent xenograft model

    PubMed Central

    Saffarini, Camelia M.; McDonnell, Elizabeth V.; Amin, Ali; Spade, Daniel J.; Huse, Susan M.; Kostadinov, Stefan; Hall, Susan J.; Boekelheide, Kim

    2015-01-01

    Background Prostate cancer is the most commonly diagnosed non-skin cancer in men. The etiology of prostate cancer is unknown, although both animal and epidemiologic data suggest that early life exposures to various toxicants, may impact DNA methylation status during development, playing an important role. Methods We have developed a xenograft model to characterize the growth and differentiation of human fetal prostate implants (gestational age 12-24 weeks) that can provide new data on the potential role of early life stressors on prostate cancer. The expression of key immunohistochemical markers responsible for prostate maturation was evaluated, including p63, cytokeratin 18, α-smooth muscle actin, vimentin, caldesmon, Ki-67, prostate specific antigen, estrogen receptor-α, and androgen receptor. Xenografts were separated into epithelial and stromal compartments using laser capture microdissection (LCM), and the DNA methylation status was assessed in >480,000 CpG sites throughout the genome. Results Xenografts demonstrated growth and maturation throughout the 200 days of post-implantation evaluation. DNA methylation profiles of laser capture micro-dissected tissue demonstrated tissue-specific markers clustered by their location in either the epithelium or stroma of human prostate tissue. Differential methylated promoter region CpG-associated gene analysis revealed significantly more stromal than epithelial DNA methylation in the 30 and 90-day xenografts. Functional classification analysis identified CpG-related gene clusters in methylated epithelial and stromal human xenografts. Conclusion This study of human fetal prostate tissue establishes a xenograft model that demonstrates dynamic growth and maturation, allowing for future mechanistic studies of the developmental origins of later life proliferative prostate disease. PMID:24038131

  11. Selective Spectrum Antibiotic Modulation of the Gut Microbiome in Obesity and Diabetes Rodent Models.

    PubMed

    Rajpal, Deepak K; Klein, Jean-Louis; Mayhew, David; Boucheron, Joyce; Spivak, Aaron T; Kumar, Vinod; Ingraham, Karen; Paulik, Mark; Chen, Lihong; Van Horn, Stephanie; Thomas, Elizabeth; Sathe, Ganesh; Livi, George P; Holmes, David J; Brown, James R

    2015-01-01

    The gastrointestinal tract microbiome has been suggested as a potential therapeutic target for metabolic diseases such as obesity and Type 2 diabetes mellitus (T2DM). However, the relationship between changes in microbial communities and metabolic disease-phenotypes are still poorly understood. In this study, we used antibiotics with markedly different antibacterial spectra to modulate the gut microbiome in a diet-induced obesity mouse model and then measured relevant biochemical, hormonal and phenotypic biomarkers of obesity and T2DM. Mice fed a high-fat diet were treated with either ceftazidime (a primarily anti-Gram negative bacteria antibiotic) or vancomycin (mainly anti-Gram positive bacteria activity) in an escalating three-dose regimen. We also dosed animals with a well-known prebiotic weight-loss supplement, 10% oligofructose saccharide (10% OFS). Vancomycin treated mice showed little weight change and no improvement in glycemic control while ceftazidime and 10% OFS treatments induced significant weight loss. However, only ceftazidime showed significant, dose dependent improvement in key metabolic variables including glucose, insulin, protein tyrosine tyrosine (PYY) and glucagon-like peptide-1 (GLP-1). Subsequently, we confirmed the positive hyperglycemic control effects of ceftazidime in the Zucker diabetic fatty (ZDF) rat model. Metagenomic DNA sequencing of bacterial 16S rRNA gene regions V1-V3 showed that the microbiomes of ceftazidime dosed mice and rats were enriched for the phylum Firmicutes while 10% OFS treated mice had a greater abundance of Bacteroidetes. We show that specific changes in microbial community composition are associated with obesity and glycemic control phenotypes. More broadly, our study suggests that in vivo modulation of the microbiome warrants further investigation as a potential therapeutic strategy for metabolic diseases. PMID:26709835

  12. Aminoguanidine attenuates the delayed circulatory failure and improves survival in rodent models of endotoxic shock.

    PubMed Central

    Wu, C C; Chen, S J; Szabó, C; Thiemermann, C; Vane, J R

    1995-01-01

    1. We have investigated the effects of aminoguanidine, a relatively selective inhibitor of the cytokine-inducible isoform of nitric oxide synthase (iNOS), on the delayed circulatory failure, vascular hyporeactivity to vasoconstrictor agents, and iNOS activity in a rat model of circulatory shock induced by bacterial endotoxin (E. coli lipopolysaccharide; LPS). In addition, we have evaluated the effect of aminoguanidine on the 24 h survival rate in a murine model of endotoxaemia. 2. Male Wistar rats were anaesthetized and instrumented for the measurement of mean arterial blood pressure (MAP) and heart rate (HR). Injection of LPS (10 mg kg-1, i.v.) resulted in a fall in MAP from 115 +/- 4 mmHg (time 0, control) to 79 +/- 9 mmHg at 180 min (P < 0.05, n = 10). The pressor effect of noradrenaline (NA, 1 microgram kg-1, i.v.) was also significantly reduced at 60, 120 and 180 min after LPS injection. In contrast, animals pretreated with aminoguanidine (15 mg kg-1, i.v., 20 min prior to LPS injection) maintained a significantly higher MAP (at 180 min, 102 +/- 3 mmHg, n = 10, P < 0.05) when compared to rats given only LPS (LPS-rats). Cumulative administration of aminoguanidine (15 mg kg-1 and 45 mg kg-1) given 180 min after LPS caused a dose-related increase in MAP and reversed the hypotension. Aminoguanidine also significantly alleviated the reduction of the pressor response to NA: indeed, at 180 min, the pressor response returned to normal in aminoguanidine pretreated LPS-rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7541282

  13. Selective Spectrum Antibiotic Modulation of the Gut Microbiome in Obesity and Diabetes Rodent Models

    PubMed Central

    Rajpal, Deepak K.; Klein, Jean-Louis; Mayhew, David; Boucheron, Joyce; Spivak, Aaron T.; Kumar, Vinod; Ingraham, Karen; Paulik, Mark; Chen, Lihong; Van Horn, Stephanie; Thomas, Elizabeth; Sathe, Ganesh; Livi, George P.; Holmes, David J.; Brown, James R.

    2015-01-01

    The gastrointestinal tract microbiome has been suggested as a potential therapeutic target for metabolic diseases such as obesity and Type 2 diabetes mellitus (T2DM). However, the relationship between changes in microbial communities and metabolic disease-phenotypes are still poorly understood. In this study, we used antibiotics with markedly different antibacterial spectra to modulate the gut microbiome in a diet-induced obesity mouse model and then measured relevant biochemical, hormonal and phenotypic biomarkers of obesity and T2DM. Mice fed a high-fat diet were treated with either ceftazidime (a primarily anti-Gram negative bacteria antibiotic) or vancomycin (mainly anti-Gram positive bacteria activity) in an escalating three-dose regimen. We also dosed animals with a well-known prebiotic weight-loss supplement, 10% oligofructose saccharide (10% OFS). Vancomycin treated mice showed little weight change and no improvement in glycemic control while ceftazidime and 10% OFS treatments induced significant weight loss. However, only ceftazidime showed significant, dose dependent improvement in key metabolic variables including glucose, insulin, protein tyrosine tyrosine (PYY) and glucagon-like peptide-1 (GLP-1). Subsequently, we confirmed the positive hyperglycemic control effects of ceftazidime in the Zucker diabetic fatty (ZDF) rat model. Metagenomic DNA sequencing of bacterial 16S rRNA gene regions V1-V3 showed that the microbiomes of ceftazidime dosed mice and rats were enriched for the phylum Firmicutes while 10% OFS treated mice had a greater abundance of Bacteroidetes. We show that specific changes in microbial community composition are associated with obesity and glycemic control phenotypes. More broadly, our study suggests that in vivo modulation of the microbiome warrants further investigation as a potential therapeutic strategy for metabolic diseases. PMID:26709835

  14. Sex Differences in Mechanisms and Outcome of Neonatal Hypoxia-Ischemia in Rodent Models: Implications for Sex-Specific Neuroprotection in Clinical Neonatal Practice

    PubMed Central

    Hill, Courtney A.; Fitch, R. Holly

    2012-01-01

    Clinical findings show that male infants with hypoxic-ischemic injury (HI) fare more poorly than matched females on cognitive outcomes. Rodent models of neonatal hypoxia-ischemia support this difference, with data showing that perinatal brain injury leads to long-term behavioral deficits primarily in male rodents and in female rodents treated with early androgens. Results support the idea that sex-specific gonadal hormones may modulate developmental response to injury and dovetail with overwhelming evidence of developmental androgen effects on typical brain morphology and behavior. However, mechanisms underlying sex differences in response to early brain injury may be more complicated. Specifically, activation of cell death pathways in response to HI may also differ by sex. In females, the preferential activation of the caspase-dependent apoptotic pathway may actually afford greater protection, potentially due to the actions of X-linked inhibitor of apoptosis (XIAP) within this pathway. This contrasts the pattern of preferential activation of the caspase-independent pathway in males. While an integrated model of sex-specific hormonal and genetic modulation of response to early injury remains to be fully elucidated, these findings suggest that infants might benefit from sex-specific neuroprotection following HI injury. PMID:22474588

  15. Sex differences in mechanisms and outcome of neonatal hypoxia-ischemia in rodent models: implications for sex-specific neuroprotection in clinical neonatal practice.

    PubMed

    Hill, Courtney A; Fitch, R Holly

    2012-01-01

    Clinical findings show that male infants with hypoxic-ischemic injury (HI) fare more poorly than matched females on cognitive outcomes. Rodent models of neonatal hypoxia-ischemia support this difference, with data showing that perinatal brain injury leads to long-term behavioral deficits primarily in male rodents and in female rodents treated with early androgens. Results support the idea that sex-specific gonadal hormones may modulate developmental response to injury and dovetail with overwhelming evidence of developmental androgen effects on typical brain morphology and behavior. However, mechanisms underlying sex differences in response to early brain injury may be more complicated. Specifically, activation of cell death pathways in response to HI may also differ by sex. In females, the preferential activation of the caspase-dependent apoptotic pathway may actually afford greater protection, potentially due to the actions of X-linked inhibitor of apoptosis (XIAP) within this pathway. This contrasts the pattern of preferential activation of the caspase-independent pathway in males. While an integrated model of sex-specific hormonal and genetic modulation of response to early injury remains to be fully elucidated, these findings suggest that infants might benefit from sex-specific neuroprotection following HI injury. PMID:22474588

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

    USGS Publications Warehouse

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

    2007-01-01

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

  17. Yeast-containing feed additive alters gene expression profiles associated with innate immunity in whole blood of a rodent model.

    PubMed

    Branson, Jennifer A; McLean, Derek J; Forsberg, Neil E; Bobe, Gerd

    2016-05-01

    Feeding a yeast-containing additive (YCA; OmniGen-AF) improves immune responses in ruminant livestock and reduces subsequent production losses. The objective was to identify molecular pathways by which dietary YCA may modify immune responses using a rodent model. Thirty-seven healthy, unchallenged CD rats received a diet containing 0 (control; n = 5, only 28 d), 0.5% (n = 15) or 1% (n = 17) YCA for 7 (n = 4/group), 14 (n = 3 or 4/group), 21 (n = 3 or 4/group) or 28 (n = 5/group) d. At the end of the feeding periods, whole blood was collected and the isolated RNA was analyzed for the expression of 84 genes involved in innate and cell-mediated adaptive immune responses. Three bacterial pattern recognition receptors TLR1 (0.5%: + 2.01; 1%: + 2.38), TLR6 (0.5%: + 2.11; 1%: + 2.34) and NOD2 (0.5%: + 2.32; 1%: + 2.23), two APC surface receptors CD1D1 (0.5%: + 1.75; 1%: + 2.33) and CD80 (0.5%: +2.45; 1%: +3.00), and the cell signaling molecule MAPK8 (0.5%: +1.87; 1%: +2.35) were significantly up-regulated by YCA at both inclusion rates. In conclusion, feeding YCA may potentially increase recognition and responses to bacterial pathogens and T-cell activation and differentiation and thereby maintain health and prevent production losses. PMID:27033362

  18. Seizure Suppression Efficacy of Closed-Loop Versus Open-Loop Deep Brain Stimulation in a Rodent Model of Epilepsy.

    PubMed

    Salam, M Tariqus; Perez Velazquez, Jose Luis; Genov, Roman

    2016-06-01

    We assess and compare the effects of both closed-loop and open-loop neurostimulation of the rat hippocampus by means of a custom low-power programmable therapeutic neurostimulation device on the suppression of spontaneous seizures in a rodent model of epilepsy. Chronic seizures were induced by intraperitoneal kainic acid injection. Two bipolar electrodes were implanted into the CA1 regions of both hippocampi. The electrodes were connected to the custom-built programmable therapeutic neurostimulation device that can trigger an electrical stimulation either in a periodic manner or upon detection of the intracerebral electroencephalographic (icEEE) seizure onset. This device includes a microchip consisting of a 256-channel icEEG recording system and a 64-channel stimulator, and a programmable seizure detector implemented in a field-programmable gate array (FPGA). The neurostimulator was used to evaluate seizure suppression efficacy in ten epileptic rats for a total of 240 subject-days (5760 subject-hours). For this purpose, all rats were randomly divided into two groups: the no-stimulation group and the stimulation group. The no-stimulation group did not receive stimulation. The stimulation group received, first, closed-loop stimulation and, next, open-loop stimulation. The no-stimulation and stimulation groups had a similar seizure frequency baseline, averaging five seizures per day. Closed-loop stimulation reduced seizure frequency by 90% and open-loop stimulation reduced seizure frequency by 17%, both in the stimulation group as compared to the no-stimulation group. PMID:26571534

  19. Delayed Post-Injury Administration of Riluzole Is Neuroprotective in a Preclinical Rodent Model of Cervical Spinal Cord Injury

    PubMed Central

    Wu, Yongchao; Satkunendrarajah, Kajana; Teng, Yang; Chow, Diana S.-L.; Buttigieg, Josef

    2013-01-01

    Abstract Riluzole, a sodium/glutamate antagonist has shown promise as a neuroprotective agent. It is licensed for amyotrophic lateral sclerosis and is in clinical trial development for spinal cord injury (SCI). This study investigated the therapeutic time-window and pharmacokinetics of riluzole in a rodent model of cervical SCI. Rats were treated with riluzole (8 mg/kg) at 1 hour (P1) and 3 hours (P3) after injury or with vehicle. Afterward, P1 and P3 groups received riluzole (6 (mg/kg) every 12 hours for 7 days. Both P1 and P3 animals had significant improvements in locomotor recovery as measured by open field locomotion (BBB score, BBB subscore). Von Frey stimuli did not reveal an increase in at level or below level mechanical allodynia. Sensory-evoked potential recordings and quantification of axonal cytoskeleton demonstrated a riluzole-mediated improvement in axonal integrity and function. Histopathological and retrograde tracing studies demonstrated that delayed administration leads to tissue preservation and reduces apoptosis and inflammation. High performance liquid chromatography (HPLC) was undertaken to examine the pharmacokinetics of riluzole. Riluzole penetrates the spinal cord in 15 min, and SCI slowed elimination of riluzole from the spinal cord, resulting in a longer half-life and higher drug concentration in spinal cord and plasma. Initiation of riluzole treatment 1 and 3 hours post-SCI led to functional, histological, and molecular benefits. While extrapolation of post-injury time windows from rat to man is challenging, evidence from SCI-related biomarker studies would suggest that the post-injury time window is likely to be at least 12 hours in man. PMID:23517137

  20. Real-time Closed-loop Control in a Rodent Model of Medically-induced Coma Using Burst Suppression

    PubMed Central

    Ching, ShiNung; Liberman, Max Y.; Chemali, Jessica J.; Westover, M. Brandon; Kenny, Jonathan; Solt, Ken; Purdon, Patrick L.; Brown, Emery N.

    2013-01-01

    Background A medically-induced coma is an anesthetic state of profound brain inactivation created to treat status epilepticus and to provide cerebral protection following traumatic brain injuries. We hypothesized that a closed-loop anesthetic delivery system could automatically and precisely control the electroencephalogram state of burst suppression and efficiently maintain a medically-induced coma. Methods In six rats, we implemented a closed-loop anesthetic delivery system for propofol consisting of: a computer-controlled pump infusion, a two-compartment pharmacokinetics model defining propofol’s electroencephalogram effects, the burst suppression probability algorithm to compute in real time from the electroencephalogram the brain’s burst suppression state, an on-line parameter estimation procedure and a proportional-integral controller. In the control experiment each rat was randomly assigned to one of the six burst suppression probability target trajectories constructed by permuting the burst suppression probability levels of 0.4, 0.65 and 0.9 with linear transitions between levels. Results In each animal the controller maintained approximately 60 min of tight, real-time control of burst suppression by tracking each burst suppression probability target level for 15 min and two between-level transitions for 5 to 10 min. The posterior probability that the closed-loop anesthetic delivery system was reliable across all levels was 0.94 [95% confidence interval; (0.77 to 1.00) n = 18] and that the system was accurate was 1.00 [95% confidence interval; (0.84 to 1.00) n = 18]. Conclusion Our findings establish the feasibility of using a closed-loop anesthetic delivery systems to achieve in real-time reliable and accurate control of burst suppression in rodents and suggest a paradigm to precisely control medically-induced coma in patients. PMID:23770601

  1. Activation of orexin neurons in dorsomedial/perifornical hypothalamus and antidepressant reversal in a rodent model of depression.

    PubMed

    Nollet, Mathieu; Gaillard, Philippe; Minier, Frédéric; Tanti, Arnaud; Belzung, Catherine; Leman, Samuel

    2011-01-01

    Chronic stressful life events are risk factors for depression often accompanied by homeostatic disturbances. Hypothalamic neuropeptides, such as orexins (OXs) and melanin-concentrating hormone (MCH), are involved in regulation of several autonomic functions that are altered in depression. However, little is known about the link between orexinergic or MCH-ergic systems and depression. Using double immunohistochemical labeling for OX- or MCH-containing neurons and Fos protein, we studied the effects of a chronic selective serotonin reuptake inhibitor antidepressant treatment (fluoxetine) on the OX and MCH neuronal activation in mice exposed to unpredictable chronic mild stress (UCMS), a rodent model of depression. Western blot was also performed to assess OX and MCH receptor expression in various brain areas. Finally, almorexant, a dual OX receptor antagonist, was assessed in the tail suspension test. UCMS induced physical and behavioral disturbances in mice reversed by 6-week fluoxetine treatment. Orexinergic neurons were more activated in the dorsomedial and perifornical hypothalamic area (DMH-PFA) of UCMS-subjected mice compared to the lateral hypothalamus (LH), and this increase was reversed by 6-week fluoxetine treatment. UCMS also reduced expression of OX-receptor 2 in the thalamus and hypothalamus, but not in animals chronically treated with fluoxetine. MCH neurons were neither affected by UCMS nor by antidepressant treatment, while UCMS modulated MCH receptor 1 expression in thalamus and hippocampus. Finally, chronic but not acute administration of almorexant, induced antidepressant-like effect in the tail suspension test. These data suggest that OX neurons in the DMH-PFA and MCH-ergic system may contribute to the pathophysiology of depressive disorders. PMID:21530551

  2. The biological effects of tocotrienol on bone: a review on evidence from rodent models

    PubMed Central

    Chin, Kok-Yong; Ima-Nirwana, Soelaiman

    2015-01-01

    Osteoporosis causes significant health care and economic burden to society, leading to a relentless search for effective preventive agents. Tocotrienol, a member of the vitamin E family, has demonstrated promising potential as an osteoporosis-preventing agent. This review summarizes evidence on the effects of tocotrienol on bone in animal models. Techniques used to examine the effects of tocotrienol on bone in animals included bone histomorphometry, X-ray microtomography, dual-energy X-ray absorptiometry, bone turnover markers, bone calcium content, and biomechanical strength. Tocotrienol was shown to improve osteoblast number, bone formation, mineral deposition, and bone microarchitecture in osteopenic rats. It also decreased osteoclast number and bone erosion in the rats. Tocotrienol supplementation resulted in an improvement in bone mineral density, although biomechanical strength was not significantly altered in the rats. The beneficial effects of tocotrienol on bone can be attributed to its role as an antioxidant, anti-inflammatory agent, suppressor of the mevalonate pathway, and modulator of genes favorable to bone formation. PMID:25897211

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

    PubMed Central

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

    2015-01-01

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

  4. Premenopausal Obesity and Breast Cancer Growth Rates in a Rodent Model

    PubMed Central

    Matthews, Shawna B.; McGinley, John N.; Neil, Elizabeth S.; Thompson, Henry J.

    2016-01-01

    Obese premenopausal women with breast cancer have poorer prognosis for long term survival, in part because their tumors are larger at the time of diagnosis than are found in normal weight women. Whether larger tumor mass is due to obesity-related barriers to detection or to effects on tumor biology is not known. This study used polygenic models for obesity and breast cancer to deconstruct this question with the objective of determining whether cell autonomous mechanisms contribute to the link between obesity and breast cancer burden. Assessment of the growth rates of 259 chemically induced mammary carcinomas from rats sensitive to dietary induced obesity (DS) and of 143 carcinomas from rats resistant (DR) to dietary induced obesity revealed that tumors in DS rats grew 1.8 times faster than in DR rats. This difference may be attributed to alterations in cell cycle machinery that permit more rapid tumor cell accumulation. DS tumors displayed protein expression patterns consistent with reduced G1/S checkpoint inhibition and a higher threshold of factors required for execution of the apoptotic cell death pathway. These mechanistic insights identify regulatory targets for life style modifications or pharmacological interventions designed to disrupt the linkage between obesity and tumor burden. PMID:27077880

  5. An in vitro model of epithelial cell growth stimulation in the rodent mammary gland.

    PubMed

    Ehmann, U K; DeVries, J T; Chen, M S C; Adamos, A A; Guzman, R C; Omary, M B

    2003-08-01

    Mouse mammary epithelial cell cultures previously described bring about extensive proliferation and a cell population with the appropriate markers for luminal ductal epithelial cells, and also the ability to form normal tissue after implantation into mice. This success may result from a culture environment that resembles certain aspects of the environment in the mammary gland. Mouse mammary epithelial cells, whose proliferation is limited when plated alone, can be stimulated to multiply by contact with lethally irradiated cells of the LA7 rat mammary tumour line. Most of the proliferative stimulus is imparted by direct cell contact between LA7 and mouse mammary cells. Junctions, including adherens junctions, form among all cells in the culture, much as junctions form in the mammary gland. LA7 cells secrete TGFalpha and bFGF, factors found in the mammary gland, and factors to which mouse mammary cells respond in culture. Mouse mammary cells express keratins 8 and 18, markers for luminal cells of the mammary duct. LA7 cells express keratin 14 and vimentin, markers for myoepithelial cells. These facts, taken together, fit a model of cell replacement in an epithelial tissue and also imitate the relationship between luminal ductal cells and myoepithelial cells in the mammary gland. This method of culturing cells is useful, not only for in vitro-in vivo carcinogenesis studies, but also for the study of mechanisms by which growth signals are imparted from one cell to another. PMID:12950387

  6. The xanthine oxidase inhibitor febuxostat suppresses development of nonalcoholic steatohepatitis in a rodent model.

    PubMed

    Nakatsu, Yusuke; Seno, Yasuyuki; Kushiyama, Akifumi; Sakoda, Hideyuki; Fujishiro, Midori; Katasako, Aya; Mori, Keiichi; Matsunaga, Yasuka; Fukushima, Toshiaki; Kanaoka, Ryuhei; Yamamotoya, Takeshi; Kamata, Hideaki; Asano, Tomoichiro

    2015-07-01

    Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnel-positive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia. PMID:25999428

  7. Premenopausal Obesity and Breast Cancer Growth Rates in a Rodent Model.

    PubMed

    Matthews, Shawna B; McGinley, John N; Neil, Elizabeth S; Thompson, Henry J

    2016-01-01

    Obese premenopausal women with breast cancer have poorer prognosis for long term survival, in part because their tumors are larger at the time of diagnosis than are found in normal weight women. Whether larger tumor mass is due to obesity-related barriers to detection or to effects on tumor biology is not known. This study used polygenic models for obesity and breast cancer to deconstruct this question with the objective of determining whether cell autonomous mechanisms contribute to the link between obesity and breast cancer burden. Assessment of the growth rates of 259 chemically induced mammary carcinomas from rats sensitive to dietary induced obesity (DS) and of 143 carcinomas from rats resistant (DR) to dietary induced obesity revealed that tumors in DS rats grew 1.8 times faster than in DR rats. This difference may be attributed to alterations in cell cycle machinery that permit more rapid tumor cell accumulation. DS tumors displayed protein expression patterns consistent with reduced G1/S checkpoint inhibition and a higher threshold of factors required for execution of the apoptotic cell death pathway. These mechanistic insights identify regulatory targets for life style modifications or pharmacological interventions designed to disrupt the linkage between obesity and tumor burden. PMID:27077880

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

    PubMed

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

    2016-02-01

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

  9. Impaired Limbic Cortico-Striatal Structure and Sustained Visual Attention in a Rodent Model of Schizophrenia

    PubMed Central

    Barnes, Samuel A.; Sawiak, Stephen J.; Caprioli, Daniele; Jupp, Bianca; Buonincontri, Guido; Mar, Adam C.; Harte, Michael K.; Fletcher, Paul C.; Robbins, Trevor W.; Neill, Jo C.

    2015-01-01

    Background: N-methyl-d-aspartate receptor (NMDAR) dysfunction is thought to contribute to the pathophysiology of schizophrenia. Accordingly, NMDAR antagonists such as phencyclidine (PCP) are used widely in experimental animals to model cognitive impairment associated with this disorder. However, it is unclear whether PCP disrupts the structural integrity of brain areas relevant to the profile of cognitive impairment in schizophrenia. Methods: Here we used high-resolution magnetic resonance imaging and voxel-based morphometry to investigate structural alterations associated with sub-chronic PCP treatment in rats. Results: Sub-chronic exposure of rats to PCP (5mg/kg twice daily for 7 days) impaired sustained visual attention on a 5-choice serial reaction time task, notably when the attentional load was increased. In contrast, sub-chronic PCP had no significant effect on the attentional filtering of a pre-pulse auditory stimulus in an acoustic startle paradigm. Voxel-based morphometry revealed significantly reduced grey matter density bilaterally in the hippocampus, anterior cingulate cortex, ventral striatum, and amygdala. PCP-treated rats also exhibited reduced cortical thickness in the insular cortex. Conclusions: These findings demonstrate that sub-chronic NMDA receptor antagonism is sufficient to produce highly-localized morphological abnormalities in brain areas implicated in the pathogenesis of schizophrenia. Furthermore, PCP exposure resulted in dissociable impairments in attentional function. PMID:25552430

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

    PubMed

    Dhanda, Saurabh; Sandhir, Rajat

    2015-06-01

    The present study was designed to evaluate the role of biogenic amines in behavioral alterations observed in rat model of hepatic encephalopathy (HE) following bile duct ligation (BDL). Male Wistar rats subjected to BDL developed biliary fibrosis after four weeks which was supported by altered liver function tests, increased ammonia levels and histological staining (Sirius red). Animals were assessed for their behavioral performance in terms of cognitive, anxiety and motor functions. The levels of dopamine (DA), serotonin (5-HT), epinephrine and norepinephrine (NE) were estimated in different regions of brain viz. cortex, hippocampus, striatum and cerebellum using HPLC along with activity of monoamine oxidase (MAO). Cognitive assessment of BDL rats revealed a progressive decline in learning, memory formation, retrieval, exploration of novel environment and spontaneous locomotor activity along with decrease in 5-HT and NE levels. This was accompanied by an increase in MAO activity. Motor functions of BDL rats were also altered which were evident from decrease in the time spent on the rotating rod and higher foot faults assessed using narrow beam walk task. A global decrease was observed in the DA content along with an increase in MAO activity. Histopathological studies using hematoxylin-eosin (H&E) and cresyl violet exhibited marked neuronal degeneration, wherein neurons appeared more pyknotic, condensed and damaged. The results reveal that dopaminergic and serotonergic pathways are disturbed in chronic liver failure post-BDL which may be responsible for behavioral impairments observed in HE. PMID:25639545

  11. A silybin-phospholipid complex prevents mitochondrial dysfunction in a rodent model of nonalcoholic steatohepatitis.

    PubMed

    Serviddio, Gaetano; Bellanti, Francesco; Giudetti, Anna Maria; Gnoni, Gabriele Vincenzo; Petrella, Antonio; Tamborra, Rosanna; Romano, Antonino Davide; Rollo, Tiziana; Vendemiale, Gianluigi; Altomare, Emanuele

    2010-03-01

    Mitochondrial dysfunction and oxidative stress are determinant events in the pathogenesis of nonalcoholic steatohepatitis. Silybin has shown antioxidant, anti-inflammatory, and antifibrotic effects in chronic liver disease. We aimed to study the effect of the silybin-phospholipid complex (SILIPHOS) on liver redox balance and mitochondrial function in a dietary model of nonalcoholic steatohepatitis. To accomplish this, glutathione oxidation, mitochondrial oxygen uptake, proton leak, ATP homeostasis, and H(2)O(2) production rate were evaluated in isolated liver mitochondria from rats fed a methionine- and choline-deficient (MCD) diet and the MCD diet plus SILIPHOS for 7 and 14 weeks. Oxidative proteins, hydroxynonenal (HNE)- and malondialdehyde (MDA)-protein adducts, and mitochondrial membrane lipid composition were also measured. Treatment with SILIPHOS limited glutathione depletion and mitochondrial H(2)O(2) production. Moreover, SILIPHOS preserved mitochondrial bioenergetics and prevented mitochondrial proton leak and ATP reduction. Finally, SILIPHOS limited the formation of HNE- and MDA-protein adducts. In conclusion, SILIPHOS is effective in preventing severe oxidative stress and preserving hepatic mitochondrial bioenergetics in nonalcoholic steatohepatitis induced by the MCD diet. The modifications of mitochondrial membrane fatty acid composition induced by the MCD diet are partially prevented by SILIPHOS, conferring anti-inflammatory and antifibrotic effects. The increased vulnerability of lipid membranes to oxidative damage is limited by SILIPHOS through preserved mitochondrial function. PMID:20008062

  12. Effect of vasopressin on hippocampal injury in a rodent model of asphyxial cardiopulmonary arrest

    PubMed Central

    ZHANG, NAN; ZANG, XIU-XIAN; DONG, NING; LIU, FANG; WANG, SHAO-KUN; YAN, HE; XU, DA-HAI; LIU, XIAO-LIANG; PANG, LI

    2016-01-01

    The effect of vasopressin on the neuronal injury following the restoration of spontaneous circulation (ROSC) in cardiac arrest (CA) is not yet fully understood. The present study was conducted in order to investigate the effect of vasopressin alone, or in combination with epinephrine, on the ROSC and hippocampal injury in a rat model of asphyxial CA. Asphyxial CA was induced in 144 rats by clamping the tracheal tube, and animals were allocated equally into the following three groups: Treatment with vasopressin (0.8 U/kg); epinephrine (0.2 mg/kg); or vasopressin (0.8 U/kg) plus epinephrine (0.2 mg/kg). An additional 48 rats underwent a sham surgical procedure without asphyxial CA and cardiopulmonary resuscitation. Hippocampal tissue was harvested at 1, 3, 6 and 12 h post-ROSC, and the levels of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) p65 were determined using immunohistochemistry. In comparison with rats treated with epinephrine alone, higher ROSC success rates were observed in rats treated with vasopressin, or vasopressin plus epinephrine. In addition, treatment with vasopressin attenuated hippocampal injury and reduced hippocampal p38 MAPK and NF-κB expression more efficiently compared with epinephrine alone. In conclusion, treatment with vasopressin exhibits a protective effect in patients experiencing CA, and this may be attributed to the inhibition of p38 MAPK and NF-κB expression. PMID:27073454

  13. A rodent model for Wilms tumors: embryonal kidney neoplasms induced by N-nitroso-N'-methylurea.

    PubMed Central

    Sharma, P M; Bowman, M; Yu, B F; Sukumar, S

    1994-01-01

    Embryonal kidney cell tumors develop in rats given the alkylating agent N-nitroso-N'-methylurea as neonates. These tumors resemble the childhood Wilms tumors in their histopathology. Deletions and mutations in the Wilms tumor suppressor gene, WT1, are present in up to 6% of childhood nephroblastomas. To investigate the role of WT1 in rat kidney tumorigenesis, we studied the genetic alterations in WT1 and its target genes. Point mutations were found in WT1 cDNA in 7 of 18 kidney tumors. Mesenchymal tumors contained G-->A transition mutations in codons 128, 364, and 372, typical of the methylating action of N-nitroso-N'-methylurea on DNA. Each of the four nephroblastomas contained the same T-->A mutation at codon 111 of WT1, reflective of transversion mutagenesis by N-nitroso-N'-methylurea in vivo. Like Wilms tumors, mRNA levels of WT1, IGF2, Pax-2, and MK genes were higher than newborn kidney in the majority of the tumors. The histopathology of the rat kidney tumors and the genetic alterations are reminiscent of those observed in Wilms tumors, establishing this as a relevant model system for the human disease. Images PMID:7937920

  14. Phosphodiesterase 7 Inhibition Preserves Dopaminergic Neurons in Cellular and Rodent Models of Parkinson Disease

    PubMed Central

    Morales-Garcia, Jose A.; Redondo, Miriam; Alonso-Gil, Sandra; Gil, Carmen; Perez, Concepción; Martinez, Ana; Santos, Angel; Perez-Castillo, Ana

    2011-01-01

    Background Phosphodiesterase 7 plays a major role in down-regulation of protein kinase A activity by hydrolyzing cAMP in many cell types. This cyclic nucleotide plays a key role in signal transduction in a wide variety of cellular responses. In the brain, cAMP has been implicated in learning, memory processes and other brain functions. Methodology/Principal Findings Here we show a novel function of phosphodiesterase 7 inhibition on nigrostriatal dopaminergic neuronal death. We found that S14, a heterocyclic small molecule inhibitor of phosphodiesterase 7, conferred significant neuronal protection against different insults both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures. S14 treatment also reduced microglial activation, protected dopaminergic neurons and improved motor function in the lipopolysaccharide rat model of Parkinson disease. Finally, S14 neuroprotective effects were reversed by blocking the cAMP signaling pathways that operate through cAMP-dependent protein kinase A. Conclusions/Significance Our findings demonstrate that phosphodiesterase 7 inhibition can protect dopaminergic neurons against different insults, and they provide support for the therapeutic potential of phosphodiesterase 7 inhibitors in the treatment of neurodegenerative disorders, particularly Parkinson disease. PMID:21390306

  15. Operant assays for assessing pain in preclinical rodent models: highlights from an orofacial assay.

    PubMed

    Murphy, Niall P; Mills, Richard H; Caudle, Robert M; Neubert, John K

    2014-01-01

    Despite an immense investment of resources, pain remains at epidemic proportions. Given this, there has been an increased effort toward appraising the process by which new painkillers are developed, focusing specifically on why so few analgesics make it from the benchside to the bedside. The use of behavioral assays and animal modeling for the preclinical stages of analgesic development is being reexamined to determine whether they are truly relevant, meaningful, and predictive. Consequently, there is a strengthening consensus that the traditional reflex-based assays upon which several decades of preclinical pain research has been based are inadequate. Thus, investigators have recently turned to the development of new preclinical assays with improved face, content, and predictive validity. In this regard, operant pain assays show considerable promise, as they are more sensitive, present better validity, and, importantly, better encompass the psychological and affective dimensions of pain that trouble human pain sufferers. Here, we briefly compare and contrast reflex assays with operant assays, and we introduce a particular operant orofacial pain assay used in a variety of experiments to emphasize how operant pain assays can be applied to preclinical studies of pain. PMID:25103871

  16. Comparisons between Garcia, Modo, and Longa rodent stroke scales: Optimizing resource allocation in rat models of focal middle cerebral artery occlusion.

    PubMed

    Bachour, Salam P; Hevesi, Mario; Bachour, Ornina; Sweis, Brian M; Mahmoudi, Javad; Brekke, Julia A; Divani, Afshin A

    2016-05-15

    The use of rodent stroke models allow for the understanding of stroke pathophysiology. There is currently no gold standard neurological assessment to measure deficits and recovery from stroke in rodent models. Agreement on a universal preclinical stroke scale allows for comparison of the outcomes among conducted studies. The present study aimed to compare three routinely used neurological assessments in rodent studies (i.e., Garcia, Modo, and Longa) to determine which is most effective for accurately and consistently quantifying neurological deficits in the context of focal middle cerebral artery occlusion (MCAo) in rats. Focal MCAo was induced in 22 male Wistar rats using a novel transfemoral approach. Rodents were assessed for neurological deficit pre-injury as well as 3 and 24h post-injury. Data was analyzed to determine Pearson correlation coefficients in addition to McNemar's χ(2) values between each pair of neurological assessments. All three stroke scales, Garcia, Modo, and Longa, showed statistically significant changes between the baseline and the 3-hour neurological assessments. A trend towards neurological recovery was observed in all three stroke scales between the 3 and 24-hour endpoints. The three scales were highly correlated with each other, with Garcia and Modo having the strongest correlation. Of the three pairwise analyses, the comparison between the Garcia and Longa tests demonstrated the highest McNemar's χ(2) value, indicating least marginal homogeneity between these two tests. The combination of high correlation between Garcia and Modo tests along with greatest marginal heterogeneity observed between the Garcia and Longa test lead us to recommend the use of Garcia and Longa neurological scales when researchers are hoping to capture the broadest range of neurological factors using only two stroke scales. PMID:27084232

  17. Automated rodent in situ muscle contraction assay and myofiber organization analysis in sarcopenia animal models.

    PubMed

    Weber, H; Rauch, A; Adamski, S; Chakravarthy, K; Kulkarni, A; Dogdas, B; Bendtsen, C; Kath, G; Alves, S E; Wilkinson, H A; Chiu, C-S

    2012-06-01

    Age-related sarcopenia results in frailty and decreased mobility, which are associated with increased falls and long-term disability in the elderly. Given the global increase in lifespan, sarcopenia is a growing, unmet medical need. This report aims to systematically characterize muscle aging in preclinical models, which may facilitate the development of sarcopenia therapies. Naïve rats and mice were subjected to noninvasive micro X-ray computed tomography (micro-CT) imaging, terminal in situ muscle function characterizations, and ATPase-based myofiber analysis. We developed a Definiens (Parsippany, NJ)-based algorithm to automate micro-CT image analysis, which facilitates longitudinal in vivo muscle mass analysis. We report development and characterization of translational in situ skeletal muscle performance assay systems in rat and mouse. The systems incorporate a custom-designed animal assay stage, resulting in enhanced force measurement precision, and LabVIEW (National Instruments, Austin, TX)-based algorithms to support automated data acquisition and data analysis. We used ATPase-staining techniques for myofibers to characterize fiber subtypes and distribution. Major parameters contributing to muscle performance were identified using data mining and integration, enabled by Labmatrix (BioFortis, Columbia, MD). These technologies enabled the systemic and accurate monitoring of muscle aging from a large number of animals. The data indicated that longitudinal muscle cross-sectional area measurement effectively monitors change of muscle mass and function during aging. Furthermore, the data showed that muscle performance during aging is also modulated by myofiber remodeling factors, such as changes in myofiber distribution patterns and changes in fiber shape, which affect myofiber interaction. This in vivo muscle assay platform has been applied to support identification and validation of novel targets for the treatment of sarcopenia. PMID:22461442

  18. Hypergravity-induced immunomodulation in a rodent model: lymphocytes and lymphoid organs

    NASA Technical Reports Server (NTRS)

    Gridley, Daila S.; Pecaut, Michael J.; Green, Lora M.; Miller, Glen M.; Nelson, Gregory A.

    2002-01-01

    The major goal of this study was to quantify changes in lymphoid organs and cells over time due to centrifugation-induced hypergravity. C57BL/6 mice were exposed to 1, 2 and 3 G and the following assays were performed on days 1, 4, 7, 10, and 21: spleen, thymus, lung, and liver masses; total leukocyte, lymphocyte, monocyte/macrophage, and granulocyte counts; level of splenocyte apoptosis; enumeration of CD3+ T, CD3+/CD4+ T helper, CD3+/CD8+ T cytotoxic, B220+ B, and NK1.1+ natural killer cells; and quantification of cells expressing CD25, CD69, and CD71 activation markers. The data show that increased gravity resulted in decreased body, spleen, thymus, and liver, but not lung, mass. Significant reductions were noted in all three major leukocyte populations (lymphocytes, granulocytes, monocyte/macrophages) [correction of macrphages] with increased gravity; persistent depletion was noted in blood but not spleen. Among the various lymphocyte populations, the CD3+/CD8+ T cells and B220+ B cells were the most affected and NK1.1+ NK cells the least affected. Overall, the changes were most evident during the first week, with a greater influence noted for cells in the spleen. A linear relationship was found between some of the measurements and the level of gravity, especially on day 4. These findings indicate that hypergravity profoundly alters leukocyte number and distribution in a mammalian model and that some aberrations persisted throughout the three weeks of the study. In certain cases, the detected changes were similar to those observed after whole-body irradiation. In future investigations we hope to combine hypergravity with low-dose rate irradiation and immune challenge.

  19. Neuroprotective profile of novel SRC kinase inhibitors in rodent models of cerebral ischemia.

    PubMed

    Liang, Shi; Pong, Kevin; Gonzales, Cathleen; Chen, Yi; Ling, Huai-Ping; Mark, Robert J; Boschelli, Frank; Boschelli, Diane H; Ye, Fei; Barrios Sosa, Ana Carolina; Mansour, Tarek S; Frost, Philip; Wood, Andrew; Pangalos, Menelas N; Zaleska, Margaret M

    2009-12-01

    Src kinase signaling has been implicated in multiple mechanisms of ischemic injury, including vascular endothelial growth factor (VEGF)-mediated vascular permeability that leads to vasogenic edema, a major clinical complication in stroke and brain trauma. Here we report the effects of two novel Src kinase inhibitors, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile (SKI-606) and 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[4-(4-methypiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927), on ischemia-induced brain infarction and short- and long-term neurological deficits. Two well established transient [transient middle cerebral artery occlusion (tMCAO)] and permanent [permanent middle cerebral artery occlusion (pMCAO)] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario. Brain penetration of Src inhibitors, their effect on blood-brain barrier integrity and VEGF signaling in human endothelial cells were also evaluated. Our results demonstrate that both agents potently block VEGF-mediated signaling in human endothelial cells, penetrate rat brain upon systemic administration, and inhibit postischemic Src activation and vascular leakage. Treatment with SKI-606 or SKS-927 (at the doses of 3-30 mg/kg i.v.) resulted in a dose-dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4- to 6-h after tMCAO. Src blockade after pMCAO resulted in accelerated improvement in recovery from motor, sensory, and reflex deficits during a long-term (3 weeks) testing period poststroke. These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke. PMID:19741150

  20. Injury predictors for traumatic axonal injury in a rodent head impact acceleration model.

    PubMed

    Li, Yan; Zhang, Liying; Kallakuri, Srinivasu; Zhou, Runzhou; Cavanaugh, John M

    2011-11-01

    A modified Marmarou impact acceleration injury model was developed to study the kinematics of the rat head to quantify traumatic axonal injury (TAI) in the corpus callosum (CC) and brainstem pyramidal tract (Py), to determine injury predictors and to establish injury thresholds for severe TAI. Thirty-one anesthetized male Sprague-Dawley rats (392±13 grams) were impacted using a modified impact acceleration injury device from 2.25 m and 1.25 m heights. Beta-amyloid precursor protein (β-APP) immunocytochemistry was used to assess and quantify axonal changes in CC and Py. Over 600 injury maps in CC and Py were constructed in the 31 impacted rats. TAI distribution along the rostro-caudal direction in CC and Py was determined. Linear and angular responses of the rat head were monitored and measured in vivo with an attached accelerometer and angular rate sensor, and were correlated to TAI data. Logistic regression analysis suggested that the occurrence of severe TAI in CC was best predicted by average linear acceleration, followed by power and time to surface righting. The combination of average linear acceleration and time to surface righting showed an improved predictive result. In Py, severe TAI was best predicted by time to surface righting, followed by peak and average angular velocity. When both CC and Py were combined, power was the best predictor, and the combined average linear acceleration and average angular velocity was also found to have good injury predictive ability. Receiver operator characteristic curves were used to assess the predictive power of individual and paired injury predictors. TAI tolerance curves were also proposed in this study. PMID:22869303

  1. The Effect of Mycophenolate Mofetil on Early Wound Healing in a Rodent Model

    PubMed Central

    Willems, Martine CM; Hendriks, Thijs; Lomme, Roger MLM; de Man, Ben M; van der Vliet, J Adam

    2016-01-01

    Background Immunosuppressant agents are inevitable for solid organ recipients, but may have a negative effect on wound healing that is difficult to measure because of clinical use of a polydrug regime. The evidence on mycophenolate mofetil (MMF) is scarce and contradictory. This study aims to investigate the effect of MMF administration on wound healing. Methods Ninety-six male Wistar rats divided into 4 groups underwent anastomotic construction in ileum and colon at day 0. Three groups received daily oral doses of 20 or 40 mg/kg MMF or saline (control group) from day 0 until the end of the experiment. Half of each group was analyzed after 3 days and half after 7 days. Another group started the medication 3 days after the laparotomy and was analyzed after 7 days, half of this group received 20 mg/kg and half 40 mg/kg MMF. Wound strength in anastomoses and in the abdominal wall was measured using bursting pressure, breaking strength, and histology. Trough levels were measured. Results Significant differences in wound strength were seen in ileum tissue after 3 days, which surprisingly showed a stronger anastomosis in the experimental groups. Bursting pressure as well as breaking strength was higher in the low-dose and high-dose MMF group compared with the control group. A negative effect was measured in abdominal wall tissue for the highest-dose group, which disappeared when the medication was delayed for 3 days. Histology showed poorer bridging of the submucosal layer and more polymorphonuclear cell infiltration in the ileum specimens of the control group compared with the treatment groups. Conclusions As a single agent in a preclinical wound healing model in the rat, MMF has no negative effect on healing of bowel anastomoses but might have a negative effect on the healing of abdominal wall. PMID:27500270

  2. The role of anxiety in vulnerability for self-injurious behaviour: studies in a rodent model.

    PubMed

    Yuan, X; Devine, D P

    2016-09-15

    Self-injurious behaviour (SIB) is a debilitating characteristic that is highly prevalent in autism and other neurodevelopmental disorders. Pathological anxiety is also common, and there are reports of comorbid anxiety and self-injury in some children. We have investigated potential interactions between anxiety and self-injury, using a rat model of pemoline-induced self-biting. In one experiment, rats were pre-screened for trait anxiety by measuring expression of anxiety-related behaviour on the elevated plus maze and open field emergence test. The rats were then treated with pemoline once daily for ten days, and vulnerability for pemoline-induced self-injury was evaluated. This revealed modest correlations between innate levels of anxiety-related behaviour in the open field test (time in the start box, and latency to enter the open field), and vulnerability for pemoline-induced self-biting (total duration of self-injurious oral contact, and total size of tissue injury). Measures in the elevated plus maze were not significantly correlated with vulnerability for pemoline-induced self-injury. In a second experiment, rats were treated with the beta-carboline FG 7142 twice daily, during 5days of treatment with pemoline. The rats that were treated with this anxiogenic drug exhibited greater duration of self-injurious oral contact, and larger injuries than vehicle-treated controls did. Overall, these results suggest that anxiety may contribute to the etiology and/or expression of self-injurious behaviour, and indicate that further research is warranted. PMID:27217100

  3. A rodent model for artificial gravity: VOR adaptation and Fos expression.

    PubMed

    Kaufman, Galen; Weng, Tianxiang; Ruttley, Tara

    2005-01-01

    Vestibulo-ocular reflex (VOR) adaptation and brainstem Fos expression as a result of short radius cross-coupling stimuli were investigated to find neural correlates of the inherent Coriolis force asymmetry from an artificial gravity (AG) environment. Head-fixed gerbils (Meriones unguiculatus, N=79) were exposed, in the dark, to 60--90 minutes of cross-coupled rotations, combinations of pitch (or roll) and yaw rotation, while binocular horizontal, vertical, and torsional eye position were determined using infrared video-oculography. Centripetal acceleration in combination with angular cross-coupling was also studied. Simultaneous sinusoidal rotations in two planes (yaw with roll or pitch) provided a net symmetrical stimulus for the right and left labyrinths. In contrast, a constant velocity yaw rotation during sinusoidal roll or pitch provided the asymmetric stimulus model for AG. We found orthogonally oriented half-cycle VOR gain changes. The results depended on the direction of horizontal rotation during asymmetrical cross-coupling, and other aspects of the stimulus, including the phase relationship between the two rotational inputs, the symmetry of the stimulus, and training. Fos expression also revealed laterality differences in the prepositus and inferior olivary C subnucleus. In contrast the inferior olivary beta and ventrolateral outgrowth were labeled bilaterally. Additional cross-coupling dependent labeling was found in the flocculus, hippocampus, and several cortical regions, including the perirhinal and temporal association cortices. Analyses showed significant differences across the brain regions for several factors (symmetry, rotation velocity and direction, the presence of centripetal acceleration or a visual surround, and training). Finally, animals compensating from a unilateral surgical labyrinthectomy who received multiple cross-coupling training sessions had improved half-cycle VOR gain in the ipsilateral eye with head rotation toward the intact

  4. Frequency-domain measurements of changes of optical pathlength during spreading depression in a rodent brain model

    NASA Astrophysics Data System (ADS)

    Maris, Michael B.; Mayevsky, Avraham; Sevick, Eva M.; Chance, Britton

    1991-05-01

    Previously, we have shown that time-resolved spectroscopy can monitor changes in the distribution of photon migration pathlengths which are reflective of the changes in the tissue absorption due primarily to oxygenated or deoxygenated hemoglobin. In this study, we have monitored mean photon migration pathlengths in the frequency domain in the rodent brain insulted by hypoxia, ischemia and spreading depression (SD) using phase modulated spectroscopy (PMS). This technique consisted of monitoring light which emerged from the exposed rodent skull at 8 mm form an incident light source of 754 nm and 816 nm whose intensity was modulated at 220 MHz. The changes in phase-shift, (theta), of the emergent light with respect to the incident light are reflective of the photon pathlengths and hemoglobin absorbance. A multiprobe assembly holding PMS source fiber, nicotinamide dinucleotide (NADH) fluorometric probe, electrocortigraph (ECoG) electrodes, and doppler blood flow probe was placed on the rodent brain to simultaneously monitor brain metabolism, electrical cortical activity (ECoG) and blood flow. The PMS detector fiber was placed 8 mm posterior to the multiprobe assembly. Correlations between changes in intracellular deoxygenation (NADH) and hemoglobin deoxygenation as measured by PMS changes at 754 nm and 816 nm during hypoxia, and ischemia were found. The depolarization phase of spreading depression resulted in a similar increase at both 754 nm and 816 nm. We attribute this result to vasoconstriction and/or the decrease of extracellular space due to water shift in the rodent brain.

  5. What is the effect of nicotinic acetylcholine receptor stimulation on osteoarthritis in a rodent animal model?

    PubMed Central

    Bock, Kilian; Plaass, Christian; Coger, Vincent; Peck, Claas-Tido; Reimers, Kerstin; Stukenborg-Colsman, Christina; Claassen, Leif

    2016-01-01

    Objectives: Despite the rising number of patients with osteoarthritis, no sufficient chondroprotective and prophylactic therapy for osteoarthritis has been established yet. The purpose of this study was to verify whether stimulation of the nicotinic acetylcholine receptor via nicotine has a beneficial effect on cartilage degeneration in the development of osteoarthritis and is capable of reducing the expression of proinflammatory cytokines and cartilage degrading enzymes in synovial membranes after osteoarthritis induction. Methods: Experimental osteoarthritis was induced in Lewis rats using a standardized osteoarthritis model with monoiodoacetate. A total of 16 Lewis rats were randomized into four groups: control, sham + nicotine application, osteoarthritis, and osteoarthritis + nicotine application. Nicotine (0.625 mg/kg twice daily) was administered intraperitoneally for 42 days. We analyzed histological sections, radiological images and the expression of the proinflammatory cytokines, such as interleukin-1β, tumor necrosis factor-α and interleukin-6, and of matrix metalloproteases 3, 9 and 13 and tissue inhibitors of metalloprotease-1 in synovial membranes via quantitative polymerase chain reaction. Results: Histological and x-ray examination revealed cartilage degeneration in the osteoarthritis group compared to control or sham + nicotine groups (histological control vs osteoarthritis: p = 0.002 and x-ray control vs osteoarthritis: p = 0.004). Nicotine treatment reduced the cartilage degeneration without significant differences. Osteoarthritis induction led to a higher expression of proinflammatory cytokines and matrix metalloproteases as compared to control groups. This effect was attenuated after nicotine administration. The differences of proinflammatory cytokines and matrix metalloproteases did not reach statistical significance. Conclusion: With the present small-scale study, we could not prove a positive effect of nicotinic

  6. Interhemispheric modulation of dopamine receptor interactions in unilateral 6-OHDA rodent model.

    PubMed

    Lawler, C P; Gilmore, J H; Watts, V J; Walker, Q D; Southerland, S B; Cook, L L; Mathis, C A; Mailman, R B

    1995-12-01

    A critical assumption in the unilateral 6-hydroxydopamine (6-OHDA) model is that interactions between the intact and denervated hemispheres do not influence the response to insult. The present study examined this issue by assessing the effects of unilateral substantia nigra 6-OHDA lesions in rats that previously had received corpus callosum transections, a treatment designed to minimize interhemispheric influences. Quantitative autoradiography in the caudate-putamen ipsilateral to the lesion revealed that corpus callosum transection did not alter the increase in D2-like receptors ([125I]-epidepride-labeled sites) that is induced by unilateral 6-OHDA lesion. There were no effects of either 6-OHDA lesion or transection on D1 receptor density ([125I]-SCH23982 autoradiography). As a functional endpoint, dopamine-stimulated cAMP efflux was measured in superfused striatal slices. In this paradigm, the net effect of dopamine (DA) represents a combination of D1 receptor-mediated stimulation and D2 receptor-mediated inhibition. 6-OHDA lesion increased cAMP efflux induced by exposure to 100 microM DA alone; corpus callosum transection did not alter this effect. An interaction between 6-OHDA lesion and transection status was revealed, however, by comparison of results obtained with DA alone vs. DA plus the D2 antagonist sulpiride (to block the D2 inhibitory effects of 100 microM DA). This comparison revealed two important effects of 6-OHDA lesion in rats with an intact corpus callosum: 1) a moderate decrease in dopamine D1 receptor-mediated stimulation; and 2) a dramatic decrease in the ability of D2 receptors to inhibit this stimulation. Corpus callosum transection prevented these effects of 6-OHDA. These results provide a biochemical demonstration of D1:D2 receptor uncoupling in unilateral 6-OHDA lesioned rats, and suggest that interhemispheric influences (e.g., contralateral cortico-striatal glutamatergic projections) may contribute to lesion-induced alterations in D1:D2

  7. Analgesic effects of noninvasive brain stimulation in rodent animal models: A systematic review of translational findings

    PubMed Central

    Volz, Magdalena Sarah; Volz, Theresa Sophie; Brunoni, Andre Russowsky; de Oliveira, João Paulo Vaz Tostes Ribeiro; Fregni, Felipe

    2014-01-01

    Objectives Noninvasive brain stimulation (NIBS) interventions have demonstrated promising results in the clinical treatment of pain, according to several preliminary trials, although the results have been mixed. The limitations of clinical research on NIBS are the insufficient understanding of its mechanisms of action, a lack of adequate safety data, and several disparities with regard to stimulation parameters, which have hindered the generalizability of such studies. Thus, experimental animal research that allows the use of more invasive interventions and creates additional control of independent variables and confounders is desirable. To this end, we systematically reviewed animal studies investigating the analgesic effects of NIBS. In addition we also explored the investigation of NIBS in animal models of stroke as to compare these findings with NIBS animal pain research. Methods Of 1916 articles that were found initially, we identified 15 studies (stroke and pain studies) per our eligibility criteria that used NIBS methods, such as transcranial direct current stimulation (tDCS), paired associative stimulation (PAS), transcranial magnetic stimulation (TMS), and transcranial electrostimulation (TES). We extracted the main outcomes on stroke and pain, as well as the methods and electrical parameters of each technique. Results NIBS techniques are effective in alleviating pain. Similar beneficial clinical effects are observed in stroke. The main insights from these animal studies are: (i) combination of NIBS with analgesic drugs has a synergistic effect; (ii) effects are dependent on the parameters of stimulation, and in fact, not necessarily the strongest stimulation parameter (i.e., the largest intensity of stimulation) is associated with the largest benefit; (iii) pain studies show an overall good quality as indexed by ARRIVE guidelines of the reporting of animal experiments, but insufficient with regard to the reporting of safety data for brain stimulation; (iv

  8. Older Adults in Child Care: A Job-Training Model.

    ERIC Educational Resources Information Center

    Ward, Christopher R.; Smith, Thomas B.

    Recognizing the increasing demand for older adults to work as child care employees, this manual presents the Generations Together model for training older adults at the community college level to work in child care settings. The manual describes the steps necessary to implement a community-college-based, older-adult child care employment training…

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

    PubMed

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

    2010-09-01

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

  10. Competency-Based Adult Education: Florida Model.

    ERIC Educational Resources Information Center

    Singer, Elizabeth

    This compilation of program materials serves as an introduction to Florida's Brevard Community College's (BCC's) Competency-Based Adult High School Completion Project, a multi-year project designed to teach adult administrators, counselors, and teachers how to organize and implement a competency-based adult education (CBAE) program; to critique…

  11. Evaluation of Serotonin 5-HT1A Receptors in Rodent Models using [18F]Mefway PET¶

    PubMed Central

    Saigal, Neil; Bajwa, Alisha K.; Faheem, Sara S.; Coleman, Robert A.; Pandey, Suresh K.; Constantinescu, Cristian C.; Fong, Vanessa; Mukherjee, Jogeshwar

    2013-01-01

    receptor imaging agent in rodents for studies of various disease models. PMID:23504990

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

    PubMed Central

    Xu, Xiao-meng; Cai, Guang-yan; Bu, Ru; Wang, Wen-juan; Bai, Xue-yuan; Sun, Xue-feng; Chen, Xiang-mei

    2015-01-01

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

  13. Non-Invasive Ultrasound Liver Ablation Using Histotripsy: Chronic Study in an In Vivo Rodent Model.

    PubMed

    Vlaisavljevich, Eli; Greve, Joan; Cheng, Xu; Ives, Kimberly; Shi, Jiaqi; Jin, Lifang; Arvidson, Alexa; Hall, Tim; Welling, Theodore H; Owens, Gabe; Roberts, William; Xu, Zhen

    2016-08-01

    Hepatocellular carcinoma, or liver cancer, has the fastest growing incidence among cancers in the United States. Current liver ablation methods are thermal-based and share limitations due to the heat sink effect from the blood flow through the highly vascular liver. Recently, our group has investigated histotripsy as a non-invasive liver cancer ablation method. Histotripsy is a non-thermal ultrasonic ablation method that fractionates tissue through the control of acoustic cavitation. Previous experiments in an in vivo porcine model show that histotripsy can create well-confined lesions in the liver through ribcage obstruction without damaging the overlying ribs and other tissues. Histotripsy can also completely fractionate liver tissue surrounding major vessels while preserving the vessels. In this study, we investigate the long-term effects of histotripsy liver ablation in a rodent model. We hypothesize that the fractionated histotripsy lesion will be resorbed by the liver, resulting in effective tissue healing. To test this hypothesis, the livers of 20 healthy rats were treated with histotripsy using an 8-element 1-MHz histotripsy transducer. Rats were euthanized after 0, 3, 7, 14 and 28 days (n = 4). In vivo and post mortem results showed histotripsy lesions were successfully generated through the intact abdomen in all 20 rats. Magnetic resonance imaging found primarily negative contrast on day 0, positive contrast on day 3 and rapid normalization of signal intensity thereafter (i.e., signal amplitude returned to baseline levels seen in healthy liver tissue). Histologically, lesions were completely fractionated into an acellular homogenate. The lesions had a maximum cross-sectional area of 17.2 ± 1.9 mm(2) and sharp boundaries between the lesion and the healthy surrounding tissue after treatment. As the animals recovered after treatment, the histotripsy tissue homogenate was almost completely replaced by regenerated liver parenchyma, resulting in a

  14. The Effects of Prenatal Alcohol Exposure on Behavior: Rodent and Primate Studies

    PubMed Central

    Moore, Colleen F.; Adkins, Miriam M.

    2014-01-01

    The use of alcohol by women during pregnancy is a continuing problem. In this review the behavioral effects of prenatal alcohol from animal models are described and related to studies of children and adults with FASD. Studies with monkeys and rodents show that prenatal alcohol exposure adversely affects neonatal orienting, attention and motor maturity, as well as activity level, executive function, response inhibition, and sensory processing later in life. The primate moderate dose behavioral findings fill an important gap between human correlational data and rodent mechanistic research. These animal findings are directly translatable to human findings. Moreover, primate studies that manipulated prenatal alcohol exposure and prenatal stress independently show that prenatal stress exacerbates prenatal alcohol-induced behavioral impairments, underscoring the need to consider stress-induced effects in fetal alcohol research. Studies in rodents and primates show long-term effects of prenatal and developmental alcohol exposure on dopamine system functioning, which could underpin the behavioral effects. PMID:21499982

  15. A mechanism-mediated model for carcinogenicity: model content and prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 25 organic chemicals.

    PubMed Central

    Purdy, R

    1996-01-01

    A hierarchical model consisting of quantitative structure-activity relationships based mainly on chemical reactivity was developed to predict the carcinogenicity of organic chemicals to rodents. The model is comprised of quantitative structure-activity relationships, QSARs based on hypothesized mechanisms of action, metabolism, and partitioning. Predictors included octanol/water partition coefficient, molecular size, atomic partial charge, bond angle strain, atomic acceptor delocalizibility, atomic radical superdelocalizibility, the lowest unoccupied molecular orbital (LUMO) energy of hypothesized intermediate nitrenium ion of primary aromatic amines, difference in charge of ionized and unionized carbon-chlorine bonds, substituent size and pattern on polynuclear aromatic hydrocarbons, the distance between lone electron pairs over a rigid structure, and the presence of functionalities such as nitroso and hydrazine. The model correctly classified 96% of the carcinogens in the training set of 306 chemicals, and 90% of the carcinogens in the test set of 301 chemicals. The test set by chance contained 84% of the positive thio-containing chemicals. A QSAR for these chemicals was developed. This posttest set modified model correctly predicted 94% of the carcinogens in the test set. This model was used to predict the carcinogenicity of the 25 organic chemicals the U.S. National Toxicology Program was testing at the writing of this article. PMID:8933058

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

    PubMed

    Turner, Andrew K; Paterson, Steve

    2013-04-01

    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 Blackwell Publishing Ltd. PMID:23550923

  17. Characterization of a Graded Cervical Hemicontusion Spinal Cord Injury Model in Adult Male Rats

    PubMed Central

    Dunham, Kelly A.; Siriphorn, Akkradate; Chompoopong, Supin

    2010-01-01

    Abstract Most experimental models of spinal cord injury (SCI) in rodents induce damage in the thoracic cord and subsequently examine hindlimb function as an indicator of recovery. In these models, functional recovery is most attributable to white-matter preservation and is less influenced by grey-matter sparing. In contrast, most clinical cases of SCI occur at the lower cervical levels, a region in which both grey-matter and white-matter sparing contribute to functional motor recovery. Thus experimental cervical SCI models are beginning to be developed and used to assess protective and pharmacological interventions following SCI. The objective of this study was to characterize a model of graded cervical hemicontusion SCI with regard to several histological and behavioral outcome measures, including novel forelimb behavioral tasks. Using a commercially available rodent spinal cord impactor, adult male rats received hemicontusion SCI at vertebral level C5 at 100, 200, or 300 kdyn force, to produce mild, moderate, or severe injury severities. Tests of skilled and unskilled forelimb and locomotor function were employed to assess functional recovery, and spinal cord tissue was collected to assess lesion severity. Deficits in skilled and unskilled forelimb function and locomotion relating to injury severity were observed, as well as decreases in neuronal numbers, white-matter area, and white-matter gliosis. Significant correlations were observed between behavioral and histological data. Taken together, these data suggest that the forelimb functional and locomotor assessments employed here are sensitive enough to measure functional changes, and that this hemicontusion model can be used to evaluate potential protective and regenerative therapeutic strategies. PMID:21087156

  18. New generalized poisson mixture model for bimodal count data with drug effect: An application to rodent brief-access taste aversion experiments.

    PubMed

    Sheng, Y; Soto, J; Orlu Gul, M; Cortina-Borja, M; Tuleu, C; Standing, J F

    2016-08-01

    Pharmacodynamic (PD) count data can exhibit bimodality and nonequidispersion complicating the inclusion of drug effect. The purpose of this study was to explore four different mixture distribution models for bimodal count data by including both drug effect and distribution truncation. An example dataset, which exhibited bimodal pattern, was from rodent brief-access taste aversion (BATA) experiments to assess the bitterness of ascending concentrations of an aversive tasting drug. The two generalized Poisson mixture models performed the best and was flexible to explain both under and overdispersion. A sigmoid maximum effect (Emax ) model with logistic transformation was introduced to link the drug effect to the data partition within each distribution. Predicted density-histogram plot is suggested as a model evaluation tool due to its capability to directly compare the model predicted density with the histogram from raw data. The modeling approach presented here could form a useful strategy for modeling similar count data types. PMID:27472892

  19. New generalized poisson mixture model for bimodal count data with drug effect: An application to rodent brief‐access taste aversion experiments

    PubMed Central

    Soto, J; Orlu Gul, M; Cortina‐Borja, M; Tuleu, C; Standing, JF

    2016-01-01

    Pharmacodynamic (PD) count data can exhibit bimodality and nonequidispersion complicating the inclusion of drug effect. The purpose of this study was to explore four different mixture distribution models for bimodal count data by including both drug effect and distribution truncation. An example dataset, which exhibited bimodal pattern, was from rodent brief‐access taste aversion (BATA) experiments to assess the bitterness of ascending concentrations of an aversive tasting drug. The two generalized Poisson mixture models performed the best and was flexible to explain both under and overdispersion. A sigmoid maximum effect (Emax) model with logistic transformation was introduced to link the drug effect to the data partition within each distribution. Predicted density‐histogram plot is suggested as a model evaluation tool due to its capability to directly compare the model predicted density with the histogram from raw data. The modeling approach presented here could form a useful strategy for modeling similar count data types. PMID:27472892

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

    PubMed Central

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

    2012-01-01

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

  1. Ablating Adult Neurogenesis in the Rat Has No Effect on Spatial Processing: Evidence from a Novel Pharmacogenetic Model

    PubMed Central

    Groves, James O.; Leslie, Isla; Huang, Guo-Jen; McHugh, Stephen B.; Taylor, Amy; Mott, Richard; Munafò, Marcus; Bannerman, David M.; Flint, Jonathan

    2013-01-01

    The function of adult neurogenesis in the rodent brain remains unclear. Ablation of adult born neurons has yielded conflicting results about emotional and cognitive impairments. One hypothesis is that adult neurogenesis in the hippocampus enables spatial pattern separation, allowing animals to distinguish between similar stimuli. We investigated whether spatial pattern separation and other putative hippocampal functions of adult neurogenesis were altered in a novel genetic model of neurogenesis ablation in the rat. In rats engineered to express thymidine kinase (TK) from a promoter of the rat glial fibrillary acidic protein (GFAP), ganciclovir treatment reduced new neurons by 98%. GFAP-TK rats showed no significant difference from controls in spatial pattern separation on the radial maze, spatial learning in the water maze, contextual or cued fear conditioning. Meta-analysis of all published studies found no significant effects for ablation of adult neurogenesis on spatial memory, cue conditioning or ethological measures of anxiety. An effect on contextual freezing was significant at a threshold of 5% (P = 0.04), but not at a threshold corrected for multiple testing. The meta-analysis revealed remarkably high levels of heterogeneity among studies of hippocampal function. The source of this heterogeneity remains unclear and poses a challenge for studies of the function of adult neurogenesis. PMID:24039591

  2. Ablating adult neurogenesis in the rat has no effect on spatial processing: evidence from a novel pharmacogenetic model.

    PubMed

    Groves, James O; Leslie, Isla; Huang, Guo-Jen; McHugh, Stephen B; Taylor, Amy; Mott, Richard; Munafò, Marcus; Bannerman, David M; Flint, Jonathan

    2013-01-01

    The function of adult neurogenesis in the rodent brain remains unclear. Ablation of adult born neurons has yielded conflicting results about emotional and cognitive impairments. One hypothesis is that adult neurogenesis in the hippocampus enables spatial pattern separation, allowing animals to distinguish between similar stimuli. We investigated whether spatial pattern separation and other putative hippocampal functions of adult neurogenesis were altered in a novel genetic model of neurogenesis ablation in the rat. In rats engineered to express thymidine kinase (TK) from a promoter of the rat glial fibrillary acidic protein (GFAP), ganciclovir treatment reduced new neurons by 98%. GFAP-TK rats showed no significant difference from controls in spatial pattern separation on the radial maze, spatial learning in the water maze, contextual or cued fear conditioning. Meta-analysis of all published studies found no significant effects for ablation of adult neurogenesis on spatial memory, cue conditioning or ethological measures of anxiety. An effect on contextual freezing was significant at a threshold of 5% (P = 0.04), but not at a threshold corrected for multiple testing. The meta-analysis revealed remarkably high levels of heterogeneity among studies of hippocampal function. The source of this heterogeneity remains unclear and poses a challenge for studies of the function of adult neurogenesis. PMID:24039591

  3. Implementation of a Two-dimensional Behavior Matrix to Distinguish Individuals with Differential Depression States in a Rodent Model of Depression

    PubMed Central

    Park, Jin-Young; Kim, Tae-Kyung; Choi, Juli; Lee, Jung-Eun; Kim, Hannah; Lee, Eun-Hwa

    2014-01-01

    Animal models of depression are used to study pathophysiology of depression and to advance therapeutic strategies. Stress-induced depression models in rodents are widely used. However, amenable behavioral criteria and experimental procedures that are suitable for animal models have not been established. Given that depression is clinically diagnosed by multiple symptomatic criteria and stress effects are imposed to the brain non-specifically in stress-induced depression models, analyses of depression states in rodents using multiple symptomatic criteria may provide more power than any methods relying on a single symptomatic criterion. To address this, C57BL/6 inbred mice were restrained for 2 h daily for 14 d, and depression states of individual mice were assessed using the U-field test, behavioral assessment developed to measure animal's sociability, and the tail suspension test and/or forced swim test, which are the typical methods that measure psychomotor withdrawal states. Although the majority of these mice showed severe depressive behaviors in both tests, a significant proportion of them, which were all inbred mice and received the same amount of restraints, expressed differential depression states in the sociability test and psychomotor withdrawal tests. To easily read-out differential depression states of individuals in two different tests, a standard method and basic parameters required to construct two-way behavior matrix were introduced. The utility and features of this two-way behavior analysis method for studies of different depressive states of individuals were discussed. PMID:25258568

  4. Seasonal variation in telomere length of a hibernating rodent

    PubMed Central

    Turbill, Christopher; Ruf, Thomas; Smith, Steve; Bieber, Claudia

    2013-01-01

    Small hibernating rodents have greater maximum lifespans and hence appear to age more slowly than similar-sized non-hibernators. We tested for a direct effect of hibernation on somatic maintenance and ageing by measuring seasonal changes in relative telomere length (RTL) in the edible dormouse Glis glis. Average RTL in our population did not change significantly over the hibernation season, and a regression model explaining individual variation in post-hibernation RTL suggested a significant negative effect of the reduction in body mass over the inactive hibernation period (an index of time spent euthermic), supporting the idea that torpor slows ageing. Over the active season, RTL on average decreased in sub-adults but increased in adults, supporting previous findings of greater telomere shortening at younger ages. Telomere length increase might also have been associated with reproduction, which occurred only in adults. Our study reveals how seasonal changes in physiological state influence the progress of life-history traits, such as somatic maintenance and ageing, in a small hibernating rodent. PMID:23389666

  5. The effects of the fibrin-derived peptide Bbeta(15-42) in acute and chronic rodent models of myocardial ischemia-reperfusion.

    PubMed

    Zacharowski, Kai; Zacharowski, Paula A; Friedl, Peter; Mastan, Parissa; Koch, Alexander; Boehm, Olaf; Rother, Russell P; Reingruber, Sonja; Henning, Rainer; Emeis, Jef J; Petzelbauer, Peter

    2007-06-01

    Many compounds have been shown to prevent reperfusion injury in various animal models, although to date, translation into clinic has revealed several obstacles. Therefore, the National Heart, Lung, and Blood Institute convened a working group to discuss reasons for such failure. As a result, the concept of adequately powered, blinded, randomized studies for preclinical development of a compound has been urged. We investigated the effects of a fibrin-derived peptide Bbeta(15-42) in acute and chronic rodent models of ischemia-reperfusion at three different study centers (Universities of Dusseldorf and Vienna, TNO Biomedical Research). A total of 187 animals were used, and the peptide was compared with the free radical scavenger Tempol, CD18 antibody, alpha-C5 antibody, and the golden standard, ischemic preconditioning. We show that Bbeta(15-42) robustly and reproducibly reduced infarct size in all models of ischemia-reperfusion. Moreover, the peptide significantly reduced plasma levels of the cytokines interleukin 1beta, tumor necrosis factor alpha, and interleukin 6. In rodents, Bbeta(15-42) inhibits proinflammatory cytokine release and is cardioprotective during ischemia-reperfusion injury. PMID:17505302

  6. Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models.

    PubMed

    Yang, Shilong; Xiao, Yao; Kang, Di; Liu, Jie; Li, Yuan; Undheim, Eivind A B; Klint, Julie K; Rong, Mingqiang; Lai, Ren; King, Glenn F

    2013-10-22

    Loss-of-function mutations in the human voltage-gated sodium channel NaV1.7 result in a congenital indifference to pain. Selective inhibitors of NaV1.7 are therefore likely to be powerful analgesics for treating a broad range of pain conditions. Herein we describe the identification of µ-SLPTX-Ssm6a, a unique 46-residue peptide from centipede venom that potently inhibits NaV1.7 with an IC50 of ∼25 nM. µ-SLPTX-Ssm6a has more than 150-fold selectivity for NaV1.7 over all other human NaV subtypes, with the exception of NaV1.2, for which the selectivity is 32-fold. µ-SLPTX-Ssm6a contains three disulfide bonds with a unique connectivity pattern, and it has no significant sequence homology with any previously characterized peptide or protein. µ-SLPTX-Ssm6a proved to be a more potent analgesic than morphine in a rodent model of chemical-induced pain, and it was equipotent with morphine in rodent models of thermal and acid-induced pain. This study establishes µ-SPTX-Ssm6a as a promising lead molecule for the development of novel analgesics targeting NaV1.7, which might be suitable for treating a wide range of human pain pathologies. PMID:24082113

  7. Antitumor efficacy testing in rodents.

    PubMed

    Hollingshead, Melinda G

    2008-11-01

    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

  8. Radical Reeducation: Alcoholics Anonymous as a Model in Adult Education.

    ERIC Educational Resources Information Center

    Crossman, Lenard H.

    1980-01-01

    The peer self-help group approach used by Alcoholics Anonymous can be a model for other types of adult learning. The group's power, solidarity, experience sharing, and values clarification can provide positive social and educational experiences to others such as the chronically unemployed, illiterate adults, and high school dropouts. (SK)

  9. Adult Community Education: A Model for Regional Policy Development.

    ERIC Educational Resources Information Center

    Jones, Peter

    1998-01-01

    The adult community education (ACE) sector in the state of Victoria provides an example of best practice in regional rural policy in Australia that may serve as a model for other areas of government effort. In 1997, 309,000 Victorians enrolled in adult and community education courses, such as business and technical skills development, literacy and…

  10. A MODEL INFORMATION SYSTEM FOR THE ADULT EDUCATION PROFESSION.

    ERIC Educational Resources Information Center

    DECROW, ROGER

    A MODEL OF INFORMATION SERVICES FOR THE ADULT EDUCATION PROFESSION PROVIDES FOR--(1) ACCESS TO THE LITERATURE THROUGH BIBLIOGRAPHIES, REVIEWS, AND MECHANIZED RETRIEVAL, (2) PHYSICAL ACCESS (MAINLY IN MICROFORM), (3) SPECIALIZED INFORMATION SERVICES LINKED WITH ONE ANOTHER AND THE ERIC CLEARINGHOUSE ON ADULT EDUCATION, (4) COORDINATION, RESEARCH,…

  11. Building a Data Based Model for Senior Adult Basic Education.

    ERIC Educational Resources Information Center

    Courtenay, Bradley C.; And Others

    Research shows that developing a curriculum model for senior adult education requires consideration of at least four important factors: (1) the heterogeneous nature of the senior adult population; (2) their specific information and interest needs; (3) the specific nature of the learning activities; and (4) the specific barriers and facilitators…

  12. Infant Imitation from Televised Peer and Adult Models

    ERIC Educational Resources Information Center

    Seehagen, Sabine; Herbert, Jane S.

    2011-01-01

    Developmental changes in learning from peers and adults during the second year of life were assessed using an imitation paradigm. Independent groups of 15- and 24-month-old infants watched a prerecorded video of an unfamiliar child or adult model demonstrating a series of actions with objects. When learning was assessed immediately, 15-month-old…

  13. Exendin-4 reverses biochemical and behavioral deficits in a pre-motor rodent model of Parkinson's disease with combined noradrenergic and serotonergic lesions.

    PubMed

    Rampersaud, N; Harkavyi, A; Giordano, G; Lever, R; Whitton, J; Whitton, P S

    2012-10-01

    Research on Parkinson's disease (PD) has mainly focused on the degeneration of the dopaminergic neurons of nigro-striatal pathway; however, post-mortem studies have demonstrated that other brain regions such as the locus coeruleus (LC) and raphe nuclei (RN) are significantly affected as well. Degeneration of these crucial neuronal cell bodies may be responsible for depressive behavior and cognitive decline present in the pre-motor stage of PD. We have thus set out to create a pre-motor rodent model of PD which mimics the early stages of the condition. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a selective noradrenergic neurotoxin, and parachloroampetamine (pCA), a selective serotonergic neurotoxin, were utilized concomitantly with bilateral 6-hydroxydopamine (6-OHDA) injections into the striatum to produce a pre-motor rodent model of PD with partial deficits in the dopaminergic, noradrenergic, and serotonergic systems. Our model exhibited a depressive/anhedonic condition as assessed using sucrose preference testing and the forced swim test. Our model also demonstrated deficits in object memory. These behavioral impairments were accompanied by a decline in both tissue and extracellular levels of all three neurotransmitters in both the frontal cortex and striatum. Immunohistochemistry also revealed a decrease in TH+ cells in the LC and substantia nigra. Exendin-4 (EX-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, promoted recovery of both the biochemical and behavioral dysfunction exhibited by our model. EX-4 was able to preserve the functional integrity of the dopaminergic, noradrenergic, and serotonergic systems. In conclusion, we have generated a novel animal model of PD that recapitulates certain pre-motor symptomology. These symptoms and causative physiology are ameliorated upon treatment with EX-4 and thus it could be used as a possible therapy for the non-motor symptoms prominent in the early stages of PD. PMID:22921965

  14. Alpha-Synuclein Expression in the Oligodendrocyte Lineage: an In Vitro and In Vivo Study Using Rodent and Human Models

    PubMed Central

    Djelloul, Mehdi; Holmqvist, Staffan; Boza-Serrano, Antonio; Azevedo, Carla; Yeung, Maggie S.; Goldwurm, Stefano; Frisén, Jonas; Deierborg, Tomas; Roybon, Laurent

    2015-01-01

    Summary In this study, we sought evidence for alpha-synuclein (ASYN) expression in oligodendrocytes, as a possible endogenous source of ASYN to explain its presence in glial inclusions found in multiple system atrophy (MSA) and Parkinson’s disease (PD). We identified ASYN in oligodendrocyte lineage progenitors isolated from the rodent brain, in oligodendrocytes generated from embryonic stem cells, and in induced pluripotent stem cells produced from fibroblasts of a healthy individual and patients diagnosed with MSA or PD, in cultures in vitro. Notably, we observed a significant decrease in ΑSYN during oligodendrocyte maturation. Additionally, we show the presence of transcripts in PDGFRΑ/CD140a+ cells and SOX10+ oligodendrocyte lineage nuclei isolated by FACS from rodent and human healthy and diseased brains, respectively. Our work identifies ASYN in oligodendrocyte lineage cells, and it offers additional in vitro cellular models that should provide significant insights of the functional implication of ASYN during oligodendrocyte development and disease. PMID:26235891

  15. Extracellular vesicles derived from mesenchymal stromal cells may possess increased therapeutic potential for acute kidney injury compared with conditioned medium in rodent models: A meta-analysis

    PubMed Central

    ZHANG, GUANGYUAN; WANG, DANDAN; MIAO, SHUAI; ZOU, XIANGYU; LIU, GUOHUA; ZHU, YINGJIAN

    2016-01-01

    The potential involvement of the endocrine/paracrine mechanisms in the mesenchymal stromal cells (MSCs) therapy for acute kidney injury (AKI) has been increasingly studied. The aim of the present meta-analysis was to systematically review the therapeutic role of MSC-conditioned medium (CM) or MSCs released by extracellular vesicles (Evs) for the treatment of AKI in rodent models. Studies were identified using PubMed and Scopus databases using a custom search strategy and eligibility criteria. Data regarding serum creatinine (SCr) concentration, CM or Evs, measurement time point, AKI model (toxic or non-toxic) and other parameters, including delivery route, animal type and animal numbers, were extracted. Pooled analysis and subgroup analysis as well as multivariable meta-regression were performed. Heterogeneity and publication bias were also investigated. A total of 13 studies were included and analyzed. Pooled analysis showed reduced SCr (0.93 [0.67, 1.20], mg/dl) in rodent models of AKI after CM/Evs therapy. The results of the subgroup analysis suggested that Evs induced an increased therapeutic effect, in the form of SCr reduction, as compared with CM (P=0.05). There were also other significant influential factors for SCr reduction including measurement time point (P=0.0004) and therapeutic time point (P<0.0001) after surgery. By contrast, parameters such as delivery route, injury type and cell type were not significant influential factors. Multivariable meta-regression analysis showed that measurement time point (P=0.041), therapeutic time point (P=0.03), Evs or CM (P=0.0003) and cell type (P<0.0001) were influential factors in the reduction of SCr. The present meta-analysis indicates that CM or Evs derived from MSCs are able to improve the impaired renal function in rodents modelling AKI. Compared with CM, Evs may produce a more marked therapeutic effect in recovery from renal failure. In addition, CM or Evs administration in early stages of AKI may result in

  16. A transcriptomics-based hepatotoxicity comparison between the zebrafish embryo and established human and rodent in vitro and in vivo models using cyclosporine A, amiodarone and acetaminophen.

    PubMed

    Driessen, Marja; Vitins, Alexa P; Pennings, Jeroen L A; Kienhuis, Anne S; Water, Bob van de; van der Ven, Leo T M

    2015-01-22

    The zebrafish embryo (ZFE) is a promising alternative, non-rodent model in toxicology, which has an advantage over the traditionally used models as it contains complete biological complexity and provides a medium to high-throughput setting. Here, we assess how the ZFE compares to the traditionally used models for liver toxicity testing, i.e., in vivo mouse and rat liver, in vitro mouse and rat hepatocytes, and primary human hepatocytes. For this comparison, we analyzed gene expression changes induced by three model compounds for cholestasis, steatosis, and necrosis. The three compounds, cyclosporine A, amiodarone, and acetaminophen, were chosen because of their relevance to human toxicity and these compounds displayed hepatotoxic-specific changes in the mouse in vivo data. Compound induced expression changes in the ZFE model shared similarity with both in vivo and in vitro. Comparison on single gene level revealed the presence of model specific changes and no clear concordance across models. However, concordance was identified on the pathway level. Specifically, the pathway "regulation of metabolism - bile acids regulation of glucose and lipid metabolism via FXR" was affected across all models and compounds. In conclusion, our study with three hepatotoxic model compounds shows that the ZFE model is at least as comparable to traditional models in identifying hepatotoxic activity and has the potential for use as a pre-screen to determine the hepatotoxic potential of compounds. PMID:25448281

  17. Examining a Model of Life Satisfaction among Unemployed Adults

    ERIC Educational Resources Information Center

    Duffy, Ryan D.; Bott, Elizabeth M.; Allan, Blake A.; Torrey, Carrie L.

    2013-01-01

    The present study examined a model of life satisfaction among a diverse sample of 184 adults who had been unemployed for an average of 10.60 months. Using the Lent (2004) model of life satisfaction as a framework, a model was tested with 5 hypothesized predictor variables: optimism, job search self-efficacy, job search support, job search…

  18. A Coping Model for Adult Survivors of Childhood Sexual Abuse.

    ERIC Educational Resources Information Center

    Draucker, Claire B.

    1995-01-01

    A group of 149 adult survivors of childhood sexual abuse was tested using a causal model that identifies relationships among sexual abuse situation characteristics, the accomplishment of cognitive coping tasks, and long-term effects. Results indicated the model did not fit the data. A revised model is proposed and examined. (JBJ)

  19. Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models.

    PubMed

    Focken, Thilo; Liu, Shifeng; Chahal, Navjot; Dauphinais, Maxim; Grimwood, Michael E; Chowdhury, Sultan; Hemeon, Ivan; Bichler, Paul; Bogucki, David; Waldbrook, Matthew; Bankar, Girish; Sojo, Luis E; Young, Clint; Lin, Sophia; Shuart, Noah; Kwan, Rainbow; Pang, Jodie; Chang, Jae H; Safina, Brian S; Sutherlin, Daniel P; Johnson, J P; Dehnhardt, Christoph M; Mansour, Tarek S; Oballa, Renata M; Cohen, Charles J; Robinette, C Lee

    2016-03-10

    We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of NaV1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNaV1.7 as a drug target for the treatment of pain. PMID:26985315

  20. Acellular dermal matrix seeded with autologous fibroblasts improves wound breaking strength in a rodent soft tissue damage model in neoadjuvant settings.

    PubMed

    Roessner, Eric Dominic; Thier, Steffen; Hohenberger, Peter; Schwarz, Markus; Pott, Peter; Dinter, Dietmar; Smith, Mark

    2011-01-01

    Soft tissue defects following resectional surgery or trauma often result in deadspaces and require free or pedicled flaps. A programmed formation of filling tissue with enhanced biomechanical properties could be helpful. This study examined the effects on wound healing of acellular dermal matrix (ADM) seeded with autologous fibroblasts in a standardized rodent model. As pre- or postoperative radiotherapy is standard in many treatments of malignancies, we also investigated the effects of additional radiotherapy. Fischer rats were randomised and received a standardized unilateral soft tissue defect at the buttock. The defect was filled with ADM+fibroblasts or ADM alone. Controls received no filling. Either no radiation, adjuvant (postoperative) or neoadjuvant (preoperative) radiation was applied to the defect site. Six weeks later the defect volume was measured by MR-tomography. Wound breaking strength was examined by tensiometry according to German Industrial Standards. Filling of the defect side was significantly larger in ADM and ADM+fibroblast treated groups compared to the control group in all settings. Wound breaking strength in the unimodal setting was significantly improved in the ADM+fibroblasts group compared to the ADM group. In the neoadjuvant setting there was no significant difference between control and ADM group. However, the ADM+fibroblasts groups showed a significantly increased wound breaking strength compared to the control and the ADM-alone group. Seeded or unseeded ADM is able to fill deadspace in this rodent model in all settings. Implanting non-irradiated, vital, proliferating autologous fibroblasts on ADM results in significantly increased wound breaking strength. PMID:20042428

  1. β2-Adrenergic agonist-induced hypertrophy of the quadriceps skeletal muscle does not modulate disease severity in the rodent meniscectomy model of osteoarthritis

    PubMed Central

    Tonge, D.P.; Jones, S.W.; Parr, T.; Bardsley, R.; Doherty, M.; Maciewicz, R.A.

    2010-01-01

    Summary Objective To examine whether β2-adrenergic agonist-induced hypertrophy of the quadriceps skeletal muscle can modulate the severity of osteoarthritis (OA) in the rodent meniscectomy (MNX) model. Methods Male Lewis rats were subcutaneously administered with 1.5 mg/kg/day clenbuterol hydrochloride (n = 15) or saline vehicle (n = 20) for 14 days. Following pre-treatment, five animals from each group were sacrificed to assess the immediate effects of clenbuterol. The remaining animals underwent either invasive knee surgery (clenbuterol pre-treated n = 10; saline pre-treated n = 10) or a sham control surgical procedure (saline pre-treated n = 5). During disease initiation and progression, weight bearing was assessed by hindlimb loading. Myosin heavy chain (MHC) protein isoforms were quantified by silver stained SDS PAGE. OA severity was graded by assessment of toluidine blue stained step coronal sections of the total knee joint. Results Clenbuterol treatment resulted in an increase in total bodyweight, growth rate and in quadriceps skeletal muscle mass. Meniscal surgery resulted in the development of OA-like lesions, changes to weight bearing, and changes in MHC protein expression in the quadriceps. Clenbuterol-induced skeletal muscle hypertrophy had no effect on either weight bearing or articular pathology following MNX surgery. Conclusions Our data reveal that clenbuterol-induced skeletal muscle hypertrophy is unable to mimic the beneficial clinical effects of increased musculature derived through targeted strength training in humans, in a rodent model of MNX-induced OA. In addition we observed fibre-type switching to “slow twitch” in the quadriceps muscle during the induction of OA that warrants further investigation as to its relationship to joint stability. PMID:20060953

  2. Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders

    PubMed Central

    Le Poul, Emmanuel; Boléa, Christelle; Girard, Françoise; Campo, Brice; Fonsi, Massimiliano; Royer-Urios, Isabelle; Browne, Susan E.; Uslaner, Jason M.; Davis, Matthew J.; Raber, Jacob; Duvoisin, Robert; Bate, Simon T.; Reynolds, Ian J.; Celanire, Sylvain

    2014-01-01

    There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu4) leads to anxiolytic- and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolytic-like efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressant-like efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]–induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis. PMID:24947466

  3. Characterization of the novel positive allosteric modulator of the metabotropic glutamate receptor 4 ADX88178 in rodent models of neuropsychiatric disorders.

    PubMed

    Kalinichev, Mikhail; Le Poul, Emmanuel; Boléa, Christelle; Girard, Françoise; Campo, Brice; Fonsi, Massimiliano; Royer-Urios, Isabelle; Browne, Susan E; Uslaner, Jason M; Davis, Matthew J; Raber, Jacob; Duvoisin, Robert; Bate, Simon T; Reynolds, Ian J; Poli, Sonia; Celanire, Sylvain

    2014-09-01

    There is growing evidence that activation of metabotropic glutamate receptor 4 (mGlu4) leads to anxiolytic- and antipsychotic-like efficacy in rodent models, yet its relevance to depression-like reactivity remains unclear. Here, we present the pharmacological evaluation of ADX88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine], a novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 receptor in rodent models of anxiety, obsessive compulsive disorder (OCD), fear, depression, and psychosis. ADX88178 dose-dependently reduced the number of buried marbles in the marble burying test and increased open-arm exploration in the elevated plus maze (EPM) test, indicative of anxiolytic-like efficacy. Target specificity of the effect in the EPM test was confirmed using male and female mGlu4 receptor knockout mice. In mice, ADX88178 reduced the likelihood of conditioned freezing in the acquisition phase of the fear conditioning test, yet had no carryover effect in the expression phase. Also, ADX88178 dose-dependently reduced duration of immobility in the forced swim test, indicative of antidepressant-like efficacy. ADX88178 reduced DOI (2,5-dimethoxy-4-iodoamphetamine)-mediated head twitches (albeit with no dose-dependency), and MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]-induced locomotor hyperactivity in mice, but was inactive in the conditioned avoidance response test in rats. The compound showed good specificity as it had no effect on locomotor activity in mice and rats at efficacious doses. Thus, allosteric activation of mGlu4 receptors can be a promising new therapeutic approach for treatment of anxiety, OCD, fear-related disorders, and psychosis. PMID:24947466

  4. 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

  5. Glycosylphosphatidylinositols of Plasmodium chabaudi chabaudi: a basis for the study of malarial glycolipid toxins in a rodent model.

    PubMed Central

    Gerold, P; Vivas, L; Ogun, S A; Azzouz, N; Brown, K N; Holder, A A; Schwarz, R T

    1997-01-01

    Free and protein-bound glycosylphosphatidylinositols (GPIs) of the blood stages of the rodent malarial parasite Plasmodium chabaudi chabaudi AS were identified and characterized. TLC analysis of material extracted by organic solvents from metabolically labelled parasites revealed a distinct set of glycolipids. These glycolipids were identified as GPIs by specific chemical and enzymic treatments and by structural analysis of their glycan and hydrophobic parts. These analyses revealed that P.c.chabaudi AS synthesizes a set of GPI-biosynthesis intermediates and two potential GPI-anchor precursors exhibiting the following structures: ethanolamine-phosphate [(alpha1-2)mannose]mannose (alpha 1-2) mannose (alpha 1-6) mannose (alpha 1-4) glucosamine - (acyl) inositol-phosphate-diacylglycerol (P.ch. alpha) and ethanolamine-phosphate - mannose (alpha 1-2) mannose (alpha 1-6) mannose (alpha 1-4) glucosamine-(acyl)inositol-phosphate-diacylglycerol (P.ch. beta). One of these GPI-anchor precursors (P.ch. alpha) possesses the same carbohydrate structure as the GPI membrane anchor of merozoite surface protein-1 from P.c.chabaudi AS. PMID:9396737

  6. Tissue-specific Variation of Ube3a Protein Expression in Rodents and in a Mouse Model of Angelman Syndrome

    PubMed Central

    Gustin, Richard M.; Bichell, Terry Jo; Bubser, Michael; Daily, Jennifer; Filonova, Irina; Mrelashvili, Davit; Deutch, Ariel Y.; Colbran, Roger J.; Weeber, Edwin J.; Haas, Kevin F.

    2010-01-01

    Angelman syndrome (AS) is a neurogenetic disorder caused by loss of maternal UBE3A expression or mutation-induced dysfunction of its protein product, the E3 ubiquitin-protein ligase, UBE3A. In humans and rodents, UBE3A/Ube3a transcript is maternally imprinted in several brain regions, but the distribution of native UBE3A/Ube3a1 protein expression has not been comprehensively examined. To address this, we systematically evaluated Ube3a expression in the brain and peripheral tissues of wild-type (WT) and Ube3a maternal knockout mice (AS mice). Immunoblot and immunohistochemical analyses revealed a marked loss of Ube3a protein in hippocampus, hypothalamus, olfactory bulb, cerebral cortex, striatum, thalamus, midbrain, and cerebellum in AS mice relative to WT littermates. Also, Ube3a expression in heart and liver of AS mice showed greater than the predicted 50% reduction relative to WT mice. Co-localization studies showed Ube3a expression to be primarily neuronal in all brain regions and present in GABAergic interneurons as well as principal neurons. These findings suggest that neuronal function throughout the brain is compromised in AS. PMID:20423730

  7. Effect of Dietary-Resistant Starch on Inhibition of Colonic Preneoplasia and Wnt Signaling in Azoxymethane-Induced Rodent Models.

    PubMed

    Nelson, Bridget; Cray, Nicole; Ai, Yongfeng; Fang, Yinan; Liu, Peng; Whitley, Elizabeth M; Birt, Diane

    2016-01-01

    Dietary fiber has been reported to prevent preneoplastic colon lesions. The aim of this study was to determine the effect of resistant starches, novel dietary fibers, on the development of colonic preneoplasia and Wnt signaling in azoxymethane (AOM)-treated rats and mice fed resistant starches at 55% of the diet after AOM treatment. Another objective was to determine the effect of resistant starches on the development of preneoplasia in rats treated with antibiotics (Ab), administered between AOM treatment and resistant starch feeding. Diets containing resistant starches, high-amylose (HA7), high-amylose-octenyl succinic anhydride (OS-HA7), or high-amylose-stearic acid (SA-HA7) were compared with control cornstarch (CS). The resistant starch content of the diets did not alter the yield of colonic lesions but animals treated with AOM and fed the diet with the highest resistant starch content, SA-HA7 developed the highest average aberrant crypt foci (ACF) per animal. Mice fed the OS-HA7 diet had decreased expression of some upstream Wnt genes in the colonic crypts. This study suggests that further research is needed to determine if resistant starch impacts colon carcinogenesis in rodents. PMID:27367460

  8. The Changing Nature of Adult Education in the Age of Transnational Migration: Toward a Model of Recognitive Adult Education

    ERIC Educational Resources Information Center

    Guo, Shibao

    2015-01-01

    This chapter examines the changing nature of adult education in the age of transnational migration and proposes recognitive adult education as an inclusive model that acknowledges and affirms cultural difference and diversity as positive and desirable assets.

  9. A preclinical rodent model of radiation-induced lung injury for medical countermeasure screening in accordance with the FDA animal rule.

    PubMed

    Jackson, Isabel L; Xu, Puting; Hadley, Caroline; Katz, Barry P; McGurk, Ross; Down, Julian D; Vujaskovic, Zeljko

    2012-10-01

    The purpose of preclinical murine model development is to establish that the pathophysiological outcome of the rodent model of radiation-induced lung injury is sufficiently representative of the anticipated pulmonary response in the human population. This objective is based on concerns that the C57BL/6J strain may not be the most appropriate preclinical model of lethal radiation lung injury in humans. In this study, the authors assessed this issue by evaluating the relationship between morbidity (pulmonary function, histopathologic damage) and mortality among three strains of mice: C57BL/6J, CBA/J, and C57L/J. These different strains display variations in latency and phenotypic expression of radiation-induced lung damage. By comparing the response of each strain to the human pulmonary response, an appropriate animal model(s) of human radiation-induced pulmonary injury was established. Observations in the C57L/J and CBA/J murine models can be extrapolated to the human lung for evaluation of the mechanisms of action of radiation as well as future efficacy testing and approving agents that fall under the "Animal Rule" of the U.S. Food and Drug Administration (FDA) (21 CFR Parts 314 and 601). PMID:22929472

  10. Graft-mediated functional recovery on a skilled forelimb use paradigm in a rodent model of Parkinson's disease is dependent on reward contingency.

    PubMed

    Cordeiro, Karina Kohn; Jiang, Wei; Papazoglou, Anna; Tenório, Sérgio Bernardo; Döbrössy, Máté; Nikkhah, Guido

    2010-10-15

    The Staircase test measures lateralised deficits in skilled paw reaching in rodents, and there is a long-standing discrepancy in the literature on whether the paradigm is sensitive to graft-mediated functional recovery in the rodent model of Parkinson's disease. The aim of the current study was to evaluate the critical influence of test conditions like pellet density on dopamine-dependent graft-mediated functional recovery. Rats were pre-trained on the Staircase test with a configuration of 8 pellets in each of the 6 wells bilaterally prior to receiving unilateral 6-OHDA lesions of the medial forebrain bundle. Later, the lesioned animals received E14 VM grafts into the striatum, and were tested on the Staircase test under one of two test configurations: bilaterally, either with 10 (HIGH) or with 2 (LOW) pellets per well. Subsequent sessions included unilateral forced-choice testing under the same pellet configuration, and second bilateral and forced-choice sessions with the pellet density configurations switched around between the groups (Cross-over). Animals were also tested on the Corridor and the Cylinder test, and subjected to drug-induced rotation. Graft-mediated functional recovery was observed in the pellets taken criteria only under the HIGH pellet configuration during the bilateral and the forced choice condition. When tested under the LOW configuration, the graft provided no measurable benefit. The presence of VM grafts reduced lateralised motor deficits in the Cylinder test, the adjacent version of the Corridor test, and drug-induced rotation. Our results confirm that VM transplants can partially restore skilled forelimb sensorimotor deficits under specific testing configuration. PMID:20394782

  11. Model-Based Assessment of an In-Vivo Predictive Relationship from CA1 to CA3 in the Rodent Hippocampus

    PubMed Central

    Sandler, Roman A.; Song, Dong; Hampson, Robert E.; Deadwyler, Sam A.; Berger, Theodore W.; Marmarelis, Vasilis Z.

    2014-01-01

    Although an anatomical connection from CA1 to CA3 via the Entorhinal Cortex (EC) and through backprojecting interneurons has long been known it exist, it has never been examined quantitatively on the single neuron level, in the in-vivo nonpatholgical, nonperturbed brain. Here, single spike activity was recorded using a multi-electrode array from the CA3 and CA1 areas of the rodent hippocampus (N=7) during a behavioral task. The predictive power from CA3→CA1 and CA1→CA3 was examined by constructing Multivariate Autoregressive (MVAR) models from recorded neurons in both directions. All nonsignificant inputs and models were identified and removed by means of Monte Carlo simulation methods. It was found that 121/166 (73%) CA3→CA1 models and 96/145 (66%) CA1→CA3 models had significant predictive power, thus confirming a predictive ‘Granger’ causal relationship from CA1 to CA3. This relationship is thought to be caused by a combination of truly causal connections such as the CA1→EC→CA3 pathway and common inputs such as those from the Septum. All MVAR models were then examined in the frequency domain and it was found that CA3 kernels had significantly more power in the theta and beta range than those of CA1, confirming CA3’s role as an endogenous hippocampal pacemaker. PMID:25260381

  12. Modeling heading in adult soccer players.

    PubMed

    Ponce, Ernesto; Ponce, Daniel; Andresen, Max

    2014-01-01

    Heading soccer balls can generate mild brain injuries and in the long run can lead to difficulty in solving problems, memory deficits, and language difficulties. Researchers evaluated the effects on the head for both correct and incorrect heading techniques. They based the head's geometry on medical images. They determined the injury's magnitude by comparing the neurological tissue's resistance with predictions of the generated stresses. The evaluation examined fast playing conditions in adult soccer, taking into account the ball's speed and the type of impact. Mathematical simulations using the finite element method indicated that correctly heading balls arriving at moderate speed presents a low risk of brain injury. However, damage can happen around the third cervical vertebra. These results coincide with medical studies. Incorrect heading greatly increases the brain injury risk and can alter the parietal area. PMID:25248195

  13. Data Sources Available for Modeling Environmental Exposures in Older Adults

    EPA Science Inventory

    This report, “Data Sources Available for Modeling Environmental Exposures in Older Adults,” focuses on information sources and data available for modeling environmental exposures in the older U.S. population, defined here to be people 60 years and older, with an emphasis on those...

  14. Adult Intellectual Development as Social-Cognitive Growth: A Model.

    ERIC Educational Resources Information Center

    Sinnott, Jan D.

    This paper describes a tentative model to assist in conceptualization of the dynamics of adult social-cognitive development based on Piaget's and Riegel's thought, gerontological studies, and dialectical theory. The proposed model possesses several qualities: (1) it derives from the concept of intelligence as an adaptive biological entity; (2) it…

  15. Andragogy in Practice: Clarifying the Andragogical Model of Adult Learning.

    ERIC Educational Resources Information Center

    Holton, Elwood F., III; Swanson, Richard A.; Naquin, Sharon S.

    2001-01-01

    Discusses aspects of andragogy that are important for performance improvement professionals. Topics include the core andragogical model that presents core principles of adult learning; andragogy as an individual-transactional framework; individual learner differences; situational differences; and the Andragogy in Practice Model. (Contains 70…

  16. Research-Based Model for Adult Consumer-Homemaking Education.

    ERIC Educational Resources Information Center

    Ball State Univ., Muncie, IN.

    This model is designed to be used as a guide by all teachers and designers of adult vocational consumer and homemaking courses who usually function as program planners. Chapter 1 contains an operational definition, the rationale, and description of intended users. Chapter 2 presents the model description with an overview and discussion of the…

  17. 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. PMID:22683486

  18. Effects of UR-12633, a new antagonist of platelet-activating factor, in rodent models of endotoxic shock.

    PubMed Central

    Giral, M.; Balsa, D.; Ferrando, R.; Merlos, M.; Garcia-Rafanell, J.; Forn, J.

    1996-01-01

    which many mediators may be involved, the new potent PAF antagonist, UR-12633, proved effective in protecting against changes in most shock markers. These data strongly suggest a key role for PAF in the pathogenesis of endotoxic shock in rodents. Images Figure 4 PMID:8818347

  19. Microdialysis in Rodents

    PubMed Central

    Zapata, Agustin; Chefer, Vladimir I.; Shippenberg, Toni S.

    2010-01-01

    Microdialysis is an in vivo sampling technique that permits the quantification of various substances (e.g., neurotransmitters, peptides, electrolytes) in blood and tissue. It is also used to infuse substances into the brain and spinal cord. This unit describes methods for the construction and stereotaxic implantation of microdialysis probes into discrete brain regions of the rat and mouse. Procedures for the conduct of conventional and quantitative microdialysis experiments in the awake and anesthetized rodent are also provided. PMID:19340813

  20. Fetal origin of endocrine dysfunction in the adult: the phthalate model.

    PubMed

    Martinez-Arguelles, D B; Campioli, E; Culty, M; Zirkin, B R; Papadopoulos, V

    2013-09-01

    Di-(2-ethylhexyl) phthalate (DEHP) is a plasticizer with endocrine disrupting properties that is found ubiquitously in the environment as well as in human amniotic fluid, umbilical cord blood, human milk, semen, and saliva. It is used in the industry to add flexibility to polyvinyl chloride-derived plastics and its wide spread use and presence has resulted in constant human exposure through fetal development and postnatal life. Epidemiological studies have suggested an association between phthalate exposures and human reproductive effects in infant and adult populations. The effects of fetal exposure to phthalates on the male reproductive system were unequivocally shown on animal models, principally rodents, in which short term deleterious reproductive effects are well established. By contrast, information on the long term effects of DEHP in utero exposure on gonadal function are scarce, while its potential effects on other organs are just starting to emerge. The present review focuses on these novel findings, which suggest that DEHP exerts more complex and broader disruptive effects on the endocrine system and metabolism than previously thought. This article is part of a Special Issue entitled "CSR 2013". PMID:23333934

  1. A systematic review comparing sex differences in cognitive function in schizophrenia and in rodent models for schizophrenia, implications for improved therapeutic strategies.

    PubMed

    Leger, Marianne; Neill, Joanna C

    2016-09-01

    Sex is often overlooked in animal and human research. Cognitive impairment associated with schizophrenia (CIAS) remains an unmet clinical need, as current antipsychotic medication does not provide clinically meaningful improvements. One explanation could be lack of appreciation of gender differences in CIAS. Animal models play a critical role in drug development and improved translation to the clinic is an on-going process. Our systematic review aims to evaluate how well the animal studies translate into clinical findings. Supporting clinical results, our review highlights a male working memory advantage and a female advantage for visual memory and social cognition in rodent models for schizophrenia. Not investigated in animals, a female advantage for attention and speed of processing has been found in schizophrenia patients. Sex differences in reasoning and problem solving are poorly investigated in both human and animal studies. Overall, our review provides evidence of good translation from the animal models into the clinic when sexual dimorphism is assessed. Enhanced understanding of these sex differences will improve the management of CIAS. PMID:27344000

  2. Adult Zebrafish model of streptococcal infection

    PubMed Central

    Phelps, Hilary A.; Runft, Donna L.

    2009-01-01

    Streptococcal pathogens cause a wide array of clinical syndromes in humans, including invasive systemic infections resulting in high mortality rates. Many of these pathogens are human specific, and therefore difficult to analyze in vivo using typical animal models, as these models rarely replicate what is observed in human infections. This unit describes the use of the zebrafish (Danio rerio) as an animal model for streptococcal infection to analyze multiple disease states. This model closely mimics the necrotizing fasciitis/myositis pathology observed in humans from a Streptococcus pyogenes infection. The use of a zoonotic pathogen, Streptococcus iniae, which replicates systemic infections caused by many streptococcal pathogens, including dissemination to the brain, is also described. Included protocols describe both intraperitoneal and intramuscular infections, as well as methods for histological and quantitative measurements of infection. PMID:19412913

  3. The application of a generativity model for older adults.

    PubMed

    Ehlman, Katie; Ligon, Mary

    2012-01-01

    Generativity is a concept first introduced by Erik Erikson as a part of his psychosocial theory which outlines eight stages of development in the human life. Generativity versus stagnation is the main developmental concern of middle adulthood; however, generativity is also recognized as an important theme in the lives of older adults. Building on the work of Erikson, McAdams and de St. Aubin (1992) developed a model explaining the generative process. The aims of this article are: (a) to explore the relationship between generativity and older adults as it appears in research literature; and (b) to examine McAdam's model and use it to explain the role of generativity in older adults who share life stories with gerontology students through an oral history project. PMID:22950351

  4. Evaluation of Mitochondrial Function in the CNS of Rodent Models of Alzheimer's Disease - High Resolution Respirometry Applied to Acute Hippocampal Slices.

    PubMed

    Dias, Candida; Barbosa, Rui M; Laranjinha, Joao; Ledo, Ana

    2014-10-01

    Alzheimer's disease (AD) is a multifactorial disease characterized by extracellular deposits of amyloid plaques and intracellular neurofibrillary tangles. These hallmark alterations are preceded by synaptic deterioration, changes in neuromolecular plasticity phenomena, mitochondrial dysfunction, increase in oxidative damage to cellular constituents and decreased energy metabolism. The hippocampus is a structure of the temporal medial lobe implicated in specific forms of memory processes. It is also one of the first and most affected regions of the CNS in AD. Here we present a novel approach to the study if mitochondrial function/disfunction in 2 rodent models of AD: an acute rat model obtained by intracerebroventricular injection of the toxin streptozotocin (STZ) and a progressive triple transgenic mouse model (3TgAD) harboring PS1M146V, APPSwe, and tauP301L transgenes. Mitochondrial dysfunction has classically been assessed in such models by isolating mitochondria, synaptossoms or working with cell cultures. Anyone of these approaches destroys the intricate intercellular connectivity and cytoarchitecture of neuronal tissue. We used acute hippocampal slices obtained from the 2 models of AD and evaluated changes in mitochondrial function as a function of disease and/or age. Mitochondrial stress test were performed on the high resolution respirometry (Oroboros 2K Oxymeter). Upon analysis of oxygen consumption rates (OCR) we observed significant decreases in basal OCR, maximal respiratory capacity, ATP turnover and a tendency for decrease in sparing capacity in the STZ rat model compared to shame injected animals. Regarding the 3TgAD model we observed an age-dependent decrease in all parameters evaluated in the mitochondrial stress test, in both 3TgAD and NTg animals. However, although a tendency towards decreased OCR was observed when comparing 3TgAD and age-matched NTg animals, no statistically significant difference was observed. PMID:26461355

  5. Susceptibility of Laboratory Rodents to Trichinella papuae

    PubMed Central

    Sadaow, Lakkhana; Intapan, Pewpan M.; Boonmars, Thidarut; Morakote, Nimit

    2013-01-01

    Members of the genus Trichinella are small nematodes that can infect a wide range of animal hosts. However, their infectivity varies depending on the parasite and host species combination. In this study, we examined the susceptibility of 4 species of laboratory rodents, i.e., mice, rats, hamsters, and gerbils to Trichinella papuae, an emerging non-encapsulated Trichinella species. Trichinella spiralis and Trichinella pseudospiralis were also included in this study for comparison. Fifteen animals of each rodent species were infected orally with 100 muscle larvae of each Trichinella species. Intestinal worm burden was determined at day 6 and 10 post-inoculation (PI). The numbers of muscle larvae were examined at day 45 PI. The reproductive capacity index (RCI) of the 3 Trichinella species in different rodent hosts was determined. By day 6 PI, 33.2-69.6% of the inoculated larvae of the 3 Trichinella species became adult worms in the small intestines of the host animals. However, in rats, more than 96% of adult worms of all 3 Trichinella species were expelled from the gut by day 10 PI. In gerbils, only 4.8-18.1% of adult worms were expelled by day 10 PI. In accordance with the intestinal worm burden and the persistence of adults, the RCI was the highest in gerbils with values of 241.5±41.0 for T. papuae, 432.6±48 for T. pseudospiralis, and 528.6±20.6 for T. spiralis. Hamsters ranked second and mice ranked third in susceptibility in terms of the RCI, Rats yielded the lowest parasite RCI for all 3 Trichinella species. Gerbils may be an alternative laboratory animal for isolation and maintenance of Trichinella spp. PMID:24516265

  6. Susceptibility of laboratory rodents to Trichinella papuae.

    PubMed

    Sadaow, Lakkhana; Intapan, Pewpan M; Boonmars, Thidarut; Morakote, Nimit; Maleewong, Wanchai

    2013-12-01

    Members of the genus Trichinella are small nematodes that can infect a wide range of animal hosts. However, their infectivity varies depending on the parasite and host species combination. In this study, we examined the susceptibility of 4 species of laboratory rodents, i.e., mice, rats, hamsters, and gerbils to Trichinella papuae, an emerging non-encapsulated Trichinella species. Trichinella spiralis and Trichinella pseudospiralis were also included in this study for comparison. Fifteen animals of each rodent species were infected orally with 100 muscle larvae of each Trichinella species. Intestinal worm burden was determined at day 6 and 10 post-inoculation (PI). The numbers of muscle larvae were examined at day 45 PI. The reproductive capacity index (RCI) of the 3 Trichinella species in different rodent hosts was determined. By day 6 PI, 33.2-69.6% of the inoculated larvae of the 3 Trichinella species became adult worms in the small intestines of the host animals. However, in rats, more than 96% of adult worms of all 3 Trichinella species were expelled from the gut by day 10 PI. In gerbils, only 4.8-18.1% of adult worms were expelled by day 10 PI. In accordance with the intestinal worm burden and the persistence of adults, the RCI was the highest in gerbils with values of 241.5±41.0 for T. papuae, 432.6±48 for T. pseudospiralis, and 528.6±20.6 for T. spiralis. Hamsters ranked second and mice ranked third in susceptibility in terms of the RCI, Rats yielded the lowest parasite RCI for all 3 Trichinella species. Gerbils may be an alternative laboratory animal for isolation and maintenance of Trichinella spp. PMID:24516265

  7. Rodent-associated Bartonella Febrile Illness, Southwestern United States

    PubMed Central

    Iralu, Jonathan; Bai, Ying; Crook, Larry; Tempest, Bruce; Simpson, Gary; McKenzie, Taylor

    2006-01-01

    Serum specimens from 114 patients hospitalized with a febrile illness were tested with an indirect immunofluorescence assay (IFA) using Bartonella antigens prepared from 6 species of sigmodontine rodents and 3 known human Bartonella pathogens: B. henselae, B. quintana, and B. elizabethae. Acute- and convalescent-phase serum samples from 5 of these patients showed seroconversion with an IFA titer >512 to rodent-associated Bartonella antigens. The highest titer was against antigen derived from the white-throated woodrat (Neotoma albigula), although this rodent is not necessarily implicated as the source of infection. Three of the 5 who seroconverted showed no cross-reaction to the 3 Bartonella human pathogens. Common clinical characteristics were fever, chills, myalgias, leukopenia, thrombocytopenia, and transaminasemia. Although antibodies to Bartonella are cross-reactive, high-titer seroconversions to rodent-associated Bartonella antigens in adults with common clinical characteristics should stimulate the search for additional Bartonella human pathogens. PMID:16836824

  8. A TRAINING MODEL FOR THE JOBLESS ADULT.

    ERIC Educational Resources Information Center

    ULRICH, BERNARD

    THE TRAINING SYSTEMS DESIGN, AN INTERDISCIPLINARY APPROACH UTILIZING KNOWLEDGE OF BEHAVIORAL SCIENCES, NEW INSTRUCTIONAL TECHNOLOGY, AND SYSTEMS DESIGN, HAS BEEN APPLIED TO DEVELOP A MODEL FOR RE-EDUCATING AND TRAINING THE AGING UNEMPLOYED. RESEARCH INTO EXISTING MDTA DEMONSTRATION PROGRAMS BY THE COOPERATIVE EFFORTS OF MCGRAW-HILL AND THE…

  9. Continuously growing rodent molars result from a predictable quantitative evolutionary change over 50 million years.

    PubMed

    Tapaltsyan, Vagan; Eronen, Jussi T; Lawing, A Michelle; Sharir, Amnon; Janis, Christine; Jernvall, Jukka; Klein, Ophir D

    2015-05-01

    The fossil record is widely informative about evolution, but fossils are not systematically used to study the evolution of stem-cell-driven renewal. Here, we examined evolution of the continuous growth (hypselodonty) of rodent molar teeth, which is fuelled by the presence of dental stem cells. We studied occurrences of 3,500 North American rodent fossils, ranging from 50 million years ago (mya) to 2 mya. We examined changes in molar height to determine whether evolution of hypselodonty shows distinct patterns in the fossil record, and we found that hypselodont taxa emerged through intermediate forms of increasing crown height. Next, we designed a Markov simulation model, which replicated molar height increases throughout the Cenozoic and, moreover, evolution of hypselodonty. Thus, by extension, the retention of the adult stem cell niche appears to be a predictable quantitative rather than a stochastic qualitative process. Our analyses predict that hypselodonty will eventually become the dominant phenotype. PMID:25921530

  10. Continuously growing rodent molars result from a predictable quantitative evolutionary change over 50 million years

    PubMed Central

    Mushegyan, Vagan; Eronen, Jussi T.; Lawing, A. Michelle; Sharir, Amnon; Janis, Christine; Jernvall, Jukka; Klein, Ophir D.

    2015-01-01

    Summary The fossil record is widely informative about evolution, but fossils are not systematically used to study the evolution of stem cell-driven renewal. Here, we examined evolution of the continuous growth (hypselodonty) of rodent molar teeth, which is fuelled by the presence of dental stem cells. We studied occurrences of 3500 North American rodent fossils, ranging from 50 million years ago (mya) to 2 mya. We examined changes in molar height to determine if evolution of hypselodonty shows distinct patterns in the fossil record, and we found that hypselodont taxa emerged through intermediate forms of increasing crown height. Next, we designed a Markov simulation model, which replicated molar height increases throughout the Cenozoic, and, moreover, evolution of hypselodonty. Thus, by extension, the retention of the adult stem-cell niche appears to be a predictable quantitative rather than a stochastic qualitative process. Our analyses predict that hypselodonty will eventually become the dominant phenotype. PMID:25921530

  11. Intraperitoneal Administration of a Novel TAT-BDNF Peptide Ameliorates Cognitive Impairments via Modulating Multiple Pathways in Two Alzheimer’s Rodent Models

    PubMed Central

    Wu, Yuanyuan; Luo, Xiaobin; Liu, Xinhua; Liu, Deyi; Wang, Xiong; Guo, Ziyuan; Zhu, Lingqiang; Tian, Qing; Yang, Xifei; Wang, Jian-Zhi

    2015-01-01

    Although Alzheimer’s disease (AD) has been reported for more than 100 years, there is still a lack of effective cures for this devastating disorder. Among the various obstacles that hold back drug development, the blood-brain barrier (BBB) is one of them. Here, we constructed a novel fusion peptide by linking the active domain of brain-derived neurotrophic factor (BDNF) with an HIV-encoded transactivator of transcription (TAT) that has a strong membrane-penetrating property. After intraperitoneal injection, the eGFP-TAT could be robustly detected in different brain regions. By using scopolamine-induced rats and APPswe mice representing AD-like cholinergic deficits and amyloidosis, respectively, we found that intraperitoneal administration of the peptide significantly improved spatial memory with activation of the TrkB/ERK1/2/Akt pathway and restoration of several memory-associated proteins in both models. Administration of the peptide also modulated β-amyloid and tau pathologies in APPswe mice, and it increased the amount of M receptor with modulation of acetylcholinesterase in scopolamine-induced rats. We conclude that intraperitoneal administration of our TAT-BDNF peptide could efficiently target multiple molecular pathways in the brain and improve the cognitive functions in AD-like rodent models. PMID:26463268

  12. Effects of space flight conditions on the function of the immune system and catecholamine production simulated in a rodent model of hindlimb unloading

    NASA Technical Reports Server (NTRS)

    Aviles, Hernan; Belay, Tesfaye; Vance, Monique; Sonnenfeld, Gerald

    2005-01-01

    The rodent model of hindlimb unloading has been successfully used to simulate some of the effects of space flight conditions. Previous studies have indicated that mice exposed to hindlimb-unloading conditions have decreased resistance to infections compared to restrained and normally housed control mice. OBJECTIVE: The purpose of this study was to clarify the mechanisms involved in resistance to infection in this model by examining the effects of hindlimb unloading on the function of the immune system and its impact on the production of catecholamines. METHODS: Female Swiss Webster mice were hindlimb-unloaded during 48 h and the function of the immune system was assessed in spleen and peritoneal cells immediately after this period. In addition, the kinetics of catecholamine production was measured throughout the hindlimb-unloading period. RESULTS: The function of the immune system was significantly suppressed in the hindlimb-unloaded group compared to restrained and normally housed control mice. Levels of catecholamines were increased in the hindlimb-unloaded group and peaked at 12 h following the commencement of unloading. CONCLUSION: These results suggest that physiological responses of mice are altered early after hindlimb unloading and that catecholamines may play a critical role in the modulation of the immune system. These changes may affect the ability of mice to resist infections. Copyright (c) 2005 S. Karger AG, Basel.

  13. Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.

    PubMed

    Brindisi, Margherita; Maramai, Samuele; Gemma, Sandra; Brogi, Simone; Grillo, Alessandro; Di Cesare Mannelli, Lorenzo; Gabellieri, Emanuele; Lamponi, Stefania; Saponara, Simona; Gorelli, Beatrice; Tedesco, Daniele; Bonfiglio, Tommaso; Landry, Christophe; Jung, Kwang-Mook; Armirotti, Andrea; Luongo, Livio; Ligresti, Alessia; Piscitelli, Fabiana; Bertucci, Carlo; Dehouck, Marie-Pierre; Campiani, Giuseppe; Maione, Sabatino; Ghelardini, Carla; Pittaluga, Anna; Piomelli, Daniele; Di Marzo, Vincenzo; Butini, Stefania

    2016-03-24

    We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood-brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity. Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist. Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin. Given these evidence, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain. PMID:26888301

  14. Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia.

    PubMed

    Ewing, Samuel G; Grace, Anthony A

    2013-11-01

    A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced "noise" in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbitofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the "signal-to-noise" ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input. PMID:23932574

  15. 3D reconstruction of 2D fluorescence histology images and registration with in vivo MR images: application in a rodent stroke model.

    PubMed

    Stille, Maik; Smith, Edward J; Crum, William R; Modo, Michel

    2013-09-30

    To validate and add value to non-invasive imaging techniques, the corresponding histology is required to establish biological correlates. We present an efficient, semi-automated image-processing pipeline that uses immunohistochemically stained sections to reconstruct a 3D brain volume from 2D histological images before registering these with the corresponding 3D in vivo magnetic resonance images (MRI). A multistep registration procedure that first aligns the "global" volume by using the centre of mass and then applies a rigid and affine alignment based on signal intensities is described. This technique was applied to a training set of three rat brain volumes before being validated on three normal brains. Application of the approach to register "abnormal" images from a rat model of stroke allowed the neurobiological correlates of the variations in the hyper-intense MRI signal intensity caused by infarction to be investigated. For evaluation, the corresponding anatomical landmarks in MR and histology were defined to measure the registration accuracy. A registration error of 0.249 mm (approximately one in-plane voxel dimension) was evident in healthy rat brains and of 0.323 mm in a rodent model of stroke. The proposed reconstruction and registration pipeline allowed for the precise analysis of non-invasive MRI and corresponding microstructural histological features in 3D. We were thus able to interrogate histology to deduce the cause of MRI signal variations in the lesion cavity and the peri-infarct area. PMID:23816399

  16. Diverse Short-Term Dynamics of Inhibitory Synapses Converging on Striatal Projection Neurons: Differential Changes in a Rodent Model of Parkinson's Disease

    PubMed Central

    Barroso-Flores, Janet; Herrera-Valdez, Marco A.; Lopez-Huerta, Violeta Gisselle; Galarraga, Elvira; Bargas, José

    2015-01-01

    Most neurons in the striatum are projection neurons (SPNs) which make synapses with each other within distances of approximately 100 µm. About 5% of striatal neurons are GABAergic interneurons whose axons expand hundreds of microns. Short-term synaptic plasticity (STSP) between fast-spiking (FS) interneurons and SPNs and between SPNs has been described with electrophysiological and optogenetic techniques. It is difficult to obtain pair recordings from some classes of interneurons and due to limitations of actual techniques, no other types of STSP have been described on SPNs. Diverse STSPs may reflect differences in presynaptic release machineries. Therefore, we focused the present work on answering two questions: Are there different identifiable classes of STSP between GABAergic synapses on SPNs? And, if so, are synapses exhibiting different classes of STSP differentially affected by dopamine depletion? Whole-cell voltage-clamp recordings on SPNs revealed three classes of STSPs: depressing, facilitating, and biphasic (facilitating-depressing), in response to stimulation trains at 20 Hz, in a constant ionic environment. We then used the 6-hydroxydopamine (6-OHDA) rodent model of Parkinson's disease to show that synapses with different STSPs are differentially affected by dopamine depletion. We propose a general model of STSP that fits all the dynamics found in our recordings. PMID:26167304

  17. Evidence for impaired sound intensity processing during prepulse inhibition of the startle response in a rodent developmental disruption model of schizophrenia

    PubMed Central

    Ewing, Samuel G.; Grace, Anthony A.

    2013-01-01

    A number of studies have implicated disruptions in prepulse inhibition (PPI) of the startle response in both schizophrenia patients and animal models of this disorder. These disruptions are believed to reflect deficits in sensorimotor gating and are ascribed to aberrant filtering of sensory inputs leading to sensory overload and enhanced “noise” in neural structures. Here we examined auditory evoked potentials in a rodent model of schizophrenia (MAM-GD17) during an auditory PPI paradigm to better understand this phenomenon. MAM rats exhibited reductions in specific components of auditory evoked potentials in the orbtiofrontal cortex and an abolition of the graded response to stimuli of differing intensities indicating deficient intensity processing in the orbitofrontal cortex. These data indicate that aberrant sensory information processing, rather than being attributable to enhanced noise in neural structures, may be better attributed to diminished evoked amplitudes resulting in a reduction in the “signal-to-noise” ratio. Therefore, the ability for sensory input to modulate the ongoing background activity may be severely disrupted in schizophrenia yielding an internal state which is insufficiently responsive to external input. PMID:23932574

  18. Individual differences in the effects of prenatal stress exposure in rodents.

    PubMed

    Boersma, Gretha J; Tamashiro, Kellie L

    2015-01-01

    Exposure to prenatal stress alters the phenotype of the offspring in adulthood. When the prenatal and adult environments do not match, these alterations may induce pathology risk. There are, however, large individual differences in the effects of prenatal stress. While some individuals seem vulnerable, others appear to be relatively resistant to its effects. In this review we discuss potential mechanisms underlying these individual differences with a focus on animal models. Differences between rodent models selected for stress coping traits are discussed. In addition, the role of circulating factors, like glucocorticoids and cytokines, factors involved in brain development and influences of epigenetic and genetic factors in prenatal stress induced phenotype are covered. PMID:27589662

  19. Suggesting a General ESP Model for Adult Learners

    ERIC Educational Resources Information Center

    Al-Jumaily, Samir

    2011-01-01

    The study suggests a general model that could guarantee the cooperation between teachers and their students to overcome the difficulties encountered in ESP learning. It tries to join together different perspectives in the research of adult education, specifically in the teaching of English for Specific Purposes. It also provides some sort of trust…

  20. Characterization of Disopyramide derivative ADD424042 as a non-cardiotoxic neuronal sodium channel blocker with broad-spectrum anticonvulsant activity in rodent seizure models.

    PubMed

    Król, Marek; Ufnal, Marcin; Szulczyk, Bartłomiej; Podsadni, Piotr; Drapała, Adrian; Turło, Jadwiga; Dawidowski, Maciej

    2016-01-01

    It was reported that antiarrhythmic drugs (AADs) can be useful in controlling refractory seizures in humans or in enhancing the action of antiepileptic drugs (AEDs) in animal models. Disopyramide phosphate (DISO) is an AAD that blocks sodium channels in cardiac myocytes. We evaluated a DISO derivative, 2-(2-chlorophenyl)-2-(pyridin-2-yl)acetamide (ADD424042) for its anticonvulsant activity in a battery of rodent models of epileptic seizures. The compound displayed a broad spectrum of activity in the 'classical' models as well as in the models of pharmacoresistant seizures. Furthermore, ADD424042 showed good therapeutic indices between the anticonvulsant activity and the motor impairment. On the contrary, no anticonvulsant effects but severe lethality were observed in the primary anticonvulsant testing of the parent DISO. By performing the whole-cell voltage-clamp experiments in dispersed cortical neurons we demonstrated that ADD424042 decreased the maximal amplitude of voltage-gated sodium channels with an IC50 value in nM range. Moreover, the compound enhanced use-dependent block and decreased excitability in pyramidal neurons in the current-clamp experiments in cortical slices. Importantly, we found that ADD424042 possessed either no, or very small cardiotoxic effect. In contrast to DISO, ADD424042 did not produce any apparent changes in electrocardiogram (ECG) and arterial blood pressure recordings. ADD424042 had no effect on QT and corrected QT intervals, at a dose which was 15 times higher than ED50 for the anticonvulsant effect in the MES model. Taken together, these data suggest that ADD424042 has the potential to become a lead structure for novel broadly acting AEDs with wide margin of cardiac safety. PMID:26441377

  1. In Vivo Diagnostic Imaging Using Micro-CT: Sequential and Comparative Evaluation of Rodent Models for Hepatic/Brain Ischemia and Stroke

    PubMed Central

    Hayasaka, Naoto; Nagai, Nobuo; Kawao, Naoyuki; Niwa, Atsuko; Yoshioka, Yoshichika; Mori, Yuki; Shigeta, Hiroshi; Kashiwagi, Nobuo; Miyazawa, Masaaki; Satou, Takao; Higashino, Hideaki; Matsuo, Osamu; Murakami, Takamichi

    2012-01-01

    Background There is an increasing need for animal disease models for pathophysiological research and efficient drug screening. However, one of the technical barriers to the effective use of the models is the difficulty of non-invasive and sequential monitoring of the same animals. Micro-CT is a powerful tool for serial diagnostic imaging of animal models. However, soft tissue contrast resolution, particularly in the brain, is insufficient for detailed analysis, unlike the current applications of CT in the clinical arena. We address the soft tissue contrast resolution issue in this report. Methodology We performed contrast-enhanced CT (CECT) on mouse models of experimental cerebral infarction and hepatic ischemia. Pathological changes in each lesion were quantified for two weeks by measuring the lesion volume or the ratio of high attenuation area (%HAA), indicative of increased vascular permeability. We also compared brain images of stroke rats and ischemic mice acquired with micro-CT to those acquired with 11.7-T micro-MRI. Histopathological analysis was performed to confirm the diagnosis by CECT. Principal Findings In the models of cerebral infarction, vascular permeability was increased from three days through one week after surgical initiation, which was also confirmed by Evans blue dye leakage. Measurement of volume and %HAA of the liver lesions demonstrated differences in the recovery process between mice with distinct genetic backgrounds. Comparison of CT and MR images acquired from the same stroke rats or ischemic mice indicated that accuracy of volumetric measurement, as well as spatial and contrast resolutions of CT images, was comparable to that obtained with MRI. The imaging results were also consistent with the histological data. Conclusions This study demonstrates that the CECT scanning method is useful in rodents for both quantitative and qualitative evaluations of pathologic lesions in tissues/organs including the brain, and is also suitable for

  2. Reflections on Rodent Implantation.

    PubMed

    Cha, Jeeyeon M; Dey, Sudhansu K

    2015-01-01

    Embryo implantation is a complex process involving endocrine, paracrine, autocrine, and juxtacrine modulators that span cell-cell and cell-matrix interactions. The quality of implantation is predictive for pregnancy success. Earlier observational studies formed the basis for genetic and molecular approaches that ensued with emerging technological advances. However, the precise sequence and details of the molecular interactions involved have yet to be defined. This review reflects briefly on aspects of our current understanding of rodent implantation as a tribute to Roger Short's lifelong contributions to the field of reproductive physiology. PMID:26450495

  3. Reduced levels of dopamine and altered metabolism in brains of HPRT knock-out rats: a new rodent model of Lesch-Nyhan Disease.

    PubMed

    Meek, Stephen; Thomson, Alison J; Sutherland, Linda; Sharp, Matthew G F; Thomson, Julie; Bishop, Valerie; Meddle, Simone L; Gloaguen, Yoann; Weidt, Stefan; Singh-Dolt, Karamjit; Buehr, Mia; Brown, Helen K; Gill, Andrew C; Burdon, Tom

    2016-01-01

    Lesch-Nyhan disease (LND) is a severe neurological disorder caused by loss-of-function mutations in the gene encoding hypoxanthine phosphoribosyltransferase (HPRT), an enzyme required for efficient recycling of purine nucleotides. Although this biochemical defect reconfigures purine metabolism and leads to elevated levels of the breakdown product urea, it remains unclear exactly how loss of HPRT activity disrupts brain function. As the rat is the preferred rodent experimental model for studying neurobiology and diseases of the brain, we used genetically-modified embryonic stem cells to generate an HPRT knock-out rat. Male HPRT-deficient rats were viable, fertile and displayed normal caged behaviour. However, metabolomic analysis revealed changes in brain biochemistry consistent with disruption of purine recycling and nucleotide metabolism. Broader changes in brain biochemistry were also indicated by increased levels of the core metabolite citrate and reduced levels of lipids and fatty acids. Targeted MS/MS analysis identified reduced levels of dopamine in the brains of HPRT-deficient animals, consistent with deficits noted previously in human LND patients and HPRT knock-out mice. The HPRT-deficient rat therefore provides a new experimental platform for future investigation of how HPRT activity and disruption of purine metabolism affects neural function and behaviour. PMID:27185277

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

    PubMed

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

    2016-09-01

    Central catecholamines regulate fear memory across the medial prefrontal cortex (mPFC), amygdala (AMYG), and hippocampus (HPC). However, inadequate evidence exists to address the relationships among these fear circuit areas in terms of the fear symptoms of posttraumatic stress disorder (PTSD). By examining the behavioral profile in a Pavlovian fear conditioning paradigm together with tissue/efflux levels of dopamine (DA) and norepinephrine (NE) and their reuptake abilities across the fear circuit areas in rats that experienced single prolonged stress (SPS, a rodent model of PTSD), we demonstrated that SPS-impaired extinction retrieval was concomitant with the changes of central DA/NE in a dissociable manner. For tissue levels, diminished DA and increased NE were both observed in the mPFC and AMYG. DA efflux and synaptosomal DA transporter were consistently reduced in the AMYG/vHPC, whereas SPS reduced NE efflux in the infralimbic cortex and synaptosomal NE transporter in the mPFC. Furthermore, a lower expression of synaptosomal VMAT2 was observed in the mPFC, AMYG, and vHPC after SPS. Finally, negative correlations were observed between retrieval freezing and DA in the mPFC/AMYG; nevertheless, the phenomena became invalid after SPS. Our results suggest that central catecholamines are crucially involved in the retrieval of fear extinction in which DA and NE play distinctive roles across the fear circuit areas. PMID:27492886

  5. Efficient monitoring of the blood-stage infection in a malaria rodent model by the rotating-crystal magneto-optical method.

    PubMed

    Orbán, Ágnes; Rebelo, Maria; Molnár, Petra; Albuquerque, Inês S; Butykai, Adam; Kézsmárki, István

    2016-01-01

    Intense research efforts have been focused on the improvement of the efficiency and sensitivity of malaria diagnostics, especially in resource-limited settings for the detection of asymptomatic infections. Our recently developed magneto-optical (MO) method allows the accurate quantification of malaria pigment crystals (hemozoin) in blood by their magnetically induced rotation. First evaluations of the method using β-hematin crystals and in vitro P. falciparum cultures implied its potential for high-sensitivity malaria diagnosis. To further investigate this potential, here we study the performance of the method in monitoring the in vivo onset and progression of the blood-stage infection in a rodent malaria model. Our results show that the MO method can detect the first generation of intraerythrocytic P. berghei parasites 66-76 hours after sporozoite injection, demonstrating similar sensitivity to Giesma-stained light microscopy and exceeding that of flow cytometric techniques. Magneto-optical measurements performed during and after the treatment of P. berghei infections revealed that both the follow up under treatment and the detection of later reinfections are feasible with this new technique. The present study demonstrates that the MO method - besides being label and reagent-free, automated and rapid - has a high in vivo sensitivity and is ready for in-field evaluation. PMID:26983695

  6. Evaluation of the Effectiveness of Piper cubeba Extract in the Amelioration of CCl4-Induced Liver Injuries and Oxidative Damage in the Rodent Model

    PubMed Central

    AlSaid, Mansour; Mothana, Ramzi; Raish, Mohammad; Al-Sohaibani, Mohammed; Al-Yahya, Mohammed; Ahmad, Ajaz; Al-Dosari, Mohammed; Rafatullah, Syed

    2015-01-01

    Background. Liver diseases still represent a major health burden worldwide. Moreover, medicinal plants have gained popularity in the treatment of several diseases including liver. Thus, the present study was to evaluate the effectiveness of Piper cubeba fruits in the amelioration of CCl4-induced liver injuries and oxidative damage in the rodent model. Methods. Hepatoprotective activity was assessed using various biochemical parameters like SGOT, SGPT, γ-GGT, ALP, total bilirubin, LDH, and total protein. Meanwhile, in vivo antioxidant activities as LPO, NP-SH, and CAT were measured in rat liver as well as mRNA expression of cytokines such as TNFα, IL-6, and IL-10 and stress related genes iNOS and HO-1 were determined by RT-PCR. The extent of liver damage was also analyzed through histopathological observations. Results. Treatment with PCEE significantly and dose dependently prevented drug induced increase in serum levels of hepatic enzymes. Furthermore, PCEE significantly reduced the lipid peroxidation in the liver tissue and restored activities of defense antioxidant enzymes NP-SH and CAT towards normal levels. The administration of PCEE significantly downregulated the CCl4-induced proinflammatory cytokines TNFα and IL-6 mRNA expression in dose dependent manner, while it upregulated the IL-10 and induced hepatoprotective effect by downregulating mRNA expression of iNOS and HO-1 gene. PMID:25654097

  7. Absence of social conditioned place preference in BTBR T+tf/J mice: relevance for social motivation testing in rodent models of autism

    PubMed Central

    Pearson, Brandon L.; Bettis, Jaclyn K.; Meyza, Ksenia Z.; Yamamoto, Lace Y.; Blanchard, D. Caroline; Blanchard, Robert J.

    2012-01-01

    A major goal of translation research in autism is to characterize the physiological and psychological processes underlying behavioral abnormalities. Since autism reflects impairments in social motivation, we modified the mouse three-chamber social approach apparatus for use as a social conditioned place preference arena. We paired one of two unique contexts with social interactions in juvenile mice for five or ten conditioning sessions in BTBR T+tf/J mice and a control strain with normal approach behaviors (C57BL/6J) since the BTBR T+tf/J inbred mouse strain displays a variety of behavioral alterations analogous to symptoms of autism spectrum disorders. While C57BL/6J mice formed a conditioned place preference to the context associated with social interactions, particularly those receiving ten days of conditioning, BTBR T+tf/J mice did not. Neither absence of social proximity nor avoidance due to high rates of autogrooming appeared to underlie the impaired positive incentive value of the unconditioned social stimulus in the BTBR T+tf/J strain. These data contribute to a growing body of evidence suggesting that the BTBR T+tf/J strain shows impairments in all diagnostic domains of autism including social motivation. Additionally, social conditioning testing might provide an important social motivation measure in other rodent models of neuropsychiatric disorders characterized by social abnormalities. PMID:22562042

  8. Reduced levels of dopamine and altered metabolism in brains of HPRT knock-out rats: a new rodent model of Lesch-Nyhan Disease

    PubMed Central

    Meek, Stephen; Thomson, Alison J.; Sutherland, Linda; Sharp, Matthew G. F.; Thomson, Julie; Bishop, Valerie; Meddle, Simone L.; Gloaguen, Yoann; Weidt, Stefan; Singh-Dolt, Karamjit; Buehr, Mia; Brown, Helen K.; Gill, Andrew C.; Burdon, Tom

    2016-01-01

    Lesch-Nyhan disease (LND) is a severe neurological disorder caused by loss-of-function mutations in the gene encoding hypoxanthine phosphoribosyltransferase (HPRT), an enzyme required for efficient recycling of purine nucleotides. Although this biochemical defect reconfigures purine metabolism and leads to elevated levels of the breakdown product urea, it remains unclear exactly how loss of HPRT activity disrupts brain function. As the rat is the preferred rodent experimental model for studying neurobiology and diseases of the brain, we used genetically-modified embryonic stem cells to generate an HPRT knock-out rat. Male HPRT-deficient rats were viable, fertile and displayed normal caged behaviour. However, metabolomic analysis revealed changes in brain biochemistry consistent with disruption of purine recycling and nucleotide metabolism. Broader changes in brain biochemistry were also indicated by increased levels of the core metabolite citrate and reduced levels of lipids and fatty acids. Targeted MS/MS analysis identified reduced levels of dopamine in the brains of HPRT-deficient animals, consistent with deficits noted previously in human LND patients and HPRT knock-out mice. The HPRT-deficient rat therefore provides a new experimental platform for future investigation of how HPRT activity and disruption of purine metabolism affects neural function and behaviour. PMID:27185277

  9. Efficient monitoring of the blood-stage infection in a malaria rodent model by the rotating-crystal magneto-optical method

    PubMed Central

    Orbán, Ágnes; Rebelo, Maria; Molnár, Petra; Albuquerque, Inês S.; Butykai, Adam; Kézsmárki, István

    2016-01-01

    Intense research efforts have been focused on the improvement of the efficiency and sensitivity of malaria diagnostics, especially in resource-limited settings for the detection of asymptomatic infections. Our recently developed magneto-optical (MO) method allows the accurate quantification of malaria pigment crystals (hemozoin) in blood by their magnetically induced rotation. First evaluations of the method using β-hematin crystals and in vitro P. falciparum cultures implied its potential for high-sensitivity malaria diagnosis. To further investigate this potential, here we study the performance of the method in monitoring the in vivo onset and progression of the blood-stage infection in a rodent malaria model. Our results show that the MO method can detect the first generation of intraerythrocytic P. berghei parasites 66–76 hours after sporozoite injection, demonstrating similar sensitivity to Giesma-stained light microscopy and exceeding that of flow cytometric techniques. Magneto-optical measurements performed during and after the treatment of P. berghei infections revealed that both the follow up under treatment and the detection of later reinfections are feasible with this new technique. The present study demonstrates that the MO method – besides being label and reagent-free, automated and rapid – has a high in vivo sensitivity and is ready for in-field evaluation. PMID:26983695

  10. Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus-evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain.

    PubMed

    Kumar, Naresh; Cherkas, Pavel S; Varathan, Vidya; Miyamoto, Makiko; Chiang, Chen Yu; Dostrovsky, Jonathan O; Sessle, Barry J; Coderre, Terence J

    2013-05-01

    Pregabalin is effective in treating many neuropathic pain conditions. However, the mechanisms of its analgesic effects remain poorly understood. The aim of the present study was to determine whether pregabalin suppresses facial mechanical hypersensitivity and evoked glutamate release in the medullary dorsal horn (MDH) in a rodent model of trigeminal neuropathic pain. Nociceptive mechanical sensitivity was assessed pre-operatively, and then post-operatively 1h following pregabalin or vehicle (saline) treatment on post-operative days 2 and 5 following infraorbital nerve transection (IONX). In addition, an in vivo microdialysis probe was inserted into the exposed medulla post-operatively and dialysate samples were collected. Glutamate release was then evoked by mustard oil (MO) application to the tooth pulp, and the effects of pregabalin or vehicle were examined on the MDH glutamate release. Glutamate concentrations in the dialysated samples were determined by HPLC, and data analyzed by ANOVA. IONX animals (but not control animals) showed facial mechanical hypersensitivity for several days post-operatively. In addition, tooth pulp stimulation with MO evoked a transient release of glutamate in the MDH of IONX animals. Compared to vehicle, administration of pregabalin significantly attenuated the facial mechanical hypersensitivity as well as the MO-evoked glutamate release in MDH. This study provides evidence in support of recent findings pointing to the usefulness of pregabalin in the treatment of orofacial neuropathic pain. PMID:23454190

  11. Efficient monitoring of the blood-stage infection in a malaria rodent model by the rotating-crystal magneto-optical method

    NASA Astrophysics Data System (ADS)

    Orbán, Ágnes; Rebelo, Maria; Molnár, Petra; Albuquerque, Inês S.; Butykai, Adam; Kézsmárki, István

    2016-03-01

    Intense research efforts have been focused on the improvement of the efficiency and sensitivity of malaria diagnostics, especially in resource-limited settings for the detection of asymptomatic infections. Our recently developed magneto-optical (MO) method allows the accurate quantification of malaria pigment crystals (hemozoin) in blood by their magnetically induced rotation. First evaluations of the method using β-hematin crystals and in vitro P. falciparum cultures implied its potential for high-sensitivity malaria diagnosis. To further investigate this potential, here we study the performance of the method in monitoring the in vivo onset and progression of the blood-stage infection in a rodent malaria model. Our results show that the MO method can detect the first generation of intraerythrocytic P. berghei parasites 66–76 hours after sporozoite injection, demonstrating similar sensitivity to Giesma-stained light microscopy and exceeding that of flow cytometric techniques. Magneto-optical measurements performed during and after the treatment of P. berghei infections revealed that both the follow up under treatment and the detection of later reinfections are feasible with this new technique. The present study demonstrates that the MO method – besides being label and reagent-free, automated and rapid – has a high in vivo sensitivity and is ready for in-field evaluation.

  12. Neuroprotection and Functional Recovery Associated with Decreased Microglial Activation Following Selective Activation of mGluR2/3 Receptors in a Rodent Model of Parkinson's Disease

    PubMed Central

    Chan, Hugh; Paur, Helen; Vernon, Anthony C.; Zabarsky, Virginia; Datla, Krishna P.; Croucher, Martin J.; Dexter, David T.

    2010-01-01

    Clinical trials have demonstrated positive proof of efficacy of dual metabotropic glutamate receptor 2/3 (mGluR2/3) agonists in both anxiety and schizophrenia. Importantly, evidence suggests that these drugs may also be neuroprotective against glutamate excitotoxicity, implicated in the pathogenesis of Parkinson's disease (PD). However, whether this neuroprotection also translates into functional recovery is unclear. In the current study, we examined the neuroprotective efficacy of the dual mGluR2/3 agonist, 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), and whether this is accompanied by behavioral recovery in a rodent 6-hydroxydopamine (6-OHDA) model of PD. We now report that delayed post lesion treatment with 2R,4R-APDC (10 nmol), results in robust neuroprotection of the nigrostriatal system, which translated into functional recovery as measured by improved forelimb use asymmetry and reduced (+)-amphetamine-induced rotation compared to vehicle treated animals. Interestingly, these beneficial effects were associated with a decrease in microglial markers in the SNc, which may suggest an antiinflammatory action of this drug. PMID:20948891

  13. Evaluation of vascular effects after photodynamic and photothermal therapies using benzoporphyrin derivative monoacid ring A on a rodent dorsal skinfold model

    NASA Astrophysics Data System (ADS)

    Smith, Tia K.; Choi, Bernard; Ramirez-San-Juan, Julio C.; Nelson, John S.; Kelly, Kristen M.

    2005-04-01

    Background and Objectives: Pulsed dye laser (PDL) irradiation is the standard clinical treatment for vascular lesions. However, PDL treatment of port wine stain birthmarks (PWS) is variable and unpredictable. Photodynamic therapy (PDT) using benzoporphyrin derivative monoacid ring A (BPD) and yellow light may induce substantial vascular effects and potentially offer a more effective treatment. In this study, we utilize a rodent dorsal skinfold model to evaluate the vascular effects of BPD-PDT at 576 nm as compared to PDL. Study Design/Materials and Methods: A dorsal skinfold window was created on the backs of female Sprague-Dawley rats, allowing epidermal and subdermal irradiation and subdermal imaging. One mg/kg BPD was administered intravenously via a jugular venous catheter. Study groups were: control (no BPD, no light), PDL (585 nm, τp 1.5 ms, 10 J/cm2), and PDT (BPD + continuous wave irradiation (CW) at 576nm, τp 16 min, 96 J/cm2). Vessels were imaged and assessed for damage using laser speckle imaging (LSI) before, immediately after, and 18 hours post-intervention. Results: Epidermal irradiation was accomplished without blistering, scabbing or ulceration. PDL and PDT resulted in similar reductions in vascular perfusion 18 hours post-intervention (34.6% and 33.4%, respectively). Conclusions: BPD-PDT can achieve safe and selective vascular effects and may offer an alternative therapeutic option for treatment of hypervascular skin lesions including PWS birthmarks.

  14. The analgesic and toxic effects of nornicotine enantiomers alone and in interaction with morphine in rodent models of acute and persistent pain

    PubMed Central

    Holtman, Joseph R.; Crooks, Peter A.; Johnson-Hardy, Jaime K.; Wala, Elzbieta P.

    2009-01-01

    Neuronal nicotinic acetylcholinic receptors (nAChR) are promising targets for the development of novel analgesics. Nicotine and other nAChR-agonists produce profound analgesia in rodent models of acute and persistent pain. However, significant side-effects are of concern. Nornicotine (N-desmethyl-nicotine) appears to activate different nAChR subtypes, has a better pharmacokinetic profile, and produces less toxicity than nicotine. Little is known about its analgesic properties. In the present study, the S(−)- and R(+)- enantiomers of nornicotine were characterized with regard to analgesia and side-effects profile. Efficacy was demonstrated in rat models of pain where central sensitization is involved: i.e. the chronic constriction nerve injury model of peripheral neuropathy and the formalin model of tonic inflammatory pain. The desirable (analgesic) properties resided predominantly in the S(−)- rather than the R(+)- enantiomer. In contrast, undesirable effects (motor in-coordination, reduced locomotor activity, ataxia) were more pronounced with the R(+)- enantiomer. This is an interesting finding, which may suggest separation of toxicity from analgesia by utilization of S(−)-enantiomer of nornicotine. Maximum analgesic effectiveness without significant side-effects was achieved when S(−)-nornicotine (sub-analgesic dose) was combined with a low-dose of the μ-opioid, morphine. These preclinical data suggest that S(−)-nornicotine may be of value, either alone or in combination with an opioid, for treatment of a broad-spectrum of pain (i.e. nociceptive, neuropathic, mixed pain). PMID:19800911

  15. In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models

    PubMed Central

    Yao, B B; Hsieh, G C; Frost, J M; Fan, Y; Garrison, T R; Daza, A V; Grayson, G K; Zhu, C Z; Pai, M; Chandran, P; Salyers, A K; Wensink, E J; Honore, P; Sullivan, J P; Dart, M J; Meyer, M D

    2007-01-01

    Background and purpose: Selective cannabinoid CB2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB2 in vitro functional assays. Additionally, its analgesic effects are μ-opioid receptor-dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A-796260, a novel CB2 agonist. Experimental approach: A-796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB1 and CB2 receptors. The behavioural profile of A-796260 was assessed in models of inflammatory, post-operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB1, CB2 and μ-opioid receptor antagonists. Key results: A-796260 exhibited high affinity and agonist efficacy at human and rat CB2 receptors, and was selective for the CB2 vs CB1 subtype. Efficacy in models of inflammatory, post-operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB2, but not CB1 or μ-opioid receptor-selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity. Conclusions and implications: These results further confirm the therapeutic potential of CB2 receptor-selective agonists for the treatment of pain. In addition, they demonstrate that A-796260 may be a useful new pharmacological compound for further studying CB2 receptor pharmacology and for evaluating its role in the modulation of pain. PMID:17994110

  16. Experience-Dependent Neural Plasticity in the Adult Damaged Brain

    ERIC Educational Resources Information Center

    Kerr, Abigail L.; Cheng, Shao-Ying; Jones, Theresa A.

    2011-01-01

    Behavioral experience is at work modifying the structure and function of the brain throughout the lifespan, but it has a particularly dramatic influence after brain injury. This review summarizes recent findings on the role of experience in reorganizing the adult damaged brain, with a focus on findings from rodent stroke models of chronic upper…

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

    SciTech Connect

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

    2011-12-15

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

  18. Axonal degeneration, regeneration and ganglion cell death in a rodent model of anterior ischemic optic neuropathy (rAION).

    PubMed

    Zhang, Cheng; Guo, Yan; Slater, Bernard J; Miller, Neil R; Bernstein, Steven L

    2010-08-01

    Using laser-induced photoactivation of intravenously administered rose Bengal in rats, we generated an ischemic infarction of the intrascleral portion of the optic nerve (ON) comparable to that which occurs in humans to investigate optic nerve axon degenerative events following optic nerve infarct and the potential for axon re-growth. Animals were euthanized at different times post infarct. Axon degeneration was evaluated with SMI312 immunolabeling, and GAP-43 immunostaining was used to identify axon regeneration. Terminal dUTP nick end labeling (TUNEL) was used to evaluate retinal ganglion cell (RGC) death. There was significant axon structural disruptinot ion at the anterior intrascleral portion of the ON by 3d post-infarct, extending to the posterior ON by 7d post-stroke. Destruction of normal axon structure and massive loss of axon fibers occurred by 2 weeks. GAP-43 immunoreactivity occurred in the anterior ON by 7d post-infarct, lasting 3-4 weeks, without extension past the primary ischemic lesion. TUNEL-positive cells in the RGC layer appeared by 7d post-insult. These results indicate that following induction of ischemic optic neuropathy, significant axon damage occurs by 3d post-infarct, with later neuronal death. Post-stroke adult rat retinal ganglion cells attempt to regenerate their axons, but this effort is restricted to the unmyelinated region of the anterior ON. These responses are important in understanding pathologic process that underlies human non-arteritic anterior ischemic optic neuropathy (NAION) and may guide both the appropriate treatment of NAION and the window of opportunity for such treatment. PMID:20621651

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

    SciTech Connect

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

    2013-11-15

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

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

    PubMed

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

    2015-09-01

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

  1. The effect of the palmitoylethanolamide analogue, palmitoylallylamide (L-29) on pain behaviour in rodent models of neuropathy

    PubMed Central

    Wallace, V C J; Segerdahl, A R; Lambert, D M; Vandevoorde, S; Blackbeard, J; Pheby, T; Hasnie, F; Rice, A S C

    2007-01-01

    Background and Purpose: Cannabinoids are associated with analgesia in acute and chronic pain states. A spectrum of central cannabinoid (CB1) receptor-mediated motor and psychotropic side effects limit their therapeutic potential. Here, we investigate the analgesic effect of the palmitoylethanolamide (PEA) analogue, palmitoylallylamide (L-29), which via inhibition of fatty acid amide hydrolase (FAAH) may potentiate endocannabinoids thereby avoiding psychotropic side effects. Experimental Approach: The in vivo analysis of the effect of L-29 on measures of pain behaviour in three rat models of neuropathic pain. Key Results: Systemically administered L-29 (10 mg kg−1) reduced hypersensitivity to mechanical and thermal stimuli in the partial sciatic nerve injury (PSNI) model of neuropathic pain; and mechanical hypersensitivity in a model of antiretroviral (ddC)-associated hypersensitivity and a model of varicella zoster virus (VZV)-associated hypersensitivity. The effects of L-29 were comparable to those of gabapentin (50 mg kg−1). The CB1 receptor antagonist SR141716a (1 mg kg−1) and the CB2 receptor antagonist SR144528 (1 mg kg−1) reduced the effect of L-29 on hypersensitivity in the PSNI and ddC models, but not in the VZV model. The peroxisome proliferator-activated receptor-α antagonist, MK-886 (1 mg kg−1), partially attenuated the effect of L-29 on hypersensitivity in the PSNI model. L-29 (10 mg kg−1) significantly attenuated thigmotactic behaviour in the open field arena without effect on locomotor activity. Conclusions and Implications: L-29 produces analgesia in a range of neuropathic pain models. This presents L-29 as a novel analgesic compound that may target the endogenous cannabinoid system while avoiding undesirable side effects associated with direct cannabinoid receptor activation. PMID:17558434

  2. 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

  3. A multi-scale distribution model for non-equilibrium populations suggests resource limitation in an endangered rodent.

    PubMed

    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

  4. Joint cytokine quantification in two rodent arthritis models: kinetics of expression, correlation of mRNA and protein levels and response to prednisolone treatment.

    PubMed

    Rioja, I; Bush, K A; Buckton, J B; Dickson, M C; Life, P F

    2004-07-01

    Biomarker quantification in disease tissues from animal models of rheumatoid arthritis (RA) can help to provide insights into the mechanisms of action of novel therapeutic agents. In this study we validated the kinetics of IL-1beta, TNF-alpha and IL-6 mRNA and protein expression levels in joints from DBA/1OlaHsd murine collagen-induced arthritis (CIA) and Lewis rat Streptococcal cell wall (SCW)-induced arthritis by real-time polymerase chain reaction (PCR) TaqMan and Enzyme-linked immunosorbent assay (ELISA). Prednisolone was used as a reference to investigate any correlation between clinical response and cytokine levels at selected time-points. To our knowledge this is the first report showing a close pattern of expression between mRNA and protein for IL-1beta and IL-6, but not for TNF-alpha, in these two models of RA. The kinetics of expression for these biomarkers suggested that the optimal sampling time-points to study the effect of compounds on both inflammation and cytokine levels were day 4 postonset in CIA and day 3 after i.v challenge in SCW-induced arthritis. Prednisolone reduced joint swelling through a mechanism associated with a reduction in IL-1beta and IL-6 protein and mRNA expression levels. At the investigated time points, protein levels for TNF-alpha in arthritic joints were lower than the lower limit of detection of the ELISA, whereas mRNA levels for this cytokine were reliably detected. These observations suggest that RT-PCR TaqMan is a sensitive technique that can be successfully applied to the quantification of mRNA levels in rodent joints from experimental arthritis models providing insights into mechanisms of action of novel anti-inflammatory drugs. PMID:15196245

  5. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy.

    PubMed

    Valenzano, Kenneth J; Tafesse, Laykea; Lee, Gary; Harrison, James E; Boulet, Jamie M; Gottshall, Susan L; Mark, Lilly; Pearson, Michelle S; Miller, Wendy; Shan, Shen; Rabadi, Leyana; Rotshteyn, Yakov; Chaffer, Suzanne M; Turchin, Paul I; Elsemore, David A; Toth, Mathew; Koetzner, Lee; Whiteside, Garth T

    2005-04-01

    To date, two cannabinoid receptors have been identified, CB1 and CB2. Activation of these receptors with non-selective cannabinoid receptor agonists reduces pain sensitivity in animals and humans. However, activation of CB1 receptors is also associated with central side effects, including ataxia and catalepsy. More recently, a role for selective CB2 agonists in pain modification has been demonstrated. GW405833, a selective CB2 agonist, was recently reported to partially reverse the inflammation and hyperalgesia in a rat model of acute inflammation. In the current report, we extend the characterization and therapeutic potential of this compound. For the first time, we show that GW405833 selectively binds both rat and human CB2 receptors with high affinity, where it acts as a partial agonist (approximately 50% reduction of forskolin-mediated cAMP production compared to the full cannabinoid agonist, CP55,940). We also report for the first time that intraperitoneal administration of GW405833 (0.3-100 mg/kg) to rats shows linear, dose-dependent increases in plasma levels and substantial penetration into the central nervous system. In addition, GW405833 (up to 30 mg/kg) elicits potent and efficacious antihyperalgesic effects in rodent models of neuropathic, incisional and chronic inflammatory pain, the first description of this compound in these models. In contrast, analgesia, sedation and catalepsy were not observed in this dose range, but were apparent at 100 mg/kg. Additionally, GW405833 was not antihyperalgesic against chronic inflammatory pain in CB2 knockout mice. These data support the tenet that selective CB2 receptor agonists have the potential to treat pain without eliciting the centrally-mediated side effects associated with non-selective cannabinoid agonists, and highlight the utility of GW405833 for the investigation of CB2 physiology. PMID:15814101

  6. Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer's disease.

    PubMed

    Richetin, Kevin; Leclerc, Clémence; Toni, Nicolas; Gallopin, Thierry; Pech, Stéphane; Roybon, Laurent; Rampon, Claire

    2015-02-01

    In adult mammals, neural progenitors located in the dentate gyrus retain their ability to generate neurons and glia throughout lifetime. In rodents, increased production of new granule neurons is associated with improved memory capacities, while decreased hippocampal neurogenesis results in impaired memory performance in several memory tasks. In mouse models of Alzheimer's disease, neurogenesis is impaired and the granule neurons that are generated fail to integrate existing networks. Thus, enhancing neurogenesis should improve functional plasticity in the hippocampus and restore cognitive deficits in these mice. Here, we performed a screen of transcription factors that could potentially enhance adult hippocampal neurogenesis. We identified Neurod1 as a robust neuronal determinant with the capability to direct hippocampal progenitors towards an exclusive granule neuron fate. Importantly, Neurod1 also accelerated neuronal maturation and functional integration of new neurons during the period of their maturation when they contribute to memory processes. When tested in an APPxPS1 mouse model of Alzheimer's disease, directed expression of Neurod1 in cycling hippocampal progenitors conspicuously reduced dendritic spine density deficits on new hippocampal neurons, to the same level as that observed in healthy age-matched control animals. Remarkably, this population of highly connected new neurons was sufficient to restore spatial memory in these diseased mice. Collectively our findings demonstrate that endogenous neural stem cells of the diseased brain can be manipulated to become new neurons that could allow cognitive improvement. PMID:25518958

  7. Considerations for the sensible use of rodent models of inflammatory disease in predicting efficacy of new biological therapeutics in the clinic.

    PubMed

    Arnett, Heather A; Viney, Joanne L

    2007-09-30

    . This review will focus on the critical aspects of disease modeling in animals that should be considered when embarking on drug discovery programs, with particular attention on three of the major inflammatory diseases - rheumatoid arthritis, multiple sclerosis and asthma. We will discuss the use of rodent models in predicting the outcomes of currently approved medicines with a focus on biological therapeutics, and will highlight ongoing clinical trials where there appears to be strong correlation between animal models and the initial indication of clinical efficacy. PMID:17804112

  8. Enhanced protection against renal ischemia-reperfusion injury with combined melatonin and exendin-4 in a rodent model.

    PubMed

    Chang, Yi-Chih; Hsu, Shu-Yuan; Yang, Chih-Chao; Sung, Pei-Hsun; Chen, Yi-Ling; Huang, Tien-Hung; Kao, Gour-Shenq; Chen, Sheng-Yi; Chen, Kuan-Hung; Chiang, Hsin-Ju; Yip, Hon-Kan; Lee, Fan-Yen

    2016-08-01

    We tested the hypothesis that combined treatment with melatonin, an anti-oxidant, and exendin-4, an anti-inflammatory agent, was superior to either alone for protecting the kidney from ischemia-reperfusion (IR) injury. Male adult Sprague-Dawley rats (n=40) were equally divided into group 1 (sham-operated control), group 2 (IR only, IR=1h/72h), group 3 (IR-exendin-4, 10 µg/kg at 30 min, 24 h, 48 h after IR procedure), group 4 (IR-melatonin, i.p. 50 mg at 30 min, then 20 mg at 6 and 18 h after IR procedure), and group 5 (combined IR-exendin-4-melatonin). All animals were sacrificed by 72 h after IR/sham procedure. The results showed that the kidney injury score, plasma creatinine, and blood urea nitrogen (BUN) levels were highest in group 2 and lowest in group 1, significantly higher in groups 3 and 4 than those in group 5 and significantly higher in group 3 than those in group 4 (all p < 0.001). The protein expressions of inflammatory (toll-like receptor 4, inducible nitric oxide synthase, interleukin-1β), apoptotic (mitochondrial Bax, cleaved caspase-3 and poly(ADP-ribose) polymerase, p53), podocyte integrity (E-cadherin, P-cadherin), and cell survival (phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin) biomarkers, as well the podocyte dysfunction biomarkers (Wnt1/Wnt4/β-catenin) displayed a pattern identical to that of creatinine level among the five groups (all p < 0.001). Microscopic findings demonstrated that podocyte dysfunction (Wnt1/Wnt4/β-catenin expression) and inflammatory (CD14 and F4/80-positively stained cells) biomarkers exhibited an identical pattern, whereas that of antioxidant (HO-1(+), NQO-1(+) cells) biomarkers showed an opposite pattern compared to that of creatinine level among the five groups (all p < 0.001). Combined melatonin-exendin-4 therapy offered an additional benefit in protecting the kidney from acute IR injury. PMID:27037275

  9. Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models.

    PubMed

    Eyles, D; Feldon, J; Meyer, U

    2012-01-01

    The idea that there is some sort of abnormality in dopamine (DA) signalling is one of the more enduring hypotheses in schizophrenia research. Opinion leaders have published recent perspectives on the aetiology of this disorder with provocative titles such as 'Risk factors for schizophrenia--all roads lead to dopamine' or 'The dopamine hypothesis of schizophrenia--the final common pathway'. Perhaps, the other most enduring idea about schizophrenia is that it is a neurodevelopmental disorder. Those of us that model schizophrenia developmental risk-factor epidemiology in animals in an attempt to understand how this may translate to abnormal brain function have consistently shown that as adults these animals display behavioural, cognitive and pharmacological abnormalities consistent with aberrant DA signalling. The burning question remains how can in utero exposure to specific (environmental) insults induce persistent abnormalities in DA signalling in the adult? In this review, we summarize convergent evidence from two well-described developmental animal models, namely maternal immune activation and developmental vitamin D deficiency that begin to address this question. The adult offspring resulting from these two models consistently reveal locomotor abnormalities in response to DA-releasing or -blocking drugs. Additionally, as adults these animals have DA-related attentional and/or sensorimotor gating deficits. These findings are consistent with many other developmental animal models. However, the authors of this perspective have recently refocused their attention on very early aspects of DA ontogeny and describe reductions in genes that induce or specify dopaminergic phenotype in the embryonic brain and early changes in DA turnover suggesting that the origins of these behavioural abnormalities in adults may be traced to early alterations in DA ontogeny. Whether the convergent findings from these two models can be extended to other developmental animal models for this

  10. Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity

    PubMed Central

    Wu, Jinzi; Yan, Liang-Jun

    2015-01-01

    Chronic hyperglycemia and the corresponding glucotoxicity are the main pathogenic mechanisms of diabetes and its complications. Streptozotocin (STZ)-induced diabetic animal models are useful platforms for the understanding of β cell glucotoxicity in diabetes. As diabetes induced by a single STZ injection is often referred to as type 1 diabetes that is caused by STZ’s partial destruction of pancreas, one question often being asked is whether the STZ type 1 diabetes animal model is a good model for studying the mitochondrial mechanisms of β cell glucotoxicity. In this mini review, we provide evidence garnered from the literature that the STZ type 1 diabetes is indeed a suitable model for studying mitochondrial mechanisms of diabetic β cell glucotoxicity. Evidence presented includes: 1) continued β cell derangement is due to chronic hyperglycemia after STZ is completely eliminated out of the body; 2) STZ diabetes can be reversed by insulin treatment, which indicates that β cell responds to treatment and shows ability to regenerate; and 3) STZ diabetes can be ameliorated or alleviated by administration of phytochemicals. In addition, mechanisms of STZ action and fundamental gaps in understanding mitochondrial mechanisms of β cell dysfunction are also discussed. PMID:25897251

  11. The Effect of Prenatal Hypoxia on Brain Development: Short- and Long-Term Consequences Demonstrated in Rodent Models

    ERIC Educational Resources Information Center

    Golan, Hava; Huleihel, Mahmoud

    2006-01-01

    Hypoxia (H) and hypoxia-ischemia (HI) are major causes of foetal brain damage with long-lasting behavioral implications. The effect of hypoxia has been widely studied in human and a variety of animal models. In the present review, we summarize the latest studies testing the behavioral outcomes following prenatal hypoxia/hypoxia-ischemia in rodent…

  12. Opposing changes in thoracic and abdominal aortic biomechanical properties in rodent models of vascular calcification and hypertension.

    PubMed

    Ameer, Omar Z; Salman, Ibrahim M; Avolio, Alberto P; Phillips, Jacqueline K; Butlin, Mark

    2014-07-15

    This study investigated the effects of hypertension on regional aortic biomechanical and structural properties in three rat models of vascular calcification: the hypertensive Lewis polycystic kidney (LPK; n = 13) model of chronic kidney disease, spontaneously hypertensive rats (SHRs; n = 12), and calcification in normotensive Lewis rats induced by vitamin D3 and nicotine (VDN; n = 8). Lewis and Wistar-Kyoto rats were controls. Thoracic and abdominal aortic stiffness parameters were assessed by tensile testing. In models where aortic stiffness differences compared with controls existed in both thoracic and abdominal segments, an additional cohort was quantified by histology for thoracic and abdominal aortic elastin, collagen, and calcification. LPK and VDN animals had higher thoracic breaking strain than control animals (P < 0.01 and P < 0.05, respectively) and lower energy absorption within the tensile curve of the abdominal aorta (P < 0.05). SHRs had a lower abdominal breaking stress than Wistar-Kyoto rats. LPK and VDN rats had more elastic lamellae fractures than control rats (P < 0.001), which were associated with calcium deposition (thoracic R = 0.37, P = 0.048; abdominal: R = 0.40, P = 0.046). LPK rats had higher nuclear density than control rats (P < 0.01), which was also evident in the thoracic but not abdominal aorta of VDN rats (P < 0.01). In LPK and VDN rats, but not in control rats, media thickness and cross-sectional area were at least 1.5-fold greater in thoracic than abdominal regions. The calcification models chronic kidney disease and induced calcification in normotension caused differences in regional aortic stiffness not seen in a genetic form of hypertension. Detrimental abdominal aortic remodeling but lower stiffness in the thoracic aorta with disease indicates possible compensatory mechanisms in the proximal aorta. PMID:24838503

  13. Functional mapping of the auditory tract in rodent tinnitus model using manganese-enhanced magnetic resonance imaging.

    PubMed

    Jung, Da Jung; Han, Mun; Jin, Seong-Uk; Lee, Sang Heun; Park, Ilyong; Cho, Hyun-Ju; Kwon, Tae-Jun; Lee, Hui Joong; Cho, Jin Ho; Lee, Kyu-Yup; Chang, Yongmin

    2014-10-15

    Animal models of salicylate-induced tinnitus have demonstrated that salicylate modulates neuronal activity in several brain structures leading to neuronal hyperactivity in auditory and non-auditory brain areas. In addition, these animal tinnitus models indicate that tinnitus can be a perceptual consequence of altered spontaneous neural activity along the auditory pathway. Peripheral and/or central effects of salicylate can account for neuronal activity changes in salicylate-induced tinnitus. Because of this ambiguity, an in vivo imaging study would be able to address the peripheral and/or central involvement of salicylate-induced tinnitus. Therefore, in the present study, we developed a novel manganese-enhanced magnetic resonance imaging (MEMRI) method to map the in vivo functional auditory tract in a salicylate-induced tinnitus animal model by administrating manganese through the round window. We found that acute salicylate-induced tinnitus resulted in higher manganese uptake in the cochlea and in the central auditory structures. Furthermore, serial MRI scans demonstrated that the manganese signal increased in an anterograde fashion from the cochlea to the cochlear nucleus. Therefore, our in vivo MEMRI data suggest that acute salicylate-induced tinnitus is associated with higher spontaneous neural activity both in peripheral and central auditory pathways. PMID:24983712

  14. 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

  15. Neuroprotective Potential of Novel Multi-Targeted Isoalloxazine Derivatives in Rodent Models of Alzheimer's Disease Through Activation of Canonical Wnt/β-Catenin Signalling Pathway.

    PubMed

    Machhi, Jatin; Sinha, Anshuman; Patel, Pratik; Kanhed, Ashish M; Upadhyay, Pragnesh; Tripathi, Ashutosh; Parikh, Zalak S; Chruvattil, Ragitha; Pillai, Prakash P; Gupta, Sarita; Patel, Kirti; Giridhar, Rajani; Yadav, Mange Ram

    2016-05-01

    Previous reports suggest that Alzheimer's disease is protected by cholinesterase inhibitors. We synthesized some isoalloxazine derivatives and evaluated them using in vitro cholinesterase inhibition assay. Two of the compounds (7m and 7q) were figured out as potent cholinesterase inhibitors. They further showed anti-Aβ aggregatory activity in the in vitro assay. The current study deals with the evaluation of neuroprotective potentials of the potent compounds (7m and 7q) using different in vitro and in vivo experiments. The compounds were first assessed for their tendency to cross blood-brain barrier using in vitro permeation assay. They were evaluated using scopolamine-induced amnesic mice model. Additionally, ROS scavenging and anti-apoptotic properties of 7m and 7q were established against Aβ1-42-induced toxicity in rat hippocampal neuronal cells. 7m and 7q were also evaluated using Aβ1-42-induced Alzheimer's rat model. Lastly, their involvement in Wnt/β-catenin pathway was also demonstrated. The results indicated good CNS penetration for 7m and 7q. The neuroprotective effects of 7m and 7q were evidenced by improved cognitive ability in both scopolamine and Aβ1-42-induced Alzheimer's-like condition in rodents. The in vivo results also confirmed their anti-cholinesterase and anti-oxidant potential. Immunoblot results showed that treatment with 7m and 7q decreased Aβ1-42, p-tau, cleaved caspase-3, and cleaved PARP levels in Aβ1-42-induced Alzheimer's rat brain. Additionally, immunoblot results demonstrated that 7m and 7q activated the Wnt/β-catenin pathway as evidenced by increased p-GSK-3, β-catenin, and neuroD1 levels in Aβ1-42-induced Alzheimer's rat brain. These findings have shown that isoalloxazine derivatives (7m and 7q) could be the potential leads for developing effective drugs for the treatment of AD. PMID:26797524

  16. Comprehensive Evaluation of Peripheral Nerve Regeneration in the Acute Healing Phase Using Tissue Clearing and Optical Microscopy in a Rodent Model

    PubMed Central

    Keating, Cameron P.; Senthil-Kumar, Prabhu; Zhao, Jie; Randolph, Mark A.; Winograd, Jonathan M.; Evans, Conor L.

    2014-01-01

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

  17. Long-term characterization of the Flinders Sensitive Line rodent model of human depression: Behavioral and PET evidence of a dysfunctional entorhinal cortex.

    PubMed

    Thiele, S; Spehl, T S; Frings, L; Braun, F; Ferch, M; Rezvani, A H; Furlanetti, L L; Meyer, P T; Coenen, V A; Döbrössy, M D

    2016-03-01

    The etiology of depression is unknown but has been associated with dysregulation of neuronal activity at numerous loci on the limbic-cortical circuitry. The Flinders Sensitive Line (FSL) is a validated rodent model of human depression with spontaneously emerging behavioral and physiological phenotype, however, the durability and robustness of the phenotypes have not been described. The objective of the current study was to evaluate longitudinal dynamics of the depressive-like symptoms in this animal model. FSL and control rats of both genders were assessed over 8 months, characterizing their performance at different time points on motor, sensorimotor and complex learning/memory based tasks. Changes over time in physiological parameters, such as corticosterone and blood glucose levels, were monitored. Regional glucose metabolism, used as a marker of neuronal activity, was assessed at different time points using F18-FDG Positron Emission Tomography (PET). Results show that certain deficits at 2-3 months--on tests such as the Elevated Plus Maze, Object Recognition, and the Forced Swim Test--were transitory and the phenotype was no longer present when re-testing at 6-7 months of age. However, a stable impairment was detected on a learning and memory task, particularly indicating dysfunction in retention of spatial information. Furthermore, at multiple time points, the PET scan indicated a significate bilateral, hypo-metabolism in the temporal lobes in the FSL rats compared to healthy controls. The data suggests possible alterations of entorhinal cortex metabolism concomitant with specific behavioral changes and supports the importance of understanding the dynamics and the time and gender dependence of the phenotypes present. PMID:26658515

  18. Optical diagnosis of the progression and reversal of CCl4-induced liver injury in rodent model using minimally invasive autofluorescence spectroscopy.

    PubMed

    Nazeer, Shaiju S; Sandhyamani, S; Jayasree, Ramapurath S

    2015-06-01

    Worldwide, liver cancer is the fifth most common cancer in men and seventh most common cancer in women. Intoxicant-induced liver injury is one of the major causes for severe structural damage with fibrosis and functional derangement of the liver leading to cancer in its later stages. This report focuses on the minimally invasive autofluorescence spectroscopic (AFS) studies on intoxicant, carbon tetrachloride (CCl4)-induced liver damage in a rodent model. Different stages of liver damage, including the reversed stage, on stoppage of the intoxicant are examined. Emission from prominent fluorophores, such as collagen, nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FAD), and variations in redox ratio have been studied. A direct correlation between the severity of the disease and the levels of collagen and redox ratio was observed. On withdrawal of the intoxicant, a gradual reversal of the disease to normal conditions was observed as indicated by the decrease in collagen levels and redox ratio. Multivariate statistical techniques and principal component analysis followed by linear discriminant analysis (PC-LDA) were used to develop diagnostic algorithms for distinguishing different stages of the liver disease based on spectral features. The PC-LDA modeling on a minimally invasive AFS dataset yielded diagnostic sensitivities of 93%, 87% and 87% and specificities of 90%, 98% and 98% for pairwise classification among normal, fibrosis, cirrhosis and reversal conditions. We conclude that AFS along with PC-LDA algorithm has the potential for rapid and accurate minimally invasive diagnosis and detection of structural changes due to liver injury resulting from various intoxicants. PMID:25853289

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

    PubMed

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

    2015-02-01

    This study investigated the protective effects of the administration of steroids on optic nerves (ON) and retinal ganglion cells (RGCs) in a rodent model of non-arteritic anterior ischemic optic neuropathy (rAION). We induced rAION using rose bengal and argon laser irradiation in a photodynamic procedure on the optic discs of rats. The treated groups received methylprednisolone (MP) via peritoneal injection for 2 weeks. The control group received intraperitoneal injections of phosphate-buffered saline (PBS) post-rAION. At the 4th week post-infarct, MP treatments significantly rescued the RGCs (mm(2)) in the central retinas (1920 ± 210, p < 0.001) and mid-peripheral retinas (950 ± 240, respectively, p = 0.018) compared with those of the PBS-treated rats (central: 900 ± 210 and mid-peripheral: 440 ± 180). Functional assessment with flash visual-evoked potentials demonstrated that P1 latency (ms) was shortened in the MP group compared to the PBS group (108 ± 14 and 147 ± 9, respectively, p < 0.001). In addition, the P1 amplitude (uV) was enhanced in the MP group compared to the PBS group (55 ± 12 and 41 ± 13, respectively, p < 0.05). TUNEL assays showed a decrease in the number of apoptotic cells in the RGC layers of MP-treated retinas compared to the PBS-treated group (p < 0.05). ED1 positive cells (/HPF) were significantly decreased in the ONs of the MP group compared to the PBS group (p < 0.001). In conclusion, systemic administration of MP had neuroprotective effects on RGC survival and ON function in the rAION animal model. PMID:25543054

  20. Resting Glutamate Levels and Rapid Glutamate Transients in the Prefrontal Cortex of the Flinders Sensitive Line Rat: A Genetic Rodent Model of Depression

    PubMed Central

    Hascup, Kevin N; Hascup, Erin R; Stephens, Michelle L; Glaser, Paul EA; Yoshitake, Takashi; Mathé, Aleksander A; Gerhardt, Greg A; Kehr, Jan

    2011-01-01

    Despite the numerous drugs targeting biogenic amines for major depressive disorder (depression), the search for novel therapeutics continues because of their poor response rates (∼30%) and slow onset of action (2–4 weeks). To better understand role of glutamate in depression, we used an enzyme-based microelectrode array (MEA) that was selective for glutamate measures with fast temporal (2 Hz) and high spatial (15 × 333 μm) resolution. These MEAs were chronically implanted into the prefrontal cortex of 3- to 6-month-old and 12- to 15-month-old Flinders Sensitive Line (FSL) and control Flinders Resistant Line (FRL) rats, a validated genetic rodent model of depression. Although no changes in glutamate dynamics were observed between 3 and 6 months FRL and FSL rats, a significant increase in resting glutamate levels was observed in the 12- to 15-month-old FSL rats compared with the 3- to 6-month-old FSL and age-matched FRL rats on days 3–5 post-implantation. Our MEA also recorded, for the first time, a unique phenomenon in all the four rat groups of fluctuations in resting glutamate, which we have termed glutamate transients. Although these events lasted only for seconds, they did occur throughout the testing paradigm. The average concentration of these glutamate-burst events was significantly increased in the 12- to 15-month-old FSL rats compared with 3- to 6-month-old FSL and age-matched FRL rats. These studies lay the foundation for future studies of both tonic and phasic glutamate signaling in rat models of depression to better understand the potential role of glutamate signaling in depression. PMID:21525860

  1. A rodent model of low- to moderate-dose ethanol consumption during pregnancy: patterns of ethanol consumption and effects on fetal and offspring growth.

    PubMed

    Probyn, Megan E; Zanini, Simone; Ward, Leigh C; Bertram, John F; Moritz, Karen M

    2012-01-01

    It is unknown whether low to moderate maternal alcohol consumption adversely affects postnatal health. The aim of the present study was to develop a rodent model of low-moderate-dose prenatal ethanol (EtOH) exposure. Sprague-Dawley rats were fed a liquid diet with or without 6% v/v EtOH throughout gestation and the pattern of dietary consumption determined. Fetal bodyweights and hepatic alcohol-metabolising gene expression were measured on embryonic Day (E) 20 and offspring growth studied until 1 year. At E8 the plasma EtOH concentration was 0.03%. There was little difference in dietary consumption between the two treatment groups. At E20, EtOH-exposed fetuses were significantly lighter than controls and had significantly decreased ADH4 and increased CYP2E1 gene expression. Offspring killed on postnatal Day (PN) 30 did not exhibit any growth deficits. Longitudinal repeated measures of offspring growth demonstrated slower growth in males from EtOH-fed dams between 7 and 12 months of age; a cohort of male pups killed at 8 months of age had a reduced crown-rump length and kidney weight. In conclusion, a liquid diet of 6% v/v EtOH fed to pregnant dams throughout gestation caused a 3-8% reduction in fetal growth and brain sparing, with growth differences observed in male offspring later in life. This model will be useful for future studies on the effects of low-moderate EtOH on the developmental origins of health and disease. PMID:22781937

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

    PubMed

    McAteer, Kelly M; Corrigan, Frances; Thornton, Emma; Turner, Renee Jade; Vink, Robert

    2016-01-01

    A history of concussion, particularly repeated injury, has been linked to an increased risk for the development of neurodegenerative diseases, particularly chronic traumatic encephalopathy (CTE). CTE is characterized by abnormal accumulation of hyperphosphorylated tau and deficits in learning and memory. As yet the mechanisms associated with the development of CTE are unknown. Accordingly, the aim of the current study was to develop and characterize a novel model of repetitive mTBI that accurately reproduces the key short and long-term functional and histopathological features seen clinically. Forty male Sprague-Dawley rats were randomly assigned to receive 0, 1 or 3x mTBI spaced five days apart using a modified version of the Marmarou impact-acceleration diffuse-TBI model to deliver 110G of linear force. Functional outcomes were assessed six and twelve weeks post-injury, with histopathology assessed twenty-four hours and twelve weeks post-injury. Repetitive mTBI resulted in mild spatial and recognition memory deficits as reflected by increased escape latency on the Barnes maze and decreased time spent in the novel arm of the Y maze. There was a trend towards increased anxiety-like behavior, with decreased time spent in the inner portion of the open field. At 24 hours and 12 weeks post injury, repetitive mTBI animals showed increased tau phosphorylation and microglial activation within the cortex. Increases in APP immunoreactivity were observed in repetitive mTBI animals at 12 weeks indicating long-term changes in axonal integrity. This novel model of repetitive mTBI with its persistent cognitive deficits, neuroinflammation, axonal injury and tau hyperphosphorylation, thus represents a clinically relevant experimental approach to further explore the underlying pathogenesis of CTE. PMID:27505027

  3. A new rodent model for obstructive sleep apnea: effects on ATP-mediated dilations in cerebral arteries

    PubMed Central

    Crossland, Randy F.; Durgan, David J.; Lloyd, Eric E.; Phillips, Sharon C.; Reddy, Anilkumar K.; Marrelli, Sean P.

    2013-01-01

    Obstructive sleep apnea (OSA), a condition in which the upper airway collapses during sleep, is strongly associated with metabolic and cardiovascular diseases. Little is known how OSA affects the cerebral circulation. The goals of this study were 1) to develop a rat model of chronic OSA that involved apnea and 2) to test the hypothesis that 4 wk of apneas during the sleep cycle alters endothelium-mediated dilations in middle cerebral arteries (MCAs). An obstruction device, which was chronically implanted into the trachea of rats, inflated to obstruct the airway 30 times/h for 8 h during the sleep cycle. After 4 wk of apneas, MCAs were isolated, pressurized, and exposed to luminally applied ATP, an endothelial P2Y2 receptor agonist that dilates through endothelial-derived nitric oxide (NO) and endothelial-dependent hyperpolarization (EDH). Dilations to ATP were attenuated ∼30% in MCAs from rats undergoing apneas compared with those from a sham control group (P < 0.04 group effect; n = 7 and 10, respectively). When the NO component of the dilation was blocked to isolate the EDH component, the response to ATP in MCAs from the sham and apnea groups was similar. This finding suggests that the attenuated dilation to ATP must occur through reduced NO. In summary, we have successfully developed a novel rat model for chronic OSA that incorporates apnea during the sleep cycle. Using this model, we demonstrate that endothelial dysfunction occurred by 4 wk of apnea, likely increasing the vulnerability of the brain to cerebrovascular related accidents. PMID:23761641

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

    PubMed Central

    McAteer, Kelly M.; Corrigan, Frances; Thornton, Emma; Turner, Renee Jade; Vink, Robert

    2016-01-01

    A history of concussion, particularly repeated injury, has been linked to an increased risk for the development of neurodegenerative diseases, particularly chronic traumatic encephalopathy (CTE). CTE is characterized by abnormal accumulation of hyperphosphorylated tau and deficits in learning and memory. As yet the mechanisms associated with the development of CTE are unknown. Accordingly, the aim of the current study was to develop and characterize a novel model of repetitive mTBI that accurately reproduces the key short and long-term functional and histopathological features seen clinically. Forty male Sprague-Dawley rats were randomly assigned to receive 0, 1 or 3x mTBI spaced five days apart using a modified version of the Marmarou impact-acceleration diffuse-TBI model to deliver 110G of linear force. Functional outcomes were assessed six and twelve weeks post-injury, with histopathology assessed twenty-four hours and twelve weeks post-injury. Repetitive mTBI resulted in mild spatial and recognition memory deficits as reflected by increased escape latency on the Barnes maze and decreased time spent in the novel arm of the Y maze. There was a trend towards increased anxiety-like behavior, with decreased time spent in the inner portion of the open field. At 24 hours and 12 weeks post injury, repetitive mTBI animals showed increased tau phosphorylation and microglial activation within the cortex. Increases in APP immunoreactivity were observed in repetitive mTBI animals at 12 weeks indicating long-term changes in axonal integrity. This novel model of repetitive mTBI with its persistent cognitive deficits, neuroinflammation, axonal injury and tau hyperphosphorylation, thus represents a clinically relevant experimental approach to further explore the underlying pathogenesis of CTE. PMID:27505027

  5. Chemopreventive efficacy of naproxen and nitric oxide-naproxen in rodent models of colon, urinary bladder, and mammary cancers.

    PubMed

    Steele, Vernon E; Rao, Chinthalapally V; Zhang, Yuting; Patlolla, Jagan; Boring, Daniel; Kopelovich, Levy; Juliana, M Margaret; Grubbs, Clinton J; Lubet, Ronald A

    2009-11-01

    Nonsteroidal anti-inflammatory drugs (NSAID) have been highly effective in preventing colon, urinary bladder, and skin cancer preclinically, and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal ulceration and may increase cardiovascular events. Naproxen seems to cause the lowest cardiovascular events of the common NSAIDs other than aspirin. Nitric oxide (NO)-naproxen was tested based on the finding that adding a NO group to NSAIDs may help alleviate GI toxicity. In the azoxymethane-induced rat colon aberrant crypt foci (ACF) model, naproxen administered at 200 and 400 ppm in the diet reduced mean ACFs in the colon by about 45% to 60%, respectively. NO-naproxen was likewise administered in the diet at roughly equimolar doses (300 and 600 ppm) and reduced total ACF by 20% to 40%, respectively. In the hydroxybutyl (butyl) nitrosamine rat urinary bladder cancer model, NO-naproxen was given at 183 or 550 ppm in the diet, and naproxen at 128 ppm. The NO-naproxen groups had 77% and 73% decreases, respectively, in the development of large urinary bladder tumors, whereas the 128 ppm naproxen group also showed a strong decrease (69%). If treatments were started 3 months after hydroxybutyl (butyl) nitrosamine, NO-naproxen (550 ppm) and naproxen (400 ppm) were also highly effective (86-94% decreases). In the methylnitrosourea-induced mammary cancer model in rats, NO-naproxen and naproxen showed nonsignificant inhibitions (12% and 24%) at 550 and 400 ppm, respectively. These data show that both naproxen and NO-naproxen are effective agents against urinary bladder and colon, but not mammary, carcinogenesis. PMID:19892664

  6. CHEMOPREVENTIVE EFFICACY OF NAPROXEN AND NO-NAPROXEN IN RODENT MODELS OF COLON, URINARY BLADDER, AND MAMMARY CANCERS

    PubMed Central

    Steele, Vernon E.; Rao, Chinthalapally V.; Zhang, Yuting; Patlolla, Jagan; Boring, Daniel; Kopelovich, Levy; Juliana, M. Margaret; Grubbs, Clinton J.; Lubet, Ronald A.

    2009-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have been highly effective in preventing colon, urinary bladder, and skin cancer preclinically; and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal (GI) ulceration and may increase cardiovascular (CV) events. Naproxen appears to cause the lowest CV events of the common NSAIDs other than aspirin. NO-naproxen was tested based on the finding that adding a nitric oxide (NO) group to NSAIDs may help alleviate GI toxicity. In the azoxymethane (AOM)-induced rat colon aberrant crypt foci (ACF) model, naproxen administered at 200 and 400 ppm in the diet reduced mean ACFs in the colon by about 45–60%, respectively. NO-naproxen was likewise administered in the diet at roughly equimolar doses (300 and 600 ppm), and reduced total ACF by 20–40%, respectively. In the hydroxybutyl (butyl) nitrosamine (OH-BBN) rat urinary bladder cancer model, NO-naproxen was given at 183 ppm or 550 ppm in the diet, and naproxen at 128 ppm. The NO-naproxen groups had 77% and 73% decreases, respectively, in the development of large urinary bladder tumors, while the 128 ppm naproxen group also showed a strong decrease (69%). If treatments were started three months after OH-BBN, NO-naproxen (550 ppm) and naproxen (400 ppm) were also highly effective (86–94% decreases). In the methylnitrosourea (MNU)-induced mammary cancer model in rats, NO-naproxen and naproxen showed non-significant inhibitions (12 and 24%) at 550 and 400 ppm, respectively. These data show that both naproxen and NO-naproxen are effective agents against urinary bladder and colon, but not mammary, carcinogenesis. PMID:19892664

  7. Functional changes in glutamate transporters and astrocyte biophysical properties in a rodent model of focal cortical dysplasia

    PubMed Central

    Campbell, Susan L.; Hablitz, John J.; Olsen, Michelle L.

    2014-01-01

    Cortical dysplasia is associated with intractable epilepsy and developmental delay in young children. Recent work with the rat freeze-induced focal cortical dysplasia (FCD) model has demonstrated that hyperexcitability in the dysplastic cortex is due in part to higher levels of extracellular glutamate. Astrocyte glutamate transporters play a pivotal role in cortical maintaining extracellular glutamate concentrations. Here we examined the function of astrocytic glutamate transporters in a FCD model in rats. Neocortical freeze lesions were made in postnatal day (PN) 1 rat pups and whole cell electrophysiological recordings and biochemical studies were performed at PN 21–28. Synaptically evoked glutamate transporter currents in astrocytes showed a near 10-fold reduction in amplitude compared to sham operated controls. Astrocyte glutamate transporter currents from lesioned animals were also significantly reduced when challenged exogenously applied glutamate. Reduced astrocytic glutamate transport clearance contributed to increased NMDA receptor-mediated current decay kinetics in lesioned animals. The electrophysiological profile of astrocytes in the lesion group was also markedly changed compared to sham operated animals. Control astrocytes demonstrate large-amplitude linear leak currents in response to voltage-steps whereas astrocytes in lesioned animals demonstrated significantly smaller voltage-activated inward and outward currents. Significant decreases in astrocyte resting membrane potential and increases in input resistance were observed in lesioned animals. However, Western blotting, immunohistochemistry and quantitative PCR demonstrated no differences in the expression of the astrocytic glutamate transporter GLT-1 in lesioned animals relative to controls. These data suggest that, in the absence of changes in protein or mRNA expression levels, functional changes in astrocytic glutamate transporters contribute to neuronal hyperexcitability in the FCD model

  8. Clinical laboratory, virologic, and pathologic changes in hamsters experimentally infected with Pirital virus (Arenaviridae): a rodent model of Lassa fever.

    PubMed

    Sbrana, Elena; Mateo, Rosa I; Xiao, Shu-Yuan; Popov, Vsevolod L; Newman, Patrick C; Tesh, Robert B

    2006-06-01

    The clinical laboratory, virologic, and pathologic changes occurring in hamsters after infection with Pirital virus (Arenaviridae) are described. Pirital virus infection in the hamsters was characterized by high titered viremia, leukocytosis, coagulopathy, pulmonary hemorrhage and edema, hepatocellular and splenic necrosis, and marked elevation of serum transaminase levels. All of the animals died within 9 days. The clinical and histopathological findings in the Pirital virus-infected hamsters were very similar to those reported in severe human cases of Lassa fever, suggesting that this new animal model could serve as a low-cost and relatively safe alternative for studying the pathogenesis and therapy of Lassa fever. PMID:16760527

  9. Differential efficacy of the TSPO ligands etifoxine and XBD-173 in two rodent models of Multiple Sclerosis.

    PubMed

    Ravikumar, Brinda; Crawford, Dan; Dellovade, Tammy; Savinainen, Anneli; Graham, Danielle; Liere, Philippe; Oudinet, Jean-Paul; Webb, Mike; Hering, Heike

    2016-09-01

    Neurosteroids such as progesterone and allopregnanolone have been shown to exert neuroprotective effects under a variety of pathological or insult conditions, and there is evidence that the neurosteroid system is perturbed in Multiple Sclerosis (MS) patients. Neurosteroids are synthesized in the central nervous system (CNS) through a series of metabolic transformations, beginning with a rate-limiting step of cholesterol transport through the outer mitochondrial membrane via the transporter translocator protein (TSPO). We examined the effects of etifoxine and XBD-173, two different brain penetrant TSPO agonists, for their ability to ameliorate clinical signs in two different experimental autoimmune encephalitis (EAE) models. Etifoxine, as previously reported, was efficacious in EAE, while XBD-173 was not. Surprisingly, XBD-173, but not etifoxine elevated relevant neurosteroids in brain of female rats and differed in its ability to exert anti-inflammatory and direct neuroprotective effects in vitro as compared to etifoxine. We conclude that the neurosteroid elevations produced in brain by XBD-173 are not sufficient to ameliorate EAE and suggest that etifoxine may have additional mechanisms of action that provide therapeutic benefit in this model system. PMID:27039042

  10. Associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of Wernicke’s Encephalopathy

    PubMed Central

    Zahr, Natalie M; Alt, Carsten; Mayer, Dirk; Rohlfing, Torsten; Manning-Bog, Amy; Luong, Richard; Sullivan, Edith V; Pfefferbaum, Adolf

    2014-01-01

    Thiamine (vitamin B1) deficiency, associated with a variety of conditions, including chronic alcoholism and bariatric surgery for morbid obesity, can result in the neurological disorder Wernicke’s encephalopathy (WE). Recent work building upon early observations in animal models of thiamine deficiency has demonstrated an inflammatory component to the neuropathology observed in thiamine deficiency. The present, multilevel study including in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) and postmortem quantification of chemokine and cytokine proteins sought to determine whether a combination of these in vivo neuroimaging tools could be used to characterize an in vivo MR signature for neuroinflammation. Thiamine deficiency for 12 days was used to model neuroinflammation; glucose loading in thiamine deficiency was used to accelerate neurodegeneration. Among 38 animals with regional brain tissue assayed postmortem for cytokine/chemokine protein levels, three groups of rats (controls+glucose, n=6; pyrithiamine+saline, n=5; pyrithiamine+glucose, n=13) underwent MRI/MRS at baseline (time 1), after 12 days of treatment (time 2), and 3h after challenge (glucose or saline, time 3). In the thalamus of glucose-challenged, thiamine deficient animals, correlations between in vivo measures of pathology (lower levels of N-acetyle aspartate and higher levels of lactate) and postmortem levels of monocyte chemotactic protein-1 (MCP-1, also known as chemokine ligand 2, CCL2) support a role for this chemokine in thiamine deficiency-related neurodegeneration, but do not provide a unique in vivo signature for neuroinflammation. PMID:24973622

  11. Reduced impact of emotion on choice behavior in presymptomatic BACHD rats, a transgenic rodent model for Huntington Disease.

    PubMed

    Adjeroud, Najia; Yagüe, Sara; Yu-Taeger, Libo; Bozon, Bruno; Leblanc-Veyrac, Pascale; Riess, Olaf; Allain, Philippe; Nguyen, Huu Phuc; Doyère, Valérie; El Massioui, Nicole

    2015-11-01

    Executive dysfunction and psychiatric symptoms are hallmarks of Huntington disease (HD), a neurodegenerative disorder genetically characterized by expanded CAG repeats in the HTT gene. Using the BACHD rat model of HD (97 CAG-CAA repeats), the present research seeks to characterize the progressive emergence of decision-making impairments in a rat version of the Iowa Gambling Task (RGT) and the impact of emotional modulation, whether positive or negative, on choice behavior. The choice efficiency shown both by WT rats (independent of their age) and the youngest BACHD rats (2 and 8months old) evidenced that they are able to integrate outcomes of past decisions to determine expected reward values for each option. However, 18months old BACHD rats made fewer choices during the RGT session and were less efficient in choosing advantageous options than younger animals. Presenting either chocolate pellets or electrical footshocks half-way through a second RGT session reduced exploratory activity (inefficient nose-poking) and choices with a weaker effect on BACHD animals than on WT. Choice efficiency was left intact in transgenic rats. Our results bring new knowledge on executive impairments and impact of emotional state on decision-making at different stages of the disease, increasing the face-validity of the BACHD rat model. PMID:26463506

  12. Increasing Endocannabinoid Levels in the Ventral Pallidum Restore Aberrant Dopamine Neuron Activity in the Subchronic PCP Rodent Model of Schizophrenia

    PubMed Central

    Chen, Li; Lodge, Daniel J

    2015-01-01

    Background: Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia. Methods: Using in vivo extracellular recordings in chloral hydrate–anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats. Results: Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity. Conclusions: Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity. PMID:25539511

  13. Dorsal medial prefrontal cortex (MPFC) circuitry in rodent models of cocaine use: implications for drug addiction therapies.

    PubMed

    Jasinska, Agnes J; Chen, Billy T; Bonci, Antonello; Stein, Elliot A

    2015-03-01

    Although the importance of the medial prefrontal cortex (MPFC) in cocaine addiction is well established, its precise contribution to cocaine seeking, taking and relapse remains incompletely understood. In particular, across two different models of cocaine self-administration, pharmacological or optogenetic activation of the dorsal MPFC has been reported to sometimes promote and sometimes inhibit cocaine seeking. We highlight important methodological differences between the two experimental paradigms and propose a framework to potentially reconcile the apparent discrepancy. We also draw parallels between these pre-clinical models of cocaine self-administration and human neuro-imaging studies in cocaine users, and argue that both lines of evidence point to dynamic interactions between cue-reactivity processes and control processes within the dorsal MPFC circuitry. From a translational perspective, these findings underscore the importance of interventions and therapeutics targeting not just a brain region, but a specific computational process within that brain region, and may have implications for the design and implementation of more effective treatments for human cocaine addiction. PMID:24620898

  14. Effects of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour in the corticosterone model of depression.

    PubMed

    O'Donovan, Sinead; Dalton, Victoria; Harkin, Andrew; McLoughlin, Declan M

    2014-09-01

    Brief pulse electroconvulsive therapy (BP ECT; pulse width 0.5-1.5 ms) is the most effective treatment available for severe depression. However, its use is associated with side-effects. The stimulus in ultrabrief pulse ECT (UBP ECT; pulse width 0.25-0.3 ms) is more physiological and has been reported to be associated with less cognitive side-effects, but its antidepressant effectiveness is not yet well established. Using electroconvulsive stimulation (ECS), the animal model of ECT, we previously reported UBP ECS to be significantly less effective than well-established BP ECS in eliciting behavioural, molecular and cellular antidepressant-related effects in naïve rats. We have now compared the effects of BP and UBP ECS in an animal model of depression related to exogenous supplementation with the stress-induced glucocorticoid hormone, corticosterone. Corticosterone administration resulted in an increase in immobility time in the forced swim test (FST) (p < 0.01) and decreases in the expression of brain-derived neurotrophic factor (BDNF) (p < 0.05) and glial fibrillary acidic protein (GFAP) (p < 0.001) in the hippocampus and frontal cortex. There was no significant difference in the duration or type of seizure induced by BP (0.5 ms) or UBP (0.3 ms) ECS. UBP ECS proved to be as effective as BP ECS at inducing a behavioural antidepressant response in the FST with a significant decrease (p < 0.001) in immobility seen following administration of ECS. Both forms of ECS also induced significant increases in BDNF protein (p < 0.01) expression in the hippocampus. BP ECS (p < 0.05) but not UBP ECS induced a significant increase in GFAP levels in the hippocampus and frontal cortex. Overall, UBP ECS effectively induced antidepressant-related behavioural and molecular responses in the corticosterone supplementation model, providing the first preclinical data on the potential role of this form of ECS to treat a depression phenotype related to elevated corticosterone. PMID

  15. Evaluation of AMG 076, a potent and selective MCHR1 antagonist, in rodent and primate obesity models

    PubMed Central

    Motani, Alykhan S; Luo, Jian; Liang, Lingming; Mihalic, Jeffrey T; Chen, Xiaoqi; Tang, Liang; Li, Leping; Jaen, Juan; Chen, Jin-Long; Dai, Kang

    2013-01-01

    Melanin-concentrating hormone (MCH) regulates food intake through activation of the receptor, MCHR1. We have identified AMG 076 as an orally bioavailable potent and selective small molecule antagonist of MCHR1. In mouse models of obesity, AMG 076 caused a reduction in body weight gain in wild-type (MCHR1+/+) but not in knockout (MCHR1−/−) mice. The body weight reduction was associated with decreases in food intake and increases in energy expenditure. Importantly, we show that these MCHR1-dependent effects of AMG 076 were also reflected in improved metabolic phenotypes, increased glucose tolerance and insulin sensitivity. Preliminary data on effects of AMG 076 in obese cynomolgus monkeys are also presented. PMID:25505557

  16. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy

    PubMed Central

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