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Sample records for adult rodent models

  1. Kainate administered to adult zebrafish causes seizures similar to those in rodent models.

    PubMed

    Alfaro, Juan M; Ripoll-Gómez, Jorge; Burgos, Javier S

    2011-04-01

    Glutamate is the major excitatory neurotransmitter of the central nervous system in vertebrates. Excitotoxicity, caused by over-stimulation of the glutamate receptors, is a major cause of neuron death in several brain diseases, including epilepsy. We describe here how behavioural seizures can be triggered in adult zebrafish by the administration of kainate and are very similar to those observed in rodent models. Kainate induced a dose-dependent sequence of behavioural changes culminating in clonus-like convulsions. Behavioural seizures were suppressed by DNQX (6,7-dinitroquinoxaline-2,3-dione) dose-dependently, whilst MK-801 (a non-competitive NMDA receptor antagonist) had a lesser effect. Kainate triggers seizures in adult zebrafish, and thus this species can be considered as a new model for studying seizures and subsequent excitotoxic brain injury.

  2. 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

  3. 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

  4. Synergist Ablation as a Rodent Model to Study Satellite Cell Dynamics in Adult Skeletal Muscle.

    PubMed

    Kirby, Tyler J; McCarthy, John J; Peterson, Charlotte A; Fry, Christopher S

    2016-01-01

    In adult skeletal muscles, satellite cells are the primary myogenic stem cells involved in myogenesis. Normally, they remain in a quiescent state until activated by a stimulus, after which they proliferate, differentiate, and fuse into an existing myofiber or form a de novo myofiber. To study satellite cell dynamics in adult murine models, most studies utilize regeneration models in which the muscle is severely damaged and requires the participation from satellite cells in order to repair. Here, we describe a model to study satellite cell behavior in muscle hypertrophy that is independent of muscle regeneration.Synergist ablation surgery involves the surgical removal of the gastrocnemius and soleus muscles resulting in functional overload of the remaining plantaris muscle. This functional overload results in myofiber hypertrophy, as well as the activation, proliferation, and fusion of satellite cells into the myofibers. Within 2 weeks of functional overload, satellite cell content increases approximately 275 %, an increase that is accompanied with a ~60 % increase in the number of myonuclei. Therefore, this can be used as an alternative model to study satellite cell behavior in adulthood that is different from regeneration, and capable of revealing new satellite cell functions in regulating muscle adaptation. PMID:27492164

  5. Synergist Ablation as a Rodent Model to Study Satellite Cell Dynamics in Adult Skeletal Muscle.

    PubMed

    Kirby, Tyler J; McCarthy, John J; Peterson, Charlotte A; Fry, Christopher S

    2016-01-01

    In adult skeletal muscles, satellite cells are the primary myogenic stem cells involved in myogenesis. Normally, they remain in a quiescent state until activated by a stimulus, after which they proliferate, differentiate, and fuse into an existing myofiber or form a de novo myofiber. To study satellite cell dynamics in adult murine models, most studies utilize regeneration models in which the muscle is severely damaged and requires the participation from satellite cells in order to repair. Here, we describe a model to study satellite cell behavior in muscle hypertrophy that is independent of muscle regeneration.Synergist ablation surgery involves the surgical removal of the gastrocnemius and soleus muscles resulting in functional overload of the remaining plantaris muscle. This functional overload results in myofiber hypertrophy, as well as the activation, proliferation, and fusion of satellite cells into the myofibers. Within 2 weeks of functional overload, satellite cell content increases approximately 275 %, an increase that is accompanied with a ~60 % increase in the number of myonuclei. Therefore, this can be used as an alternative model to study satellite cell behavior in adulthood that is different from regeneration, and capable of revealing new satellite cell functions in regulating muscle adaptation.

  6. 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

  7. 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.

  8. 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

  9. 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

  10. The MAM rodent model of schizophrenia.

    PubMed

    Lodge, Daniel J

    2013-01-01

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

  11. Models of Oxygen Induced Retinopathy in Rodents.

    PubMed

    Gammons, Melissa V; Bates, David O

    2016-01-01

    Much of the knowledge we have gained into the development of pathological ocular angiogenesis has come from the development of in vivo models that enable functional assessment of key components of signaling pathways in disease progression. Indeed, rodent models have facilitated identification of several therapeutics that target pathological angiogenesis. Two of the most widely used rodent models of oxygen induced retinopathy (OIR), Smith's mouse model and Penn's rat model reproducibly induce neovascularization reminiscent of the disease retinopathy of prematurity (ROP). In this chapter we discuss development of ROP in humans and compare features with that of the rat and mouse models, focusing both on the benefits and caveats of using such models. Furthermore, we discuss in detail the methodology of both procedures and discuss the importance of various features of the model. PMID:27172964

  12. New neurons in the adult striatum: from rodents to humans

    PubMed Central

    Inta, Dragos; Cameron, Heather A.; Gass, Peter

    2015-01-01

    Most neurons are generated during development and are not replaced during adulthood, even if they are lost to injury or disease. It is firmly established, however, that new neurons are generated in the dentate gyrus of the hippocampus of virtually all adult mammals, including humans [1]. Many questions still remain, however, regarding adult neurogenesis in other brain regions and particularly in humans, where standard birthdating methods are not generally feasible. Exciting recent evidence indicates that calretinin-expressing interneurons are added to the adult human striatum at a substantial rate [2]. The role of new neurons is unknown, but studies in rodents will be able to further elucidate their identity and origin and then begin to understand their regulation and function. PMID:26298770

  13. 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

  14. Rodent Models of Amyotrophic Lateral Sclerosis.

    PubMed

    Philips, Thomas; Rothstein, Jeffrey D

    2015-06-01

    Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the central nervous system. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3 to 5 years after disease onset. The condition 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 (∼ 40% to 50% of fALS and ∼ 10% of sALS). Studies suggest that ALS is mediated through aberrant protein homeostasis (i.e., ER stress and autophagy) and/or changes in RNA processing (as in all non-SOD1-mediated ALS). In all of these cases, animal models suggest that the disorder 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 the pathogenesis. Provided in this unit is a review of ALS rodent models, including discussion of their relative advantages and disadvantages. Emphasis is placed on correlating the model phenotype with the human condition and the utility of the model for defining the disease process. Information is also presented on RNA processing studies in ALS research, with particular emphasis on the newest ALS rodent models.

  15. 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.

  16. Expression of DNA methyltransferases in adult dorsal root ganglia is cell-type specific and up regulated in a rodent model of neuropathic pain

    PubMed Central

    Pollema-Mays, Sarah L.; Centeno, Maria V.; Apkarian, A. V.; Martina, Marco

    2014-01-01

    Neuropathic pain is associated with hyperexcitability and intrinsic firing of dorsal root ganglia (DRG) neurons. These phenotypical changes can be long lasting, potentially spanning the entire life of animal models, and depend on altered expression of numerous proteins, including many ion channels. Yet, how DRGs maintain long-term changes in protein expression in neuropathic conditions remains unclear. DNA methylation is a well-known mechanism of epigenetic control of gene expression and is achieved by the action of three enzymes: DNA methyltransferase (DNMT) 1, 3a, and 3b, which have been studied primarily during development. We first performed immunohistochemical analysis to assess whether these enzymes are expressed in adult rat DRGs (L4–5) and found that DNMT1 is expressed in both glia and neurons, DNMT3a is preferentially expressed in glia and DNMT3b is preferentially expressed in neurons. A rat model of neuropathic pain was then used to determine whether nerve injury may induce epigenetic changes in DRGs at multiple time points after pain onset. Real-time RT PCR analysis revealed robust and time-dependent changes in DNMT transcript expression in ipsilateral DRGs from spared nerve injury (SNI) but not sham rats. Interestingly, DNMT3b transcript showed a robust upregulation that appeared already 1 week after surgery and persisted at 4 weeks (our endpoint); in contrast, DNMT1 and DNMT3a transcripts showed only moderate upregulation that was transient and did not appear until the second week. We suggest that DNMT regulation in adult DRGs may be a contributor to the pain phenotype and merits further study. PMID:25152711

  17. 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...

  18. 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

  19. Excitation-inhibition discoordination in rodent models of mental disorders

    PubMed Central

    Fenton, André A.

    2015-01-01

    Animal models of mental illness provide a foundation for evaluating hypotheses for the mechanistic causes of mental illness. Neurophysiological investigations of neural network activity in rodent models of mental dysfunction are reviewed from the conceptual framework of the discoordination hypothesis, which asserts that failures of neural coordination cause cognitive deficits in the judicious processing and use of information. Abnormal dynamic coordination of excitatory and inhibitory neural discharge in pharmacological and genetic rodent models support the discoordination hypothesis. These observations suggest excitation-inhibition discoordination and aberrant neural circuit dynamics as causes of cognitive impairment as well as therapeutic targets for cognition-promoting treatments. PMID:25895430

  20. 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

  1. 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

  2. Rodent Models of Vascular Cognitive Impairment.

    PubMed

    Yang, Yi; Kimura-Ohba, Shihoko; Thompson, Jeffrey; Rosenberg, Gary A

    2016-10-01

    Vascular cognitive impairment dementia (VCID), which is an increasingly important cause of dementia in the elderly, lacks effective treatments. Many different types of vascular disease are included under the diagnosis of VCID, including large vessel disease with multiple strokes and small vessel disease with lacunar infarcts and white matter disease. Animal models have been developed to study the multiple forms of VCID. Because of its progressive course, small vessel disease (SVD) is thought to be the optimal form of VCID for treatment. One theory is that the pathophysiology involves hypoxic hypoperfusion resulting in injury to the white matter and neuronal death. Bilateral occlusion of the common carotid arteries (BCAO) in a normotensive rat, which reduces cerebral blood flow, induces hypoxia with white matter damage; this model has been used to test drugs to block the injury. Another model is the spontaneously hypertensive/stroke prone rat (SHR/SP). Hypertension leads to small vessel disease resulting in progressive damage to the white matter, cortex, and hippocampus. Bilateral carotid artery stenosis (BCAS) with coils or ameroid constrictors produces a slower development of changes than BCAO, avoiding the acute ischemia. A few studies have been done with the two-clip, two-vessel occlusion renal model for induction of hypertension. There are benefits and drawbacks to each of these models with the model selected depending on the type of vascular damage that is to be studied. This review describes the most commonly used models, and the drugs that have been used to reduce the damage. PMID:27498679

  3. Rodent models for resolving extremes of exercise and health.

    PubMed

    Garton, Fleur C; North, Kathryn N; Koch, Lauren G; Britton, Steven L; Nogales-Gadea, Gisela; Lucia, Alejandro

    2016-02-01

    The extremes of exercise capacity and health are considered a complex interplay between genes and the environment. In general, the study of animal models has proven critical for deep mechanistic exploration that provides guidance for focused and hypothesis-driven discovery in humans. Hypotheses underlying molecular mechanisms of disease and gene/tissue function can be tested in rodents to generate sufficient evidence to resolve and progress our understanding of human biology. Here we provide examples of three alternative uses of rodent models that have been applied successfully to advance knowledge that bridges our understanding of the connection between exercise capacity and health status. First we review the strong association between exercise capacity and all-cause morbidity and mortality in humans through artificial selection on low and high exercise performance in the rat and the consequent generation of the "energy transfer hypothesis." Second we review specific transgenic and knockout mouse models that replicate the human disease condition and performance. This includes human glycogen storage diseases (McArdle and Pompe) and α-actinin-3 deficiency. Together these rodent models provide an overview of the advancements of molecular knowledge required for clinical translation. Continued study of these models in conjunction with human association studies will be critical to resolving the complex gene-environment interplay linking exercise capacity, health, and disease. PMID:26395598

  4. Electrophysiological endophenotypes in rodent models of schizophrenia and psychosis

    PubMed Central

    Rosen, Andrew M.; Spellman, Timothy; Gordon, Joshua A.

    2015-01-01

    Schizophrenia is caused by a diverse array of risk factors, and results in a similarly diverse set of symptoms. Electrophysiological endophenotypes lie between risks and symptoms, and have the potential to link the two. Electrophysiological studies in rodent models, described here, demonstrate that widely differing risk factors result in a similar set of core electrophysiological endophenotypes, suggesting the possibility of a shared neurobiological substrate. PMID:25910423

  5. 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.

  6. Rodent Models of Depression: Neurotrophic and Neuroinflammatory Biomarkers

    PubMed Central

    Stepanichev, Mikhail; Dygalo, Nikolay N.; Grigoryan, Grigory; Shishkina, Galina T.; Gulyaeva, Natalia

    2014-01-01

    Rodent models are an indispensable tool for studying etiology and progress of depression. Since interrelated systems of neurotrophic factors and cytokines comprise major regulatory mechanisms controlling normal brain plasticity, impairments of these systems form the basis for development of cerebral pathologies, including mental diseases. The present review focuses on the numerous experimental rodent models of depression induced by different stress factors (exteroceptive and interoceptive) during early life (including prenatal period) or adulthood, giving emphasis to the data on the changes of neurotrophic factors and neuroinflammatory indices in the brain. These parameters are closely related to behavioral depression-like symptoms and impairments of neuronal plasticity and are both gender- and genotype-dependent. Stress-related changes in expression of neurotrophins and cytokines in rodent brain are region-specific. Some contradictory data reported by different groups may be a consequence of differences of stress paradigms or their realization in different laboratories. Like all experimental models, stress-induced depression-like conditions are experimental simplification of clinical depression states; however, they are suitable for understanding the involvement of neurotrophic factors and cytokines in the pathogenesis of the disease—a goal unachievable in the clinical reality. These major regulatory systems may be important targets for therapeutic measures as well as for development of drugs for treatment of depression states. PMID:24999483

  7. 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

  8. 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

  9. 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

  10. Modeling Risky Decision Making in Rodents

    PubMed Central

    Simon, Nicholas W.; Setlow, Barry

    2012-01-01

    Excessive risk taking is a hallmark of various psychopathological disorders. We have developed a task that models such risky decision making in rats. In this task, rats are given choices between small, safe rewards and large rewards accompanied by a risk of punishment (footshock). The risk of punishment increases throughout the test session, which allows the quantification of risky decision making at different degrees of risk for each subject. Importantly, this task yields a consistently wide degree of reliable individual variability, allowing the characterization of rats as “risk taking” or “risk averse.” This task has been demonstrated to be effective for testing the effects of pharmacological agents on risk taking, and the individual variability (which mimics the human population) allows assessment of neurobiological distinctions between subjects based on risk-taking profile. PMID:22231813

  11. 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

  12. The utility of rodent models of autism spectrum disorders

    PubMed Central

    Lazaro, Maria; Golshani, Peyman

    2015-01-01

    Purpose of Review This review discusses the ways rodent models of autism spectrum disorders (ASDs) have been used to gain critical information convergent molecular pathways, the mechanisms underlying altered microcircuit structure and function, and as a screen for potential cutting edge-treatments. Recent Findings There is convergent evidence that impaired developmental pruning of connections may be a common finding among several mouse models of ASDs. Recent studies have uncovered impaired autophagy by pathological mTOR activation as a potential contributor to microcircuit dysfunction and behavior. ASD related disinhibition and exaggerated synaptic plasticity in multiple distinct circuits in cortex and reward circuits in striatum also contribute to social dysfunction and repetitive behaviors. New exciting molecular therapeutic techniques have reversed cognitive deficits in models of ASD, indicating that mouse models could be used for preclinical translational studies of new treatments. Summary Rodent models of ASDs coupled to new emerging technologies for genome editing, cell-specific functional and structural imaging, and neuronal activity manipulation will yield critical insights into ASD pathogenesis and fuel the emergence of new treatments. PMID:25734952

  13. 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

  14. Dietary resistant starch improves selected brain and behavioral functions in adult and aged rodents

    PubMed Central

    Zhou, June; Keenan, Michael J.; Fernandez-Kim, Sun Ok; Pistell, Paul J.; Ingram, Donald K.; Li, Bing; Raggio, Anne M.; Shen, Li; Zhang, Hanjie; McCutcheon, Kathleen L; Tulley, Richard T.; Blackman, Marc R.; Keller, Jeffrey N.; Martin, Roy J.

    2013-01-01

    Resistant starch (RS) is a dietary fiber that exerts multiple beneficial effects. The current study explored the effects of dietary RS on selected brain and behavioral functions in adult and aged rodents. Because glucokinase (GK) expression in hypothalamic arcuate nucleus and area postrema of the brainstem is important for brain glucose sensing, GK mRNA was measured by brain nuclei microdissection and PCR. Adult RS-fed rats had a higher GK mRNA than controls in both brain nuclei, an indicator of improved brain glucose sensing. Next, we tested whether dietary RS improve selected behaviors in aged mice. RS-fed aged mice exhibited (1) an increased eating responses to fasting, a behavioral indicator of improvement in aged brain glucose sensing; (2) a longer latency to fall from an accelerating rotarod, a behavioral indicator of improved motor coordination; and (3) a higher serum active GLP-1. Third, GLP-1 receptor null (GLP-1RKO) mice were used to test the role of GLP-1 in brain glucose sensing, and they exhibited impaired eating responses to fasting. We conclude that in rodents (1) dietary RS improves two important indicators of brain function: glucose sensing and motor coordination, and that (2) GLP-1 is important in the optimal feeding response to a fast. PMID:23818307

  15. Dietary resistant starch improves selected brain and behavioral functions in adult and aged rodents.

    PubMed

    Zhou, June; Keenan, Michael J; Fernandez-Kim, Sun Ok; Pistell, Paul J; Ingram, Donald K; Li, Bing; Raggio, Anne M; Shen, Li; Zhang, Hanjie; McCutcheon, Kathleen L; Tulley, Richard T; Blackman, Marc R; Keller, Jeffrey N; Martin, Roy J

    2013-11-01

    Resistant starch (RS) is a dietary fiber that exerts multiple beneficial effects. The current study explored the effects of dietary RS on selected brain and behavioral functions in adult and aged rodents. Because glucokinase (GK) expression in hypothalamic arcuate nucleus and area postrema of the brainstem is important for brain glucose sensing, GK mRNA was measured by brain nuclei microdissection and PCR. Adult RS-fed rats had a higher GK mRNA than controls in both brain nuclei, an indicator of improved brain glucose sensing. Next, we tested whether dietary RS improve selected behaviors in aged mice. RS-fed aged mice exhibited (i) an increased eating responses to fasting, a behavioral indicator of improvement in aged brain glucose sensing; (ii) a longer latency to fall from an accelerating rotarod, a behavioral indicator of improved motor coordination; and (iii) a higher serum active glucagon-like peptide-1 (GLP-1). Then, GLP-1 receptor null (GLP-1RKO) mice were used to test the role of GLP-1 in brain glucose sensing, and they exhibited impaired eating responses to fasting. We conclude that in rodents (i) dietary RS improves two important indicators of brain function: glucose sensing and motor coordination, and (ii) GLP-1 is important in the optimal feeding response to a fast.

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

    PubMed

    Morellini, Fabio

    2013-10-01

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

  17. 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

  18. 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

  19. Toward a rodent model of the Iowa gambling task.

    PubMed

    van den Bos, Ruud; Lasthuis, Wilma; den Heijer, Esther; van der Harst, Johanneke; Spruijt, Berry

    2006-08-01

    The Iowa gambling task in humans is, in principle, suited for the study of the long-term efficiency of behavior in a biologically relevant context. Key features of this task are uncertainty of outcomes and a conflict between the immediate and the long-term payoff options. Animal models allow us to study the underlying neurobiology of decision-making processes and the long-term efficiency of behavior in more detail and at a greater depth than is possible in humans. Therefore, we set out to develop a model of this task in rodents, using the task's key features. In this article, we describe the results of the first series of experiments with rats and mice. The data thus far suggest that mice and rats behave in a way similar to humans; that is, they tend to choose the option with the best long-term payoff more often as the test progresses. PMID:17186757

  20. Tool Use Specific Adult Neurogenesis and Synaptogenesis in Rodent (Octodon degus) Hippocampus

    PubMed Central

    Kumazawa-Manita, Noriko; Hama, Hiroshi; Miyawaki, Atsushi; Iriki, Atsushi

    2013-01-01

    We previously demonstrated that degus (Octodon degus), which are a species of small caviomorph rodents, could be trained to use a T-shaped rake as a hand tool to expand accessible spaces. To elucidate the neurobiological underpinnings of this higher brain function, we compared this tool use learning task with a simple spatial (radial maze) memory task and investigated the changes that were induced in the hippocampal neural circuits known to subserve spatial perception and learning. With the exposure to an enriched environment in home cage, adult neurogenesis in the dentate gyrus of the hippocampus was augmented by tool use learning, but not radial maze learning, when compared to control conditions. Furthermore, the proportion of new synapses formed in the CA3 region of the hippocampus, the target area for projections of mossy fiber axons emanating from newborn neurons, was specifically increased by tool use learning. Thus, active tool use behavior by rodents, learned through multiple training sessions, requires the hippocampus to generate more novel neurons and synapses than spatial information processing in radial maze learning. PMID:23516527

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

    PubMed Central

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

    2014-01-01

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

  2. 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

  3. Liver carcinogenesis: Rodent models of hepatocarcinoma and cholangiocarcinoma

    PubMed Central

    Minicis, Samuele De; Kisseleva, Tatiana; Francis, Heather; Baroni, Gianluca Svegliati; Benedetti, Antonio; Brenner, David; Alvaro, Domenico; Alpini, Gianfranco; Marzioni, Marco

    2013-01-01

    Hepatocellular carcinoma and cholangiocarcinoma are primary liver cancers, both represent a growing challenge for clinicians due to their increasing morbidity and mortality. In the last few years a number of in vivo models of hepatocellular carcinoma and cholangiocarcinoma have been developed. The study of these models is providing a significant contribution in unveiling the pathophysiology of primary liver malignancies. They are also fundamental tools to evaluate newly designed molecules to be tested as new potential therapeutic agents in a pre-clinical set. Technical aspects of each model are critical steps, and they should always be considered in order to appropriately interpret the findings of a study or its planning. The purpose of this review is to describe the technical and experimental features of the most significant rodent models, highlighting similarities or differences between the corresponding human diseases. The first part is dedicated to the discussion of models of hepatocellular carcinoma, developed using toxic agents, or through dietary or genetic manipulations. In the second we will address models of cholangiocarcinoma developed in rats or mice by toxin administration, genetic manipulation and/or bile duct incannulation or surgery. Xenograft or syngenic models are also proposed. PMID:23177172

  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. HAND1 and HAND2 are expressed in the adult-rodent heart and are modulated during cardiac hypertrophy.

    PubMed

    Thattaliyath, Bijoy D; Livi, Carolina B; Steinhelper, Mark E; Toney, Glenn M; Firulli, Anthony B

    2002-10-01

    The HAND basic Helix-Loop-Helix (bHLH) transcription factors are essential for normal cardiac and extraembryonic development. Although highly evolutionarily conserved genes, HAND cardiac expression patterns differ across species. Mouse expression of HAND1 and HAND2 was reported absent in the adult heart. Human HAND genes are expressed in the adult heart and HAND1 expression is downregulated in cardiomyopathies. As rodent and human expression profiles are inconsistent, we re-examined expression of HAND1 and HAND2 in adult-rodent hearts. HAND1 and HAND2 are expressed in adult-rodent hearts and HAND2 is expressed in the atria. Induction of cardiac hypertrophy shows modulation of HAND expression, corresponding with observations in human cardiomyopathy. The downregulation of HAND expression observed in rodent hypertrophy and human cardiomyopathy may reflect a permissive role allowing, cardiomyocytes to reinitiate the fetal gene program and initiate the adaptive physiological changes that allow the heart to compensate (hypertrophy) for the increase in afterload.

  6. 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

  7. Methods of Liver Stem Cell Therapy in Rodents as Models of Human Liver Regeneration in Hepatic Failure.

    PubMed

    Hashemi Goradel, Nasser; Darabi, Masoud; Shamsasenjan, Karim; Ejtehadifar, Mostafa; Zahedi, Sarah

    2015-09-01

    Cell therapy is a promising intervention for treating liver diseases and liver failure. Different animal models of human liver cell therapy have been developed in recent years. Rats and mice are the most commonly used liver failure models. In fact, rodent models of hepatic failure have shown significant improvement in liver function after cell infusion. With the advent of stem-cell technologies, it is now possible to re-programme adult somatic cells such as skin or hair-follicle cells from individual patients to stem-like cells and differentiate them into liver cells. Such regenerative stem cells are highly promising in the personalization of cell therapy. The present review article will summarize current approaches to liver stem cell therapy with rodent models. In addition, we discuss common cell tracking techniques and how tracking data help to direct liver cell therapy research in animal models of hepatic failure.

  8. Naturalistic Rodent Models of Chronic Early-Life Stress

    PubMed Central

    Molet, Jenny; Maras, Pamela M.; Avishai-Eliner, Sarit

    2016-01-01

    A close association between early-life experience and cognitive and emotional outcomes is found in humans. In experimental models, early-life experience can directly influence a number of brain functions long-term. Specifically, and often in concert with genetic background, experience regulates structural and functional maturation of brain circuits and alters individual neuronal function via large-scale changes in gene expression. Because adverse experience during sensitive developmental periods is often associated with neuropsychiatric disease, there is an impetus to create realistic models of distinct early-life experiences. These can then be used to study causality between early-life experiential factors and cognitive and emotional outcomes, and to probe the underlying mechanisms. Although chronic early-life stress has been linked to the emergence of emotional and cognitive disorders later in life, most commonly used rodent models of involve daily maternal separation and hence intermittent early-life stress. We describe here a naturalistic and robust chronic early-life stress model that potently influences cognitive and emotional outcomes. Mice and rats undergoing this stress develop structural and functional deficits in a number of limbic-cortical circuits. Whereas overt pathological memory impairments appear during adulthood, emotional and cognitive vulnerabilities emerge already during adolescence. This naturalistic paradigm, widely adopted around the world, significantly enriches the repertoire of experimental tools available for the study of normal brain maturation and of cognitive and stress-related disorders including depression, autism, post-traumatic stress disorder, and dementia. PMID:24910169

  9. Electrically Induced Limbic Seizures: Preliminary Findings in a Rodent Model

    PubMed Central

    Kowski, Alexander B; Holtkamp, Martin

    2015-01-01

    In epilepsy, novel pharmacological and nonpharmacological treatment approaches are commonly assessed in model systems of acute motor and often generalized seizures. We developed a rodent model with short-term electrical stimulation of the perforant path resulting in stereotyped limbic seizures. Limbic structures play a major role in human intractable epilepsy. In 10 rats, single electrical 5-second and 20-Hz stimuli to the perforant path reliably produced limbic seizures characterized by resting behavior and subtle motor signs. Electrophysiological recordings from the dentate gyrus demonstrated a seizure pattern with 4-Hz to 5-Hz discharges. Multiple inductions of seizures within 72 hours did not alter behavioral and electrophysiological seizure characteristics. Electrophysiological excitatory and inhibitory parameters assessed by evoked single and paired pulses did not change with increasing number of seizures. We present preliminary findings on a new model of electrically induced limbic seizures of mesiotemporal origin. This model may represent a reliable screening tool for new treatment approaches such as deep brain stimulation. PMID:25861223

  10. 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

  11. Schistosoma mansoni Sambon, 1907: morphometric differences between adult worms from sympatric rodent and human isolates.

    PubMed

    Neves, R H; Pereira, M J; de Oliveira, R M; Gomes, D C; Machado-Silva, J R

    1998-01-01

    A computer software for image analysis (IMAGE PRO PLUS, MEDIA CYBERNETICS) was utilized in male and females adult worms, aiming the morphological characterization of Schistosoma mansoni samples isolated from a slyvatic rodent, Nectomys squamipes, and humans in Sumidouro, Rio de Janeiro, Brazil and recovered from Mus musculus C3H/He. The following characters for males's testicular lobes were analyzed: number, area, density, larger and smaller diameter, longer and shorter axis and perimeter and extension; for females: area, longer and shorter axis, larger and smaller diameter and perimeter of the eggs and spine; oral and ventral suckers area and distance between them in both sex were determined. By the analysis of variance (one way ANOVA) significant differences (p < 0.05) were observed in all studied characters, except for the density of testicular lobes. Significant differences (p < 0.05) were detected for all characters in the female worms. Data ratify that sympatric isolates present phenotypic differences and the adult female characters are useful for the proper identification of S. mansoni isolates.

  12. Relationships between Gene Expression and Brain Wiring in the Adult Rodent Brain

    PubMed Central

    French, Leon; Pavlidis, Paul

    2011-01-01

    We studied the global relationship between gene expression and neuroanatomical connectivity in the adult rodent brain. We utilized a large data set of the rat brain “connectome” from the Brain Architecture Management System (942 brain regions and over 5000 connections) and used statistical approaches to relate the data to the gene expression signatures of 17,530 genes in 142 anatomical regions from the Allen Brain Atlas. Our analysis shows that adult gene expression signatures have a statistically significant relationship to connectivity. In particular, brain regions that have similar expression profiles tend to have similar connectivity profiles, and this effect is not entirely attributable to spatial correlations. In addition, brain regions which are connected have more similar expression patterns. Using a simple optimization approach, we identified a set of genes most correlated with neuroanatomical connectivity, and find that this set is enriched for genes involved in neuronal development and axon guidance. A number of the genes have been implicated in neurodevelopmental disorders such as autistic spectrum disorder. Our results have the potential to shed light on the role of gene expression patterns in influencing neuronal activity and connectivity, with potential applications to our understanding of brain disorders. Supplementary data are available at http://www.chibi.ubc.ca/ABAMS. PMID:21253556

  13. 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 ...

  14. 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...

  15. 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...

  16. Rodent models in neuroscience research: is it a rat race?

    PubMed Central

    2016-01-01

    ABSTRACT Rodents (especially Mus musculus and Rattus norvegicus) have been the most widely used models in biomedical research for many years. A notable shift has taken place over the last two decades, with mice taking a more and more prominent role in biomedical science compared to rats. This shift was primarily instigated by the availability of a much larger genetic toolbox for mice, particularly embryonic-stem-cell-based targeting technology for gene disruption. With the recent emergence of tools for altering the rat genome, notably genome-editing technologies, the technological gap between the two organisms is closing, and it is becoming more important to consider the physiological, anatomical, biochemical and pharmacological differences between rats and mice when choosing the right model system for a specific biological question. The aim of this short review and accompanying poster is to highlight some of the most important differences, and to discuss their impact on studies of human diseases, with a special focus on neuropsychiatric disorders. PMID:27736744

  17. Rodent models of genetic contributions to motivation to abuse alcohol.

    PubMed

    Crabbe, John C

    2014-01-01

    In summary, there are remarkably few studies focused on the genetic contributions to alcohol's reinforcing values. Almost all such studies examine the two-bottle preference test. Despite the deficiencies I have raised in its interpretation, a rodent genotype's willingness to drink ethanol when water is freely available offers a reasonable aggregate estimate of alcohol's reinforcing value relative to other genotypes (Green and Grahame 2008). As indicated above, however, preference drinking studies will likely never avoid the confounding role of taste preferences and most often yield intake levels not sufficient to yield a pharmacologically significant BAL. Thus, the quest for improved measures of reinforcing value continues. Of the potential motivational factors considered by McClearn in his seminal review in this series, we can safely conclude that rodent alcohol drinking is not primarily directed at obtaining calories. The role of taste (and odor) remains a challenge. McClearn appears to have been correct that especially those genotypes that avoid alcohol are probably doing so based on preingestive sensory cues; however, postingestive consequences are also important. Cunningham's intragastric model shows the role of both preingestional and postingestional modulating factors for the best known examples, the usually nearly absolutely alcohol-avoiding DBA/2J and HAP-2 mice. Much subsequent data reinforce McClearn's earlier conclusion that C57BL/6J mice, at least, do not regulate their intake around a given self-administered dose of alcohol by adjusting their intake. This leaves us with the puzzle of why nearly all genotypes, even those directionally selectively bred for high voluntary intake for many generations, fail to self-administer intoxicating amounts of alcohol. Since McClearn's review, many ingenious assays to index alcohol's motivational effects have been used extensively, and new methods for inducing dependence have supplanted the older ones prevalent in

  18. 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

  19. Effects of early life stress on brain activity: implications from maternal separation model in rodents.

    PubMed

    Nishi, Mayumi; Horii-Hayashi, Noriko; Sasagawa, Takayo; Matsunaga, Wataru

    2013-01-15

    Adverse experiences in early life can affect the formation of neuronal circuits during postnatal development and exert long-lasting influences on neural function. Many studies have shown that daily repeated maternal separation (RMS), an animal model of early life stress, can modulate the hypothalamic-pituitary-adrenal axis (HPA-axis) and can affect subsequent brain function and emotional behavior during adulthood. However, the molecular basis of the long-lasting effects of early life stress on brain function has not been completely elucidated. In this mini-review, we introduce various cases of maternal separation in rodents and illustrate the alterations in HPA-axis activity by focusing on corticosterone (CORT), an end-product of the HPA-axis in rodents. We then present the characterization of the brain regions affected by various patterns of MS, including RMS and single time maternal separation (SMS) at various stages before weaning, by investigating c-Fos expression, a biological marker of neuronal activity. These CORT and c-Fos studies suggest that repeated early life stress may affect neuronal function in region- and temporal-specific manners, indicating a critical period for habituation to early life stress. Furthermore, we introduce changes in behavioral aspects and gene expression in adult mice exposed to RMS.

  20. OCT-aided anastomosis platform study in the rodent model

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

    Anastomosis is one of the most commonly performed procedure in the clinical environment that involves tubular structures, such as blood vessel, lymphatic vessel, seminal duct and ureter. Suture based anastomosis is still the foundation for most basic surgical training and clinical operation, although alternate techniques have been developed and under development. For those tubular-structure-anastomosis, immediate real-time post-operative evaluation of the surgical outcome is critical to the success of surgery. Previously evaluation is mostly based on surgeons' experience. Fourier-domain optical coherence tomography is high-speed, high-resolution noninvasive 3D imaging modality that has been widely used in the biomedical research and clinical study. In this study we used Fourier-domain optical coherence tomography as an evaluation tool for anastomosis of lymphatic vessels, ureter and seminal duct in rodent model. Immediate post-operative and long term surgical site data were collected and analyzed. Critical clinical parameters such as lumen patency, anastomosed site narrowing and suture error detection are provided to surgeons.

  1. Rehabilitation and plasticity following stroke: Insights from rodent models.

    PubMed

    Caleo, M

    2015-12-17

    Ischemic injuries within the motor cortex result in functional deficits that may profoundly impact activities of daily living in patients. Current rehabilitation protocols achieve only limited recovery of motor abilities. The brain reorganizes spontaneously after injury, and it is believed that appropriately boosting these neuroplastic processes may restore function via recruitment of spared areas and pathways. Here I review studies on circuit reorganization, neuronal and glial plasticity and axonal sprouting following ischemic damage to the forelimb motor cortex, with a particular focus on rodent models. I discuss evidence pointing to compensatory take-over of lost functions by adjacent peri-lesional areas and the role of the contralesional hemisphere in recovery. One key issue is the need to distinguish "true" recovery (i.e. re-establishment of original movement patterns) from compensation in the assessment of post-stroke functional gains. I also consider the effects of physical rehabilitation, including robot-assisted therapy, and the potential mechanisms by which motor training induces recovery. Finally, I describe experimental approaches in which training is coupled with delivery of plasticizing drugs that render the remaining, undamaged pathways more sensitive to experience-dependent modifications. These combinatorial strategies hold promise for the definition of more effective rehabilitation paradigms that can be translated into clinical practice.

  2. 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

  3. Detrimental psychophysiological effects of early maternal deprivation in adolescent and adult rodents: altered responses to cannabinoid exposure.

    PubMed

    Marco, Eva M; Adriani, Walter; Llorente, Ricardo; Laviola, Giovanni; Viveros, María-Paz

    2009-04-01

    Environmental rearing conditions during the neonatal period are critical for the establishment of neurobiological factors controlling behavior and stress responsiveness. Early maternal deprivation (MD), consisting of a single 24-h maternal deprivation episode during early neonatal life, has been proposed as an animal model for certain psychopathologies including anxiety, depression and schizophrenic-related disorders. Despite first onset of mental disorders usually occur during adolescence, characterization of MD has been mostly developed in adult animals. We review here a series of experiments that were conducted on rats and mice, in which we analyzed the psychoimmunoendocrine outcomes of MD at both adolescence and adulthood. As a whole our results indicate that MD might promote a depressive-like trait that may be present from adolescence to maturity. Maternally deprived adolescent animals also displayed altered locomotor responses, a reduced interest for social investigation and seemed prone for impulsive behavior. Therefore, MD in rodents is further confirmed as a suitable animal model for the study of neuropsychiatric disorders that might become evident during adolescence. Given the increasing consumption of cannabis derivatives among the juvenile population and the reported comorbidity of neuropsychiatric symptoms with cannabis abuse, we also discuss our results indicating altered responses of maternally deprived adolescent animals to cannabinoid compounds.

  4. Barnes maze testing strategies with small and large rodent models.

    PubMed

    Rosenfeld, Cheryl S; Ferguson, Sherry A

    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 drug

  5. Barnes maze testing strategies with small and large rodent models.

    PubMed

    Rosenfeld, Cheryl S; Ferguson, Sherry A

    2014-02-26

    Spatial learning and memory of laboratory rodents is often assessed via navigational ability in mazes, most popular of which are the water and dry-land (Barnes) mazes. Improved performance over sessions or trials is thought to reflect learning and memory of the escape cage/platform location. Considered less stressful than water mazes, the Barnes maze is a relatively simple design of a circular platform top with several holes equally spaced around the perimeter edge. All but one of the holes are false-bottomed or blind-ending, while one leads to an escape cage. Mildly aversive stimuli (e.g. bright overhead lights) provide motivation to locate the escape cage. Latency to locate the escape cage can be measured during the session; however, additional endpoints typically require video recording. From those video recordings, use of automated tracking software can generate a variety of endpoints that are similar to those produced in water mazes (e.g. distance traveled, velocity/speed, time spent in the correct quadrant, time spent moving/resting, and confirmation of latency). Type of search strategy (i.e. random, serial, or direct) can be categorized as well. Barnes maze construction and testing methodologies can differ for small rodents, such as mice, and large rodents, such as rats. For example, while extra-maze cues are effective for rats, smaller wild rodents may require intra-maze cues with a visual barrier around the maze. Appropriate stimuli must be identified which motivate the rodent to locate the escape cage. Both Barnes and water mazes can be time consuming as 4-7 test trials are typically required to detect improved learning and memory performance (e.g. shorter latencies or path lengths to locate the escape platform or cage) and/or differences between experimental groups. Even so, the Barnes maze is a widely employed behavioral assessment measuring spatial navigational abilities and their potential disruption by genetic, neurobehavioral manipulations, or drug

  6. 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

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

    PubMed Central

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

    2012-01-01

    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

  8. 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

  9. 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.

  10. Hypoxia-ischemia induces DNA synthesis without cell proliferation in dying neurons in adult rodent brain.

    PubMed

    Kuan, Chia-Yi; Schloemer, Aryn J; Lu, Aigang; Burns, Kevin A; Weng, Wei-Lan; Williams, Michael T; Strauss, Kenneth I; Vorhees, Charles V; Flavell, Richard A; Davis, Roger J; Sharp, Frank R; Rakic, Pasko

    2004-11-24

    Recent studies suggest that postmitotic neurons can reenter the cell cycle as a prelude to apoptosis after brain injury. However, most dying neurons do not pass the G1/S-phase checkpoint to resume DNA synthesis. The specific factors that trigger abortive DNA synthesis are not characterized. Here we show that the combination of hypoxia and ischemia induces adult rodent neurons to resume DNA synthesis as indicated by incorporation of bromodeoxyuridine (BrdU) and expression of G1/S-phase cell cycle transition markers. After hypoxia-ischemia, the majority of BrdU- and neuronal nuclei (NeuN)-immunoreactive cells are also terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-stained, suggesting that they undergo apoptosis. BrdU+ neurons, labeled shortly after hypoxia-ischemia, persist for >5 d but eventually disappear by 28 d. Before disappearing, these BrdU+/NeuN+/TUNEL+ neurons express the proliferating cell marker Ki67, lose the G1-phase cyclin-dependent kinase (CDK) inhibitors p16INK4 and p27Kip1 and show induction of the late G1/S-phase CDK2 activity and phosphorylation of the retinoblastoma protein. This contrasts to kainic acid excitotoxicity and traumatic brain injury, which produce TUNEL-positive neurons without evidence of DNA synthesis or G1/S-phase cell cycle transition. These findings suggest that hypoxia-ischemia triggers neurons to reenter the cell cycle and resume apoptosis-associated DNA synthesis in brain. Our data also suggest that the demonstration of neurogenesis after brain injury requires not only BrdU uptake and mature neuronal markers but also evidence showing absence of apoptotic markers. Manipulating the aberrant apoptosis-associated DNA synthesis that occurs with hypoxia-ischemia and perhaps neurodegenerative diseases could promote neuronal survival and neurogenesis.

  11. Models for an arenavirus infection in a rodent population: consequences of horizontal, vertical and sexual transmission.

    PubMed

    Banerjee, Chandrani; Allen, Linda J S; Salazar-Bravo, Jorge

    2008-10-01

    Arenaviruses are associated with rodent-transmitted diseases in humans. Five arenaviruses are known to cause human illness: Lassa virus, Junin virus, Machupo virus, Guanarito virus and Sabia virus. In this investigation, we model the spread of Machupo virus in its rodent host Calomys callosus. Machupo virus infection in humans is known as Bolivian hemorrhagic fever (BHF) which has a mortality rate of approximately 5-30% [31]. Machupo virus is transmitted among rodents through horizontal (direct contact), vertical (infected mother to offspring) and sexual transmission. The immune response differs among rodents infected with Machupo virus. Either rodents develop immunity and recover (immunocompetent) or they do not develop immunity and remain infected (immunotolerant). We formulate a general deterministic model for male and female rodents consisting of eight differential equations, four for females and four for males. The four states represent susceptible, immunocompetent, immunotolerant and recovered rodents, denoted as S, I( t), I( c)and R, respectively. A unique disease-free equilibrium (DFE) is shown to exist and a basic reproduction number R( 0)is computed using the next generation matrix approach. The DFE is shown to be locally asymptotically stable if R(0) < 1and unstable if R( 0) > 1. Special cases of the general model are studied, where there is only one immune stage, either I(t) or I(c). In the first model, SI(c)R( c), it is assumed that all infected rodents are immunocompetent and recover. In the second model, SI(t), it is assumed that all infected rodents are immunotolerant. For each of these models, the basic reproduction numbers are computed and their relationship to the basic reproduction number of the general model determined. For the SI( t)model, it is shown that bistability may occur, the DFE and an enzootic equilibrium, with all rodents infectious, are locally asymptotically stable for the same set of parameter values. A simplification of the SI( t)model

  12. 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

  13. 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

  14. 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

  15. 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

  16. A novel preclinical rodent model of collagenase-induced germinal matrix/intraventricular hemorrhage.

    PubMed

    Alles, Yanet Chong Juarez; Greggio, Samuel; Alles, Raul Miguel; Azevedo, Pâmella Nunes; Xavier, Léder Leal; DaCosta, Jaderson Costa

    2010-10-14

    Germinal matrix/intraventricular hemorrhage (GMH/IVH) is a complication that arises in premature infants associated with neurological sequelae. Greater understanding of GMH/IVH is needed to develop therapies, a goal that depends on the existence of appropriate animal models. Towards this goal, we aimed to develop a rodent model of GMH/IVH based on collagenase-induced hemorrhage that exhibits histological and neurological consequences similar to that seen in patients. Male 6-day-old rats were placed on a warming pad and anesthetized with halothane/nitrous oxide delivered by face mask. Uni- or bilateral periventricular injections of 2-μl collagenase (2.0 U) were performed freehand with a needle inserted percutaneously. Sham rats were infused with saline. Early neonatal development, long-term motor and cognitive performances and alterations in brain volume were assessed. Collagenase-based GMH/IVH negatively affected ambulation, surface righting and negative geotaxis outcomes more evidently in bilaterally infused rats, which also presented an early decrease in brain volume, as assessed by the Cavalieri method. In adult animals, a unilateral collagenase infusion produced no significant alteration on forepaw preference. Only bilaterally infused rats presented an impairment of object recognition memory and locomotor deficit. Nevertheless, histological evaluation also demonstrated a persistent brain volume reduction in bilaterally infused rats. Our study provides a pioneering animal model of collagenase-based GMH/IVH, which can be used to evaluate preventive strategies and potential therapeutic interventions for this disorder. PMID:20692236

  17. 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

  18. 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

  19. 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

  20. Effects of Hypericum Perforatum, in a rodent model of periodontitis

    PubMed Central

    2010-01-01

    Background Hypericum perforatum is a medicinal plant species containing many polyphenolic compounds, namely flavonoids and phenolic acids. In this study we evaluate the effect of Hypericum perforatum in animal model of periodontitis. Methods Periodontitis was induced in adult male Sprague-Dawley rats by placing a nylon thread ligature around the lower 1st molars. Hypericum perforatum was administered at the dose of 2 mg/kg os, daily for eight days. At day 8, the gingivomucosal tissue encircling the mandibular first molar was removed. Results Periodontitis in rats resulted in an inflammatory process characterized by edema, neutrophil infiltration and cytokine production that was followed by the recruitment of other inflammatory cells, production of a range of inflammatory mediators such as NF-κB and iNOS expression, the nitration of tyrosine residues and activation of the nuclear enzyme poly (ADP-ribose) polymerase; apoptosis and the degree of gingivomucosal tissues injury. We report here that Hypericum perforatum exerts potent anti-inflammatory effects significantly reducing all of the parameters of inflammation as described above. Conclusions Taken together, our results clearly demonstrate that treatment with Hypericum reduces the development of inflammation and tissue injury, events associated with periodontitis. PMID:21092263

  1. Dietary Factors Modulate Helicobacter-Associated Gastric Cancer in Rodent Models

    PubMed Central

    Fox, James G.; Wang, Timothy C.

    2014-01-01

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

  2. 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

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

    PubMed

    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

  4. 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

  5. Modeling human nonalcoholic steatohepatitis-associated changes in drug transporter expression using experimental rodent models.

    PubMed

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

    2014-04-01

    Nonalcoholic fatty liver disease is a prevalent form of chronic liver disease that can progress to the more advanced stage of nonalcoholic steatohepatitis (NASH). NASH has been shown to alter drug transporter regulation and may have implications in the development of adverse drug reactions. Several experimental rodent models have been proposed for the study of NASH, but no single model fully recapitulates all aspects of the human disease. The purpose of the current study was to determine which experimental NASH model best reflects the known alterations in human drug transporter expression to enable more accurate drug disposition predictions in NASH. Both rat and mouse NASH models were used in this investigation and include the methionine and choline deficient (MCD) diet model, atherogenic diet model, ob/ob and db/db mice, and fa/fa rats. Pathologic scoring evaluations demonstrated that MCD and atherogenic rats, as well as ob/ob and db/db mice, developed NASH. Liver mRNA and protein expression analyses of drug transporters showed that in general, efflux transporters were induced and uptake transporters were repressed in the rat MCD and the mouse ob/ob and db/db models. Lastly, concordance analyses suggest that both the mouse and rat MCD models as well as mouse ob/ob and db/db NASH models show the most similarity to human transporter mRNA and protein expression. These results suggest that the MCD rat and mouse model, as well as the ob/ob and db/db mouse models, may be useful for predicting altered disposition of drugs with similar kinetics across humans and rodents.

  6. 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.

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

    PubMed

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

    2015-01-01

    The gut microbiota (GM) affects numerous human diseases, as well as rodent models for these. We will review this impact and summarize ways to handle this challenge in animal research. The GM is complex, with the largest fractions being the gram-positive phylum Firmicutes and the gram-negative phylum Bacteroidetes. Other important phyla are the gram-negative phyla Proteobacteria and Verrucomicrobia, and the gram-positive phylum Actinobacteria. GM members influence models for diseases, such as inflammatory bowel diseases, allergies, autoimmunity, cancer, and neuropsychiatric diseases. GM characterization of all individual animals and incorporation of their GM composition in data evaluation may therefore be considered in future protocols. Germfree isolator-housed rodents or rodents made virtually germ free by antibiotic cocktails can be used to study diverse microbial influences on disease expression. Through subsequent inoculation with selected strains or cocktails of microbes, new "defined flora" models can yield valuable knowledge on the impact of the GM, and of specific GM members and their interactions, on important disease phenotypes and mechanisms. Rodent husbandry and microbial quality assurance practices will be important to ensure and confirm appropriate and research relevant GM. PMID:26323634

  8. Three Models of Adult Development.

    ERIC Educational Resources Information Center

    Levenson, Michael R.; Crumpler, Cheryl A.

    1996-01-01

    Compares ontogenetic models, which stress development through a series of stages; sociogenic models, which stress the influence of social context on adult behavior; and liberative models. Liberative models do not treat adult development as entirely dependent on biological or social determinism, and do stress individuals' conscious efforts at…

  9. 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

  10. High throughput analysis of neural progenitor cell proliferation in adult rodent hippocampus.

    PubMed

    Henry, Sherry; Bigler, Steven; Wang, Junming

    2009-12-01

    Extensive efforts have been made to determine the status on neural progenitor cell proliferation in specific pathological conditions and to evaluate the therapeutic efficacy of drugs for preventing neurogenic deficits in neurodegenerative diseases. However, the most commonly used stereological analysis using 5-bromo-2'-deoxyuridine (BrdU) immuno-positive sections is a time consuming and labor intensive process and is often a bottle neck in neurogenic drug development, particularly when large sample sizes are needed. In addition, BrdU is toxic to new born neurons and also labels DNA damage in old cells. In this study, we established a method that quantitatively measures the number of Ki-67, an endogenous cell proliferation marker, positive cells by flow cytometry which analyzes extracted cell nuclei from rodent hippocampi in suspension. Our results demonstrate that this approach can be applied to a large number of rodent samples, can be accomplished in a short period of time (1-3 days), and can be completed in a more accurately objective manner than by using 3-D cell counting with immunohistochemically processed sections. PMID:20103852

  11. High throughput analysis of neural progenitor cell proliferation in adult rodent hippocampus

    PubMed Central

    Henry, Sherry; Bigler, Steven; Wang, Junming

    2010-01-01

    Summary Extensive efforts have been made to determine the status on neural progenitor cell proliferation in specific pathological conditions and to evaluate the therapeutic efficacy of drugs for preventing neurogenic deficits in neurodegenerative diseases. However, the most commonly used stereological analysis using 5-bromo-2′-deoxyuridine (BrdU) immuno-positive sections is a time consuming and labor intensive process and is often a bottle neck in neurogenic drug development, particularly when large sample sizes are needed. In addition, BrdU is toxic to new born neurons and also labels DNA damage in old cells. In this study, we established a method that quantitatively measures the number of Ki-67, an endogenous cell proliferation marker, positive cells by flow cytometry which analyzes extracted cell nuclei from rodent hippocampi in suspension. Our results demonstrate that this approach can be applied to a large number of rodent samples, can be accomplished in a short period of time (1-3 days), and can be completed in a more accurately objective manner than by using 3-D cell counting with immunohistochemically processed sections. PMID:20103852

  12. 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

  13. 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

  14. 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

  15. Small intestinal submucosa seeded with intestinal smooth muscle cells in a rodent jejunal interposition model

    PubMed Central

    Qin, Harry H.; Dunn, James C.Y.

    2011-01-01

    Background Small intestinal submucosa (SIS) is a porcine-derived, acellular, collagen-based matrix that has been tested without seeded smooth muscle cells (SMCs) for intestinal tissue engineering. We examined the expression patterns of contractile proteins of SIS with SMCs implanted in an in vivo rodent model. Materials and methods Intestinal SMCs were isolated from Lewis rat pups. Four-ply tubular SMCs-seeded SIS or blank SIS scaffolds were implanted in an adult rat jejunal interposition model. Recipients were sacrificed at 2, 4, and 8 weeks following the implantation. The retrieved specimens were examined using antibodies against contractile proteins of SMCs. Results Cultured intestinal SMCs expressed α-smooth muscle actin (α-SMA), calponin, and less smooth muscle myosin heavy chain (SM-MHC) in vitro. Cell-seeded SIS scaffolds contracted significantly over 8 weeks of implantation but were comparable to SIS scaffolds without cell seeding. Implanted cell-seeded SIS scaffolds at 2 weeks expressed extensive α-SMA, some calponin, and minimal SM-MHC. At 4 weeks, α-SMA-expressing cells decreased significantly, whereas calponin or SM-MHC expressing cells were rarely detected. A small number of α-SMA-expressing cells were present at 8 weeks, whereas more calponin or SM-MHC expressing cells emerged in proximity with the anastomotic interface. Conclusions Cell-seeded SIS contracted significantly after implantation, but the expressions of contractile proteins were present at the site of SIS interposition. No organized smooth muscle was formed at the site of implantation. A better scaffold design is needed to produce structured smooth muscle. PMID:21937060

  16. 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.

  17. Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors.

    PubMed

    Seaberg, Raewyn M; van der Kooy, Derek

    2002-03-01

    Neurogenesis persists in two adult brain regions: the ventricular subependyma and the subgranular cell layer in the hippocampal dentate gyrus (DG). Previous work in many laboratories has shown explicitly that multipotential, self-renewing stem cells in the subependyma are the source of newly generated migrating neurons that traverse the rostral migratory stream and incorporate into the olfactory bulb as interneurons. These stem cells have been specifically isolated from the subependyma, and their properties of self-renewal and multipotentiality have been demonstrated in vitro. In contrast, it is a widely held assumption that the "hippocampal" stem cells that can be isolated in vitro from adult hippocampus reside in the neurogenic subgranular layer and represent the source of new granule cell neurons, but this has never been tested directly. Primary cell isolates derived from the precise microdissection of adult rodent neurogenic regions were compared using two very different commonly used culture methods: a clonal colony-forming (neurosphere) assay and a monolayer culture system. Importantly, both of these culture methods generated the same conclusion: stem cells can be isolated from hippocampus-adjacent regions of subependyma, but the adult DG proper does not contain a population of resident neural stem cells. Indeed, although the lateral ventricle and other ventricular subependymal regions directly adjacent to the hippocampus contain neural stem cells that exhibit long-term self-renewal and multipotentiality, separate neuronal and glial progenitors with limited self-renewal capacity are present in the adult DG, suggesting that neuron-specific progenitors and not multipotential stem cells are the source of newly generated DG neurons throughout adulthood.

  18. 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

  19. Risk, Reward, and Decision-Making in a Rodent Model of Cognitive Aging

    PubMed Central

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

    2011-01-01

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

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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

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

    PubMed

    Durst, Paul A P; Roth, V Louise

    2015-07-01

    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

  7. Hippocampal deep brain stimulation reverses physiological and behavioural deficits in a rodent model of schizophrenia.

    PubMed

    Perez, Stephanie M; Shah, Amiksha; Asher, Amber; Lodge, Daniel J

    2013-07-01

    Subcortical dopamine system dysregulation has been suggested to underlie the positive symptoms of schizophrenia. Recent preclinical investigations and human imaging studies have proposed that the augmented dopamine system function observed in schizophrenia patients may be secondary to aberrant hippocampal activity. Thus, we posit that the hippocampus represents a novel therapeutic target for the treatment of schizophrenia. Here we provide evidence of the effectiveness of a unique approach aimed at decreasing hippocampal function in a rodent model of schizophrenia. Specifically, in a rodent model of schizophrenia, we demonstrate that ventral hippocampal (vHipp) deep brain stimulation (DBS) can normalize aberrant dopamine neuron activity and behaviours associated with positive symptoms. In addition, we provide evidence that this approach may also be effective in restoring deficits in cognitive function, often left unaltered by conventional antipsychotic medications. Therefore, we have provided initial preclinical evidence demonstrating the feasibility of hippocampal DBS as a potential novel approach for the treatment of schizophrenia.

  8. Validation of a rodent model of source memory.

    PubMed

    Crystal, Jonathon D; Alford, Wesley T

    2014-03-01

    Source memory represents the origin (source) of information. Recently, we proposed that rats (Rattus norvegicus) remember the source of information. However, an alternative to source memory is the possibility that rats selectively encoded some, but not all, information rather than retrieving an episodic memory. We directly tested this 'encoding failure' hypothesis. Here, we show that rats remember the source of information, under conditions that cannot be attributed to encoding failure. Moreover, source memory lasted at least seven days but was no longer present 14 days after studying. Our findings suggest that long-lasting source memory may be modelled in non-humans. Our model should facilitate attempts to elucidate the biological underpinnings of source memory impairments in human memory disorders such as Alzheimer's disease.

  9. AADC deficiency: occurring in humans, modeled in rodents.

    PubMed

    Hwu, Wuh-Liang; Lee, Ni-Chung; Chien, Yin-Hsiu; Muramatsu, Shin-ichi; Ichinose, Hiroshi

    2013-01-01

    Aromatic l-amino acid decarboxylase (AADC) is a homodimeric pyridoxal phosphate-dependent enzyme responsible for the syntheses of dopamine and serotonin. Defects in the AADC gene result in neurotransmitter deficiencies. Patients with AADC deficiency have severe motor and autonomic dysfunctions. A mouse model of AADC deficiency was recently established. These mice grow poorly and move awkwardly during infancy. They also show high anxiety when they grow up. Because drug therapy provides little or no benefit for many patients with AADC deficiency, a gene therapy has been attempted. The gene therapy employed an adeno-associated virus viral vector that can express the human AADC protein. The vector was injected to the brain of several children with AADC deficiency. The therapy was well tolerated, and all treated patients showed improvement. In the future, the mouse model will also help the development of treatments for AADC deficiency.

  10. 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.

  11. Circadian dysfunction in a rotenone-induced parkinsonian rodent model.

    PubMed

    Lax, Pedro; Esquiva, Gema; Esteve-Rudd, Julian; Otalora, Beatriz Baño; Madrid, Juan Antonio; Cuenca, Nicolás

    2012-03-01

    Parkinson's disease (PD) is a neurodegenerative disorder that also involves circadian rhythm alterations. Modifications of circadian rhythm parameters have been shown to occur in both PD patients and toxin-induced PD animal models. In the latter case, rotenone, a potent inhibitor of mitochondrial complex I (nicotinamide adenine dinucleotide [NADH]-quinone reductase), has been used to elicit degeneration of dopaminergic neurons and development of parkinsonian syndrome. The present work addresses alterations induced by rotenone on both locomotor and body temperature circadian rhythms in rats. Rotenone-treated rats exhibited abnormalities in equilibrium, postural instability, and involuntary movements. Long-term subcutaneous administration of rotenone significantly reduced mean daily locomotor activity in most animals. During rotenone administration, mean body temperatures (BTs) and BT rhythm amplitudes were significantly lower than those observed in the control group. After long-term rotenone administration, the circadian rhythms of both locomotor activity (LA) and BT displayed decreased amplitudes, lower interdaily phase stability, and higher rhythm fragmentation, as compared to the control rats. The magnitude of the LA and BT circadian rhythm alterations induced by rotenone positively correlated with degree of motor impairment. These results indicate that rotenone induces circadian dysfunction in rats through some of the same mechanisms as those responsible for the development of motor disturbances.

  12. 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.

  13. 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…

  14. Antinociception induced by acute oral administration of sweet substance in young and adult rodents: the role of endogenous opioid peptides chemical mediators and μ(1)-opioid receptors.

    PubMed

    de Freitas, Renato Leonardo; Kübler, João Marcus Lopes; Elias-Filho, Daoud Hibraim; Coimbra, Norberto Cysne

    2012-04-01

    The present work aimed to investigate the effects of acute sucrose treatment on the perception of painful stimuli. Specifically, we sought to determine the involvement of the endogenous opioid peptide-mediated system as well as the role of the μ(1)-opioid receptor in antinociception organisation induced by acute sucrose intake. Nociception was assessed with the tail-flick test in rats (75, 150 and 250 g) of different ages acutely pre-treated with 500 μL of a sucrose solution (25, 50, 150 and 250 g/L) or tap water. Young and Adult rats (250 g) showed antinociception after treatment with 50 g/L (during 5 min) and 150 g/L and 250 g/L (during 20 min) sucrose solutions. Surprisingly, this antinociception was more consistent in mature adult rodents than in pups. To evaluate the role of opioid systems, mature adult rodents were pre-treated with different doses (0.25, 1 or 4 mg/kg) of the non-selective opioid receptor antagonist naloxone, the selective μ(1)-opioid receptor antagonist naloxonazine or vehicle followed by 250 g/L sucrose solution treatment. Sucrose-induced antinociception was reduced by pre-treatment with both naloxone and naloxonazine. The present findings suggest that sweet substance-induced hypo-analgesia is augmented by increasing sucrose concentrations in young and adult rodents. Acute oral sucrose treatment inhibits pain in laboratory animal by mediating endogenous opioid peptide and μ(1)-opioid receptor actions.

  15. 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.

  16. Juvenile antioxidant treatment prevents adult deficits in a developmental model of schizophrenia

    PubMed Central

    Tejeda, Hugo A.; Piantadosi, Patrick; Pollock, Cameron; Calhoon, Gwendolyn G.; Sullivan, Elyse; Presgraves, Echo; Kil, Jonathan; Hong, L. Elliot; Cuenod, Michel; Do, Kim Q; O'Donnell, Patricio

    2014-01-01

    SUMMARY Abnormal development can lead to deficits in adult brain function, a trajectory likely underlying adolescent-onset psychiatric conditions such as schizophrenia. Developmental manipulations yielding adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations. Here we assessed whether oxidative stress during presymptomatic stages causes adult anomalies in rats with a neonatal ventral hippocampal lesion, a developmental rodent model useful for schizophrenia research. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal parvalbumin interneuron activity observed in this model, as well as electrophysiological and behavioral deficits relevant to schizophrenia. Adolescent treatment with the glutathione peroxidase mimic ebselen also reversed behavioral deficits in this animal model. These findings suggest that presymptomatic oxidative stress yields abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention. PMID:25132466

  17. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in Parkinsonian rats.

    PubMed

    Hargus, Gunnar; Cooper, Oliver; Deleidi, Michela; Levy, Adam; Lee, Kristen; Marlow, Elizabeth; Yow, Alyssa; Soldner, Frank; Hockemeyer, Dirk; Hallett, Penelope J; Osborn, Teresia; Jaenisch, Rudolf; Isacson, Ole

    2010-09-01

    Recent advances in deriving induced pluripotent stem (iPS) cells from patients offer new possibilities for biomedical research and clinical applications, as these cells could be used for autologous transplantation. We differentiated iPS cells from patients with Parkinson's disease (PD) into dopaminergic (DA) neurons and show that these DA neurons can be transplanted without signs of neurodegeneration into the adult rodent striatum. The PD patient iPS (PDiPS) cell-derived DA neurons survived at high numbers, showed arborization, and mediated functional effects in an animal model of PD as determined by reduction of amphetamine- and apomorphine-induced rotational asymmetry, but only a few DA neurons projected into the host striatum at 16 wk after transplantation. We next applied FACS for the neural cell adhesion molecule NCAM on differentiated PDiPS cells before transplantation, which resulted in surviving DA neurons with functional effects on amphetamine-induced rotational asymmetry in a 6-OHDA animal model of PD. Morphologically, we found that PDiPS cell-derived non-DA neurons send axons along white matter tracts into specific close and remote gray matter target areas in the adult brain. Such findings establish the transplantation of human PDiPS cell-derived neurons as a long-term in vivo method to analyze potential disease-related changes in a physiological context. Our data also demonstrate proof of principle of survival and functional effects of PDiPS cell-derived DA neurons in an animal model of PD and encourage further development of differentiation protocols to enhance growth and function of implanted PDiPS cell-derived DA neurons in regard to potential therapeutic applications.

  18. 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

  19. 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

  20. 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)

  1. 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.

  2. 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.

  3. A simple method to obtain pure cultures of multiciliated ependymal cells from adult rodents.

    PubMed

    Grondona, J M; Granados-Durán, P; Fernández-Llebrez, P; López-Ávalos, M D

    2013-01-01

    Ependymal cells form an epithelium lining the ventricular cavities of the vertebrate brain. Numerous methods to obtain primary culture ependymal cells have been developed. Most of them use foetal or neonatal rat brain and the few that utilize adult brain hardly achieve purity. Here, we describe a simple and novel method to obtain a pure non-adherent ependymal cell culture from explants of the striatal and septal walls of the lateral ventricles. The combination of a low incubation temperature followed by a gentle enzymatic digestion allows the detachment of most of the ependymal cells from the ventricular wall in a period of 6 h. Along with ependymal cells, a low percentage (less than 6 %) of non-ependymal cells also detaches. However, they do not survive under two restrictive culture conditions: (1) a simple medium (alpha-MEM with glucose) without any supplement; and (2) a low density of 1 cell/µl. This purification method strategy does not require cell labelling with antibodies and cell sorting, which makes it a simpler and cheaper procedure than other methods previously described. After a period of 48 h, only ependymal cells survive such conditions, revealing the remarkable survival capacity of ependymal cells. Ependymal cells can be maintained in culture for up to 7-10 days, with the best survival rates obtained in Neurobasal supplemented with B27 among the tested media. After 7 days in culture, ependymal cells lose most of the cilia and therefore the mobility, while acquiring radial glial cell markers (GFAP, BLBP, GLAST). This interesting fact might indicate a reprogramming of the cell identity.

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

    The elevated plus maze (EPM) is used to assess anxiety in rodents. Beam-walking tasks are used to assess vestibulomotor function. Brain injury in rodents can disrupt performance on both of these tasks. Developing novel paradigms that integrate tasks like these can reduce the need for multiple tests when attempting to assess multiple behaviors in the same animal. Using adult male rats, we evaluated the use of a modified beam-walking (MBW) apparatus as a surrogate indicator for anxiety. We used a model of blast-induced traumatic brain injury (bTBI). A total of 39 rats were assessed before and at 3, 6, 24, 72, and 168h either post- bTBI (n=33) or no-injury (n=6) using both EPM and MBW. A novel anxiety index was calculated that encompassed peeks and re-emergences on MBW. The proposed MBW anxiety index was compared with the standard anxiety index calculated from exploration into different sections of EPM. Post- bTBI, rats had an increased anxiety index when measured using EPM. Similarly, they peeked or fully emerged less out of the safe box on MBW. It was found that this novel MBW anxiety index captured similar aspects of behavior when compared to the standard anxiety index obtained from EPM. Further, these effects were dissociated from the effects of bTBI on motor function simultaneously measured on MBW. Over the course of 168h post-bTBI, rats gradually recovered on both EPM and MBW. The MBW apparatus succeeded at capturing and dissociating two separate facets of rat behavior, motor function and anxiety, simultaneously. PMID:26367471

  6. 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

  7. 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

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

    PubMed

    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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. Intramembranous bone regeneration and implant placement using mechanical femoral marrow ablation: rodent models.

    PubMed

    Moran, Meghan M; Sena, Kotaro; McNulty, Margaret A; Sumner, D R; Virdi, Amarjit S

    2016-01-01

    In this paper, we provide a detailed protocol for a model of long bone mechanical marrow ablation in the rodent, including surgical procedure, anesthesia, and pre- and post-operative care. In addition, frequently used experimental end points are briefly discussed. This model was developed to study intramembranous bone regeneration following surgical disruption of the marrow contents of long bones. In this model, the timing of the appearance of bone formation and remodeling is well-characterized and therefore the model is well-suited to evaluate the in vivo effects of various agents which influence these processes. When biomaterials such as tissue engineering scaffolds or metal implants are placed in the medullary cavity after marrow ablation, end points relevant to tissue engineering and implant fixation can also be analyzed. By sharing a detailed protocol, we hope to improve inter-laboratory reproducibility. PMID:27648259

  14. 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.

  15. A review of bioeffects of static magnetic field on rodent models.

    PubMed

    Yu, Shuguang; Shang, Peng

    2014-01-01

    This review is aimed to summarize the experimental researches in the influences of static magnetic field on laboratory rodent models, reported by laboratory scientists, experimental technicians, clinical surgeons, animal veterinarians, and other researchers. Past studies suggested that static magnetic field-singly applied or used combined with other physical or chemical substances-significantly relieved some pains and ameliorated certain diseases in different organ systems, e.g. hypertension, osteoporosis, neuralgia, diabetes and leukemia etc. But on the other hand, some harmful events have also been observed in a number of investigations, from cellular level to fetal development. So exposure to static magnetic field might have dual effects on experimental rodent in various environments, viz. there are potentially therapeutic benefits, as well as adverse effects from it. The positive effect may relate to moderate intensities, while negative influence seems to be in connection with acute strong static magnetic fields. In addition, different orientations of static magnetic field exert different degrees of impact. Thus, the bioeffects of static magnetic field exposure on mice/rats depend on magnetic field intensities, durations and directions, though the exactly relationship between them is still vague. Further researches need to perform with appropriate methodologies, ingenious designs repeatedly and systemically, not only in animal models, but also in human volunteers and patients.

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. N-acetylcysteine (NAC) decreases binge eating in a rodent model

    PubMed Central

    Hurley, Matthew M.; Resch, Jon M.; Maunze, Brian; Frenkel, Mogen M.; Baker, David A.; Choi, SuJean

    2016-01-01

    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-acetyl cysteine (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. Prior to 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 since 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

  2. 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

  3. Gnotobiotic Rodents: An In Vivo Model for the Study of Microbe-Microbe Interactions.

    PubMed

    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.

  4. 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

  5. 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.

  6. 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.

  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. 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

  9. 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

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

    PubMed

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

    2015-10-22

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

  11. The role of rodent models in the discovery of new treatments for schizophrenia: updating our strategy.

    PubMed

    Moore, Holly

    2010-11-01

    The strategies used in preclinical research in schizophrenia have evolved from experiments focused on the pharmacology of existing antipsychotic or psychotomimetic drugs to the broader study of pharmacological modulation of the neurobehavioral systems affected in schizophrenia. As an additional approach, neurodevelopmental, including genetic, manipulations have become increasingly used to model disease risk factors or to induce schizophrenia-relevant neuropathology. In the vast majority of these models, behavioral testing paradigms are used to test the effects of the drugs or developmental manipulations on psychomotor, cognitive and affective processes hypothesized to be affected in schizophrenia. The term "animal model of schizophrenia" is now applied to any combination of these strategies. The expansion in animal modeling strategies has led to significant innovation in identifying novel neural mechanisms that may contribute not only to psychosis but also to the cognitive and negative symptoms of schizophrenia. Yet one cost of innovation in the discovery of truly novel treatment targets is a higher risk for false positives--drugs that have shown promise in animal models but not in clinical trials. The goals of this commentary are to first provide a brief history and conceptualization of rodent models in preclinical research and then examine the issues to be addressed in order to increase the predictive power of animal models in the identification of new treatment targets and, ultimately, new effective treatments for schizophrenia.

  12. 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

  13. 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).

  14. 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

  15. 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.

  16. Dynamic Causal Models and Physiological Inference: A Validation Study Using Isoflurane Anaesthesia in Rodents

    PubMed Central

    Moran, Rosalyn J.; Jung, Fabienne; Kumagai, Tetsuya; Endepols, Heike; Graf, Rudolf; Dolan, Raymond J.; Friston, Karl J.; Stephan, Klaas E.; Tittgemeyer, Marc

    2011-01-01

    Generative models of neuroimaging and electrophysiological data present new opportunities for accessing hidden or latent brain states. Dynamic causal modeling (DCM) uses Bayesian model inversion and selection to infer the synaptic mechanisms underlying empirically observed brain responses. DCM for electrophysiological data, in particular, aims to estimate the relative strength of synaptic transmission at different cell types and via specific neurotransmitters. Here, we report a DCM validation study concerning inference on excitatory and inhibitory synaptic transmission, using different doses of a volatile anaesthetic agent (isoflurane) to parametrically modify excitatory and inhibitory synaptic processing while recording local field potentials (LFPs) from primary auditory cortex (A1) and the posterior auditory field (PAF) in the auditory belt region in rodents. We test whether DCM can infer, from the LFP measurements, the expected drug-induced changes in synaptic transmission mediated via fast ionotropic receptors; i.e., excitatory (glutamatergic) AMPA and inhibitory GABAA receptors. Cross- and auto-spectra from the two regions were used to optimise three DCMs based on biologically plausible neural mass models and specific network architectures. Consistent with known extrinsic connectivity patterns in sensory hierarchies, we found that a model comprising forward connections from A1 to PAF and backward connections from PAF to A1 outperformed a model with forward connections from PAF to A1 and backward connections from A1 to PAF and a model with reciprocal lateral connections. The parameter estimates from the most plausible model indicated that the amplitude of fast glutamatergic excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) behaved as predicted by previous neurophysiological studies. Specifically, with increasing levels of anaesthesia, glutamatergic EPSPs decreased linearly, whereas fast GABAergic IPSPs displayed a

  17. 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

  18. 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

  19. 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

  20. Stress-Induced Changes in Sleep in Rodents: Models and Mechanisms

    PubMed Central

    Pawlyk, Aaron C.; Morrison, Adrian R.; Ross, Richard J.; Brennan, Francis X.

    2008-01-01

    Psychological stressors have a prominent effect on sleep in general, and rapid eye movement (REM) sleep in particular. Disruptions in sleep are a prominent feature, and potentially even the hallmark, of posttraumatic stress disorder (PTSD) (Ross et al., 1989). Animal models are critical in understanding both the causes and potential treatments of psychiatric disorders. The current review describes a number of studies that have focused on the impact of stress on sleep in rodent models. The studies are also summarized in Table 1, summarizing the effects of stress in 4-hr blocks in both the light and dark phases. Although mild stress procedures have sometimes produced increases in REM sleep, more intense stressors appear to model the human condition by leading to disruptions in sleep, particularly REM sleep. We also discuss work conducted by our group and others looking at conditioning as a factor in the temporal extension of stress-related sleep disruptions. Finally, we attempt to describe the probable neural mechanisms of the sleep disruptions. A complete understanding of the neural correlates of stress-induced sleep alterations may lead to novel treatments for a variety of debilitating sleep disorders. PMID:17764741

  1. 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.

  2. 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

  3. 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

  4. Antidepressant Drugs Transactivate TrkB Neurotrophin Receptors in the Adult Rodent Brain Independently of BDNF and Monoamine Transporter Blockade

    PubMed Central

    Rantamäki, Tomi; Di Lieto, Antonio; Tammela, Päivi; Schmitt, Angelika; Lesch, Klaus-Peter; Rios, Maribel; Castrén, Eero

    2011-01-01

    Background Antidepressant drugs (ADs) have been shown to activate BDNF (brain-derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands. Methodology In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines. Principal Findings Using a chemical-genetic TrkBF616A mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf−/− knock-out mice (132.4±8.5% of control; P = 0.01), indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT) deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB. Conclusions The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the ability of ADs to

  5. Carbamazepine Potentiates the Effectiveness of Morphine in a Rodent Model of Neuropathic Pain

    PubMed Central

    Due, Michael R.; Yang, Xiao-Fang; Allette, Yohance M.; Randolph, Aaron L.; Ripsch, Matthew S.; Wilson, Sarah M.; Dustrude, Erik T.; Khanna, Rajesh; White, Fletcher A.

    2014-01-01

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

  6. Sweetness and light: perspectives for rodent models of type 1 diabetes.

    PubMed

    Avner, Philip R

    2010-01-01

    Type 1 diabetes (T1D) is a major disease affecting primarily young children with an incidence in Western societies of around 0.3% by 20 years of age. Although both genetic and environmental factors contribute to the disease aetiology, the precise nature of both the genetic and environmental contribution to human disease onset and progression remains poorly defined. Despite showing some differences from human T1D, rodent models for T1D (Leiter and von Herrath, 2004; von Herrath and Nepom, 2009) and, in particular the nonobese diabetic (NOD) mouse (Atkinson and Leiter, 1999; Kikutani and Makino, 1992), have provided important insights into the disease process, even if they have not yet allowed definitive identification of many of the genetic factors involved in the process. The recent isolation of germline-competent embryonic stem (ES) cells from the NOD mouse strain, and from the rat, will greatly facilitate the functional analysis of T1D in the mouse, and open up the possibility of improved exploitation of rat T1D models. This important technological breakthrough has the potential to remove bottlenecks from the identification of T1D genes, allowing the underlying metabolic pathways to be established and facilitating evaluation of the eventual role of the human homologues in the disease process. The current status and perspectives for an improved mechanistic understanding of the disease process will be addressed.

  7. 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

  8. Mechanisms of insulin secretion in malnutrition: modulation by amino acids in rodent models.

    PubMed

    de Oliveira, Camila Aparecida Machado; Latorraca, Márcia Queiroz; de Mello, Maria Alice Rostom; Carneiro, Everardo Magalhães

    2011-04-01

    Protein restriction at early stages of life reduces β-cell volume, number of insulin-containing granules, insulin content and release by pancreatic islets in response to glucose and other secretagogues, abnormalities similar to those seen in type 2 diabetes. Amino acids are capable to directly modulate insulin secretion and/or contribute to the maintenance of β-cell function, resulting in an improvement of insulin release. Animal models of protein malnutrition have provided important insights into the adaptive mechanisms involved in insulin secretion in malnutrition. In this review, we discuss studies focusing on the modulation of insulin secretion by amino acids, specially leucine and taurine, in rodent models of protein malnutrition. Leucine supplementation increases insulin secretion by pancreatic islets in malnourished mice. This effect is at least in part due to increase in the expression of proteins involved in the secretion process, and the activation of the PI3K/PKB/mTOR pathway seems also to contribute. Mice supplemented with taurine have increased insulin content and secretion as well as increased expression of genes essential for β-cell functionality. The knowledge of the mechanisms through which amino acids act on pancreatic β-cells to stimulate insulin secretion is of interest for clinical medicine. It can reveal new targets for the development of drugs toward the treatment of endocrine diseases, in special type 2 diabetes. PMID:20711845

  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. Effects of folic acid and lamotrigine therapy in some rodent models of epilepsy and behaviour.

    PubMed

    Ali, Atif; Pillai, K K; Pal, Shanthi N

    2003-03-01

    It has been suggested that a folic acid (FA) deficiency induced by antiepileptic drugs might be the basis for the neuropsychiatric toxicity associated with these drugs. In the present study, lamotrigine (LTG), one of the newer antiepileptic drugs, was evaluated for its effect on epilepsy, mood and memory in mice. Further, the effect of the addition of FA to LTG therapy was also investigated. The increasing current electroshock seizure test was used to evaluate the anticonvulsant effect of drugs, while the forced swimming test (FST) and spontaneous alternation behaviour (SAB) models were employed for assessing the effects on mood and memory, respectively. LTG exhibited a dose-dependent increase in seizure threshold, whereas FA did not have any effect. LTG did not affect, whereas FA decreased, behavioural depression in the FST in mice. Neither LTG nor FA affected memory scores in the SAB test. The combination of LTG and FA significantly reduced depression while enhancing the effects on memory and seizure threshold. The present observations have confirmed the antiepileptic action of LTG in yet another rodent model of epilepsy. Further, the results clearly demonstrate the additional benefits on epilepsy, mood and memory brought about by the inclusion of FA in the LTG regimen.

  11. A cognitive map model based on spatial and goal-oriented mental exploration in rodents.

    PubMed

    Zhu, Qing; Wang, Rubin; Wang, Ziyin

    2013-11-01

    The rodent hippocampus has been used to represent the spatial environment as a cognitive map. Classical theories suggest that the cognitive map is a consequence of assignment of different spatial regions to variant cell populations in the framework of rate coding. The current study constructs a novel computational neural model of the cognitive map based on firing rate coding, as widely appears in associative memory, thus providing an explanation for formation and function of the two types of cognitive maps: the spatial vector map, responsible for self localization and simultaneous updating of detailed information; and the goal-oriented vector map, important in route finding. A proposed intermediate between these two map types was constructed by combining the spatial vector and goal-orientation maps to form an effective and efficient path finding mechanism. Application of such novel cognitive map based path finding methods to a mental exploration model was explored. With adaptation as a driving force, the basic knowledge of the location relationships in the spatial cognitive map was reformed and sent to the goal-oriented cognitive map, thus solving a series of new path problems through mental exploration. This method allows for rapid identification of suitable paths under variant conditions, thus providing a simpler and safer resource for path finding. Additionally, this method also provides an improved basis for potential robotic path finding applications.

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. Vagal nerve stimulation reverses aberrant dopamine system function in the methylazoxymethanol acetate rodent model of schizophrenia.

    PubMed

    Perez, Stephanie M; Carreno, Flavia R; Frazer, Alan; Lodge, Daniel J

    2014-07-01

    Vagal nerve stimulation (VNS) is an alternative therapy for epilepsy and treatment refractory depression. Here we examine VNS as a potential therapy for the treatment of schizophrenia in the methylozoxymethanol acetate (MAM) rodent model of the disease. We have previously demonstrated that hyperactivity within ventral regions of the hippocampus (vHipp) drives the dopamine system dysregulation in this model. Moreover, by targeting the vHipp directly, we can reverse aberrant dopamine system function and associated behaviors in the MAM model. Although the central effects of VNS have not been completely delineated, positron emission topographic measurements of cerebral blood flow in humans have consistently reported that VNS stimulation induces bilateral decreases in hippocampal activity. Based on our previous observations, we performed in vivo extracellular electrophysiological recordings in MAM- and saline-treated rats to evaluate the effect of chronic (2 week) VNS treatment on the activity of putative vHipp pyramidal neurons, as well as downstream dopamine neuron activity in the ventral tegmental area. Here we demonstrate that chronic VNS was able to reverse both vHipp hyperactivity and aberrant mesolimbic dopamine neuron function in the MAM model of schizophrenia. Additionally, VNS reversed a behavioral correlate of the positive symptoms of schizophrenia. Because current therapies for schizophrenia are far from adequate, with a large number of patients discontinuing treatment due to low efficacy or intolerable side effects, it is important to explore alternative nonpharmacological treatments. These data provide the first preclinical evidence that VNS may be a possible alternative therapeutic approach for the treatment of schizophrenia.

  17. 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.

  18. Lethal Toxin is a Critical Determinant of Rapid Mortality in Rodent Models of Clostridium sordellii Endometritis

    PubMed Central

    Hao, Yibai; Senn, Tennille; Opp, Judy; Young, Vincent B.; Thiele, Teri; Srinivas, Geetha; Huang, Steven K.; Aronoff, David M.

    2009-01-01

    The toxigenic anaerobe Clostridium sordellii is an uncommon but highly lethal cause of human infection and toxic shock syndrome, yet few studies have addressed its pathogenetic mechanisms. To better characterize the microbial determinants of rapid death from infection both in vitro and in vivo studies were performed to compare a clinical strain of C. sordellii strain (DA-108), isolated from a patient who survived a disseminated infection unaccompanied by toxic shock syndrome, to a virulent reference strain (ATCC9714). Rodent models of endometrial and peritoneal infection with C. sordellii ATCC9714 were rapidly lethal, while infections with DA-108 were not. Extensive genetic and functional comparisons of virulence factor and toxin expression between these two bacterial strains yielded many similarities, with the noted exception that strain DA-108 lacked the tcsL gene, which encodes the large clostridial glucosyltransferase enzyme lethal toxin (TcsL). The targeted removal by immunoprecipitation of TcsL protected animals from death following injection of crude culture supernatants from strain ATCC9714. Injections of a monoclonal anti-TcsL IgG protected animals from death during C. sordellii ATCC9714 infection, suggesting that such an approach might improve the treatment of patients with C. sordellii-induced toxic shock syndrome. PMID:19527792

  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

    2016-01-01

    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. Adolescent vulnerabilities to chronic alcohol or nicotine exposure: findings from rodent models.

    PubMed

    Barron, Susan; White, Aaron; Swartzwelder, H Scott; Bell, Richard L; Rodd, Zachary A; Slawecki, Craig J; Ehlers, Cindy L; Levin, Edward D; Rezvani, Amir H; Spear, Linda P

    2005-09-01

    This article presents an overview of the proceedings from a symposium entitled "Is adolescence special? Possible age-related vulnerabilities to chronic alcohol or nicotine exposure," organized by Susan Barron and Linda Spear and held at the 2004 Research Society on Alcoholism Meeting in Vancouver, British Columbia. This symposium, co-sponsored by the Fetal Alcohol Syndrome Study Group and the Neurobehavioral Teratology Society, focused on our current knowledge regarding the long-term consequences of ethanol and/or nicotine exposure during adolescence with the emphasis on data from rodent models. The support from these two societies represents the understanding by these research groups that adolescence represents a unique developmental stage for the effects of chronic drug exposure and also marks an age in which many risky behaviors including alcohol consumption and smoking typically begin. The speakers included (1) Aaron White, who presented data on the effects of adolescent ethanol exposure on subsequent motor or cognitive response to an ethanol challenge in adulthood; (2) Richard Bell, who presented data suggesting that genetic differences could play a role in adolescent vulnerability to ethanol; (3) Craig Slawecki, who presented data looking at the effects of chronic exposure to alcohol or nicotine on neurophysiologic and behavioral end points; and (4) Ed Levin, who presented data on acute and long-term consequences of adolescent nicotine exposure. Finally, Linda Spear provided some summary points and recommendations regarding unresolved issues and future directions.

  1. 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.

  2. Alterations in dopamine system function across the estrous cycle of the MAM rodent model of schizophrenia.

    PubMed

    Perez, Stephanie M; Chen, Li; Lodge, Daniel J

    2014-09-01

    Clinical studies have reported differences in the incidence and severity of schizophrenia symptoms between male and female schizophrenia patients. Unfortunately, the cause of these differences is not currently known due, in part, to the fact that preclinical studies largely focus on male subjects. Dopamine neuron activity has been previously demonstrated to change across the estrous cycle, and may therefore be of relevance, as aberrant dopamine signaling is thought to underlie the positive symptoms of schizophrenia. Here we examine dopamine neuron activity across the estrous cycle in the MAM rodent model of schizophrenia. We demonstrate that the elevation in dopamine neuron activity, consistently observed in male MAM-treated rats, is most prominent during estrus and attenuated in met-estrus. Furthermore, this appears to be mediated, in part, by progesterone in the ventral hippocampus, as increases in dopamine neuron population activity (observed in estrus) were normalized by the intra-hippocampal administration of the progesterone receptor antagonist, mifepristone (but not the estrogen receptor antagonists, fulvestrant). Taken together, these data suggest that changes in dopamine system function occur across the estrous cycle in MAM-treated rats and may contribute to the differences in symptomatology between male and female schizophrenia patients.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. Evaluation of Neuroprotective Effect of Thymoquinone Nanoformulation in the Rodent Cerebral Ischemia-Reperfusion Model

    PubMed Central

    Xiao, Xiao-Yu; Zhu, Ying-Xian; Bu, Ju-Yuan; Li, Guo-Wei; Zhou, Jian-Hui

    2016-01-01

    The purpose of the present study was to evaluate the neuroprotective efficacy of optimized thymoquinone loaded PLGA-chitosan nanoparticles delivered via nose to brain route in the rodent cerebral ischemia-reperfusion model. The neuroprotective efficacy of the optimized thymoquinone loaded PLGA-chitosan nanoparticles was evaluated in middle cerebral artery occluded rats by various pharmacodynamic and biochemical studies. The pharmacokinetics of thymoquinone loaded PLGA-chitosan nanoparticles in the brain and blood plasma together with qualitative localization of florescent labelled PLGA-chitosan nanoparticles in brain tissues were also determined. Intranasal delivery of optimized thymoquinone loaded PLGA-chitosan nanoparticles (183.5 ± 8.2 nm, 33.63 ± 2.25 mV) to brain significantly reduced the ischemia infarct volume and enhanced the locomotor activity and grip strength in the middle cerebral artery occluded rats. Biochemical studies showed that intranasal delivery of thymoquinone loaded PLGA-chitosan nanoparticles significantly reduced the lipid peroxidation but elevated the glutathione, catalase, and superoxide dismutase in the brain of middle cerebral artery occluded rats. The pharmacokinetic and localization studies showed that thymoquinone loaded PLGA-chitosan nanoparticles facilitated the delivery of thymoquinone to brain by intranasal nose to brain transport pathways and enhanced their pharmacokinetic profile in brain tissues. Thus, intranasal delivery of thymoquinone loaded PLGA-chitosan nanoparticles to brain could be potentially used for the neuroprotection and treatment of cerebral ischemia. PMID:27725936

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

    PubMed

    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

  10. A rodent model of traumatic stress induces lasting sleep and quantitative electroencephalographic disturbances.

    PubMed

    Nedelcovych, Michael T; Gould, Robert W; Zhan, Xiaoyan; Bubser, Michael; Gong, Xuewen; Grannan, Michael; Thompson, Analisa T; Ivarsson, Magnus; Lindsley, Craig W; Conn, P Jeffrey; Jones, Carrie K

    2015-03-18

    Hyperarousal and sleep disturbances are common, debilitating symptoms of post-traumatic stress disorder (PTSD). PTSD patients also exhibit abnormalities in quantitative electroencephalography (qEEG) power spectra during wake as well as rapid eye movement (REM) and non-REM (NREM) sleep. Selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacological treatment for PTSD, provide modest remediation of the hyperarousal symptoms in PTSD patients, but have little to no effect on the sleep-wake architecture deficits. Development of novel therapeutics for these sleep-wake architecture deficits is limited by a lack of relevant animal models. Thus, the present study investigated whether single prolonged stress (SPS), a rodent model of traumatic stress, induces PTSD-like sleep-wake and qEEG spectral power abnormalities that correlate with changes in central serotonin (5-HT) and neuropeptide Y (NPY) signaling in rats. Rats were implanted with telemetric recording devices to continuously measure EEG before and after SPS treatment. A second cohort of rats was used to measure SPS-induced changes in plasma corticosterone, 5-HT utilization, and NPY expression in brain regions that comprise the neural fear circuitry. SPS caused sustained dysregulation of NREM and REM sleep, accompanied by state-dependent alterations in qEEG power spectra indicative of cortical hyperarousal. These changes corresponded with acute induction of the corticosterone receptor co-chaperone FK506-binding protein 51 and delayed reductions in 5-HT utilization and NPY expression in the amygdala. SPS represents a preclinical model of PTSD-related sleep-wake and qEEG disturbances with underlying alterations in neurotransmitter systems known to modulate both sleep-wake architecture and the neural fear circuitry.

  11. [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

  12. Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data.

    PubMed

    Soto, Jessica; Sheng, Yucheng; Standing, Joseph F; Orlu Gul, Mine; Tuleu, Catherine

    2015-04-01

    The rodent brief-access taste aversion (BATA) model is an efficient in vivo screening tool for taste assessment. A new E(max) (maximum effect attributable to the drug) model was developed and further investigated in comparison with three previously published models for analysing the rodent BATA data; the robustness of all the models was discussed. The rodent BATA data were obtained from a series of experiments conducted with a bitter reference compound, quinine hydrochloride dihydrate (QHD). A new E(max) model that could be applied to both "lick numbers" and "lick ratios" was built and three published models that used lick ratios were employed for analysing the BATA data. IC50, the concentration that inhibits 50% of the maximum lick numbers, quantified the oral aversiveness of QHD. One thousand bootstrap datasets were generated from the original data. All models were applied to estimate the confidence intervals of the IC50s without symmetric assumption. The IC50 value obtained from the new E(max) model was 0.0496 mM (95% CI 0.0297-0.0857) using the lick numbers for analysis, while an IC50 of 0.0502 mM (95% CI 0.0267-0.0859) was acquired with the lick ratios. Except one published model, the IC50 values have a similar range for the 95% CI. The new E(max) model enabled the analysis of both "lick numbers" and "lick ratios" whereas other models could only handle data presented as "lick ratios". IC50s obtained with these two types of datasets showed similarity among all models thereby justified the robustness of the new E(max) model.

  13. Stretching of the back improves gait, mechanical sensitivity and connective tissue inflammation in a rodent model.

    PubMed

    Corey, Sarah M; Vizzard, Margaret A; Bouffard, Nicole A; Badger, Gary J; Langevin, Helene M

    2012-01-01

    The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy.

  14. Fluoxetine Administration Exacerbates Oral Tremor and Striatal Dopamine Depletion in a Rodent Pharmacological Model of Parkinsonism

    PubMed Central

    Podurgiel, Samantha J; Milligan, Meredith N; Yohn, Samantha E; Purcell, Laura J; Contreras-Mora, Hector M; Correa, Mercè; Salamone, John D

    2015-01-01

    The cardinal motor symptoms of Parkinson's disease (PD) include resting tremor, akinesia, bradykinesia, and rigidity, and these motor abnormalities can be modeled in rodents by administration of the VMAT-2 (type-2 vesicular monoamine transporter) inhibitor tetrabenazine (9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7, 11b hexahydrobenzo[a]quinolizin-2-one; TBZ). Depression is also commonly associated with PD, and clinical data indicate that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine ((±)-N-methyl-γ-[4-(trifluoromethyl)phenoxy]benzenepropanamine hydrochloride; FLX) are frequently used to treat depression in PD patients. The aim of the present study was to characterize the effect of FLX on the motor dysfunctions induced by a low dose of TBZ (0.75 mg/kg), and investigate the neural mechanisms involved. This low dose of TBZ was selected based on studies with rat models of depressive symptoms. In rats, coadministration of FLX (2.5, 5.0, and 10.0 mg/kg) increased TBZ-induced oral tremor (tremulous jaw movements), and decreased locomotor activity compared with administration of TBZ alone. Coadministration of the serotonin 5-HT2A/2C antagonist mianserin (2.5 and 5.0 mg/kg) attenuated the increase in oral tremor induced by coadministration of TBZ (0.75 mg/kg) with FLX (5.0 mg/kg). Consistent with these behavioral data, coadministration of TBZ and FLX decreased DA tissue levels in the rat ventrolateral neostriatum compared with TBZ alone, and coadministration of mianserin with TBZ and FLX attenuated this effect, increasing DA tissue levels compared with the TBZ/FLX condition. These data suggest that SSRI administration in PD patients may result in worsening of motor symptoms, at least in part, by exacerbating existing DA depletions through 5-HT2A/2C-mediated modulation of DA neurotransmission. PMID:25759301

  15. 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

  16. 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.

  17. Challenging the Surgical Rodent Hindlimb Ischemia Model with the Miniinterventional Technique

    PubMed Central

    Zhuang, Zhen W.; Shi, Jing; Rhodes, John M.; Tsapakos, Michael J.; Simons, Michael

    2012-01-01

    Purpose To develop an interventional hindlimb ischemic model and compare its angiogenic effect versus surgical ligation (SL) and excision of the femoral artery in rats treated with transplantation of bone marrow mononuclear cells (MNCs) as an angiogenic stimulator. Materials and Methods Forty-eight Lewis rats randomly received interventional embolization (IE) with hydrogel wire or SL and excision of the right femoral artery. Rodents were intraarterially transplanted with 1.5 × 107 MNCs in 500 μL medium from 24 isogenic donor rats. Functional and structural recovery was evaluated by laser Doppler imaging (LDI), cytokine/chemokine assay, and histologic staining. Results In vivo microscopic images showed significantly dilated vasa vasorum around the embolized segment of the right femoral artery at 3 days compared with disorganized tissue structure in the SL group. However, the LDI index was significantly higher in the SL group at 3 days compared with the IE group. LDI did not significantly differ between the two groups at 2 weeks after transplantation. Cytokine assay showed higher levels of interleukin (IL)–1α and IL-18 in the SL group; the IE group had higher levels of interferon-γ, IL-6, IL-13, and granulocyte colony-stimulating factor. Histologic examination demonstrated inflammatory infiltration near the incision within nerve fibers with dilated capillaries, showing nerve degeneration in the SL group. At 2 weeks, histologic analysis demonstrated massive scarring under the skin spreading into the musculature in the SL group. Conclusions A minimally invasive hindlimb ischemia model has been successfully developed that preserves tissue integrity and minimizes inflammation and confounding factors in the early stages of angiogenesis and arteriogenesis. PMID:21459613

  18. 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

  19. Assessment of Depression in a Rodent Model of Spinal Cord Injury

    PubMed Central

    Luedtke, Kelsey; Bouchard, Sioui Maldonado; Woller, Sarah A.; Funk, Mary Katherine; Aceves, Miriam

    2014-01-01

    Abstract Despite an increased incidence of depression in patients after spinal cord injury (SCI), there is no animal model of depression after SCI. To address this, we used a battery of established tests to assess depression after a rodent contusion injury. Subjects were acclimated to the tasks, and baseline scores were collected before SCI. Testing was conducted on days 9–10 (acute) and 19–20 (chronic) postinjury. To categorize depression, subjects' scores on each behavioral measure were averaged across the acute and chronic stages of injury and subjected to a principal component analysis. This analysis revealed a two-component structure, which explained 72.2% of between-subjects variance. The data were then analyzed with a hierarchical cluster analysis, identifying two clusters that differed significantly on the sucrose preference, open field, social exploration, and burrowing tasks. One cluster (9 of 26 subjects) displayed characteristics of depression. Using these data, a discriminant function analysis was conducted to derive an equation that could classify subjects as “depressed” on days 9–10. The discriminant function was used in a second experiment examining whether the depression-like symptoms could be reversed with the antidepressant, fluoxetine. Fluoxetine significantly decreased immobility in the forced swim test (FST) in depressed subjects identified with the equation. Subjects that were depressed and treated with saline displayed significantly increased immobility on the FST, relative to not depressed, saline-treated controls. These initial experiments validate our tests of depression, generating a powerful model system for further understanding the relationships between molecular changes induced by SCI and the development of depression. PMID:24564232

  20. Stretching of the Back Improves Gait, Mechanical Sensitivity and Connective Tissue Inflammation in a Rodent Model

    PubMed Central

    Corey, Sarah M.; Vizzard, Margaret A.; Bouffard, Nicole A.; Badger, Gary J.; Langevin, Helene M.

    2012-01-01

    The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy. PMID:22238664

  1. The calcium chloride-induced rodent model of abdominal aortic aneurysm.

    PubMed

    Wang, Yutang; Krishna, Smriti; Golledge, Jonathan

    2013-01-01

    Abdominal aortic aneurysm (AAA) affects ∼5% men aged over 65 years and is an important cause of death in this population. Research into AAA pathogenesis has been fuelled by the need to identify new diagnostic biomarkers and therapeutic targets for this disease. One animal model of AAA involves peri-vascular application of calcium chloride (CaCl(2)) onto the infra-renal aorta of mice and rats to induce extracellular matrix remodelling. Twenty-three studies assessing CaCl(2)-induced AAA and six studies assessing AAA induced by a modified CaCl(2) method were identified. In the current report the preparation and pathological features of this AAA model are discussed. We also compared this animal model to human AAA. CaCl(2)-induced AAA shows the following pathological characteristics typically found in human AAA: calcification, inflammatory cell infiltration, oxidative stress, neovascularisation, elastin degradation and vascular smooth muscle cell apoptosis. A number of mechanisms involved in CaCl(2)-induced AAA have been identified which may be relevant to the pathogenesis of human AAA. Key molecules include c-Jun N-terminal kinase, peroxisome proliferator-activated receptor-γ, chemokine (C-C motif) receptor 2, group x secretory phospholipase A2 and plasminogen. CaCl(2)-induced AAA does not display aortic thrombus, atherosclerosis and rupture which are classical features of human AAA. Advantages of the CaCl(2)-induced AAA technique include (1) it can be applied to wild type mice making assessment of transgenic rodent models more straight forward and rapid; and (2) CaCl(2)-induced AAAs are usually developed in the infra-renal abdominal aorta, which is the most common location of human AAA. Currently findings obtained from the CaCl(2)-induced AAA model or other animal models of AAA have not been translated into the human situation. It is hoped that this deficiency will be corrected over the next decade with a number of clinical trials currently examining novel

  2. Alpha-Synuclein Expression in the Oligodendrocyte Lineage: an In Vitro and In Vivo Study Using Rodent and Human Models.

    PubMed

    Djelloul, Mehdi; Holmqvist, Staffan; Boza-Serrano, Antonio; Azevedo, Carla; Yeung, Maggie S; Goldwurm, Stefano; Frisén, Jonas; Deierborg, Tomas; Roybon, Laurent

    2015-08-11

    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.

  3. 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

  4. Rats anticipate damaged rungs on the elevated ladder: Applications for rodent models of Parkinson's disease.

    PubMed

    Lopatin, Daniel; Caputo, Nicole; Damphousse, Chelsey; Pandey, Siyaram; Cohen, Jerome

    2015-03-01

    The present study examined rats' ability to anticipate undetectable wider gaps between rungs produced when they stepped on and dislodged damaged rungs while they traversed a slightly inclined elevated ladder. Rats in the first of three experiments reduced running speeds when they encountered four evenly spaced damaged rungs either always placed on the first or second half of the ladder (the break-a-way (BW) phase) but quickly recovered to their baseline (BL) levels when damaged rungs where replaced with intact rungs (the recovery phase). Rats previously exposed to damaged rungs over the first half of the ladder increased their speeds above BL on its second "safer" half during the recovery phase, a delayed "relief-like" positive contrast effect. In Experiment 2, other rats decreased their speeds more as they approached a single damaged rung at a fixed location when it occurred before than after the mid-point of the ladder. Although they quickly recovered to BL speeds on the portion of the ladder after the damaged rung or replaced intact rung, they never showed any "relief-like"/escape effects. Rats also reduced their likelihood of dislodging the damaged rung with a fore paw over extended BW training. In the third experiment rats encountered a more easily dislodged damaged rung that was signaled by a closer intact rung on half the trials. Under these conditions rats displayed a more reliable positive contrast "relief-like" effect. We discussed how traditional associative and cognitive theories of aversive conditioning account for these findings and their relationship to normal changes in dopamine production and possible effects of reduced production from the substantia nigra pars compacta (SNpc) in the Basal ganglia in rodent models of Parkinson's disease. PMID:25747570

  5. Nicotinic modulation of auditory evoked potential electroencephalography in a rodent neurodevelopmental model of schizophrenia.

    PubMed

    Kohlhaas, Kathy L; Robb, Holly M; Roderwald, Victoria A; Rueter, Lynne E

    2015-10-15

    Schizophrenia is a chronic disease that has been hypothesized to be linked to neurodevelopmental abnormalities. Schizophrenia patients exhibit impairments in basic sensory processing including sensory gating deficits in P50 and mismatch negativity (MMN). Neuronal nicotinic acetylcholine receptor (nAChR) agonists have been reported to attenuate these deficits. Gestational exposure of rats to methylazoxymethanol acetate (MAM) at embryonic day 17 leads to developmental disruption of the limbic-cortical system. MAM exposed offspring show neuropathological and behavioral changes that have similarities with those seen in schizophrenia. In this study, we aimed to assess whether N40 auditory sensory gating (the rodent form of P50 gating) and MMN deficits as measures of auditory evoked potential (AEP) electroencephalography (EEG) are present in MAM rats and whether nAChR agonists could attend the deficit. E17 male MAM and sham rats were implanted with cortical electrodes at 2 months of age. EEG recordings evaluating N40 gating and MMN paradigms were done comparing effects of vehicle (saline), nicotine and the α7 agonist ABT-107. Deficits were seen for MAM rats compared to sham animals in both N40 auditory sensory gating and MMN AEP recordings. There was a strong trend for N40 deficits to be attenuated by both nicotine (0.16mg/kg i.p. base) and ABT-107 (1.0mg/kg i.p. base). MMN deficits were significantly attenuated by ABT-107 but not by nicotine. These data support the MAM model as a useful tool for translating pharmacodynamic effects in clinical medicine studies of novel therapeutic treatments for schizophrenia. PMID:26032639

  6. Nicotinic modulation of auditory evoked potential electroencephalography in a rodent neurodevelopmental model of schizophrenia.

    PubMed

    Kohlhaas, Kathy L; Robb, Holly M; Roderwald, Victoria A; Rueter, Lynne E

    2015-10-15

    Schizophrenia is a chronic disease that has been hypothesized to be linked to neurodevelopmental abnormalities. Schizophrenia patients exhibit impairments in basic sensory processing including sensory gating deficits in P50 and mismatch negativity (MMN). Neuronal nicotinic acetylcholine receptor (nAChR) agonists have been reported to attenuate these deficits. Gestational exposure of rats to methylazoxymethanol acetate (MAM) at embryonic day 17 leads to developmental disruption of the limbic-cortical system. MAM exposed offspring show neuropathological and behavioral changes that have similarities with those seen in schizophrenia. In this study, we aimed to assess whether N40 auditory sensory gating (the rodent form of P50 gating) and MMN deficits as measures of auditory evoked potential (AEP) electroencephalography (EEG) are present in MAM rats and whether nAChR agonists could attend the deficit. E17 male MAM and sham rats were implanted with cortical electrodes at 2 months of age. EEG recordings evaluating N40 gating and MMN paradigms were done comparing effects of vehicle (saline), nicotine and the α7 agonist ABT-107. Deficits were seen for MAM rats compared to sham animals in both N40 auditory sensory gating and MMN AEP recordings. There was a strong trend for N40 deficits to be attenuated by both nicotine (0.16mg/kg i.p. base) and ABT-107 (1.0mg/kg i.p. base). MMN deficits were significantly attenuated by ABT-107 but not by nicotine. These data support the MAM model as a useful tool for translating pharmacodynamic effects in clinical medicine studies of novel therapeutic treatments for schizophrenia.

  7. Combined drug and surgery treatment of plutonium-contaminated wounds: indications obtained using a rodent model.

    PubMed

    Griffiths, Nina M; Coudert, Sylvie; Wilk, Jean Claude; Renault, Daniel; Angulo, Jaime F; Van der Meeren, Anne

    2014-06-01

    There is an important requirement following accidental actinide contamination of wounds to limit the dissemination and retention of such alpha-emitting radionuclides. To reduce wound and systemic contamination, treatment approaches include chelation therapy with or without wound excision. However, it has been hypothesized that wound excision could lead to increased contaminant release and systemic organ retention. This study in the rat addresses this question. Anesthetized rats were contaminated with plutonium nitrate following wounding by deep incision of hind leg muscle. Excision of tissue at the contaminated site was performed 7 d later with or without Diethylene Triamine Pentaacetic Acid (DTPA) treatment (30 μmol kg⁻¹ i.v.). Pu urinary excretion was then measured for a further 3 d, and animals were euthanized at 14 d after contamination. Tissue samples were evaluated for Pu activity and histology. At 7 d after contamination, around 50% of the initial activity remained at the wound site. An average of 16% of this activity was then removed by surgery. Surgery alone resulted in increased urinary excretion, suggesting release from the wound site, but no subsequent increases in organ retention (bone, liver) were observed at 14 d. Indeed, organ Pu activity was slightly reduced. The combination of surgery and DTPA or DTPA treatment alone was much more effective than excision alone as shown by the markedly increased urinary Pu excretion and decreased tissue levels. This is the first report in an experimental rodent model of resection of Pu-contaminated wound. Urinary excretion data provide evidence for the release of activity as a result of surgery, but this does not appear to lead to further Pu organ retention. However, a combination of prior DTPA treatment with wound excision is particularly effective.

  8. In vivo viability of Echinococcus multilocularis eggs in a rodent model after different thermo-treatments.

    PubMed

    Federer, Karin; Armua-Fernandez, Maria Teresa; Hoby, Stefan; Wenker, Christian; Deplazes, Peter

    2015-07-01

    Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a serious and emerging zoonotic disease in many parts of the northern hemisphere. Humans but also primates and other accidental hosts can acquire the infection by the ingestion of eggs excreted by the carnivore definitive hosts, e.g. after hand contact with egg-contaminated environments or by consumption of contaminated food or beverages. The goal of this study was to develop a sensitive in vivo method to determine the viability of E. multilocularis eggs and to establish suitable conditions (optimal temperature, exposure time and humidity) for their (prophylactic) inactivation. The sensitivity of a rodent model was evaluated and, conclusively, C57Bl/6 mice were most susceptible to subcutaneous inoculation of small numbers of sodium hypochlorite-resistant oncospheres, even more than to oral inoculation of mature eggs. In the second part of the study, various combinations of exposure temperature (between 45 °C and 80 °C), times (between 30 min and 180 min) and relative humidity (70% vs. suspended in water) were tested. After heat treatment in an incubator, the sodium hypochlorite resistance test was used to assess in vitro egg viability at the time of inoculation. Subsequently, the infectivity of the oncospheres was evaluated by subcutaneous inoculation in mice. Eggs exposed to increasing temperatures were more resistant to heat if suspended in water as compared to eggs exposed on a filter paper at 70% relative humidity. As survival of eggs in water droplets on the vegetables cannot be excluded, further experiments were performed with eggs suspended in water only. Eggs were infectious after heat exposure at 65 °C for up to 120 min, however, no echinococcosis developed after treatment of the eggs at 65 °C for 180 min or at 70, 75 and 80 °C for 7.5, 15 or 30 min.

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

    PubMed

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

    2014-02-01

    Hypoxia-ischemia (HI) occurs when blood and/or oxygen delivery to the brain is compromised. HI injuries can occur in infants born prematurely (<37 weeks gestational age) or at very low birth weight (<1500 g), as well as in term infants with birth complications. In both preterm and term HI populations, brain injury is associated with subsequent behavioral deficits. Neonatal HI injury can be modeled in rodents (e.g., the Rice-Vannucci method, via cautery of right carotid followed by hypoxia). When this injury is induced early in life (between postnatal day (P)1-5), neuropathologies typical of human preterm HI are modeled. When injury is induced later (P7-12), neuropathologies typical of those seen in HI term infants are modeled. The current study sought to characterize the similarities/differences between outcomes following early (P3) and late (P7) HI injury in rats. Male rats with HI injury on P3 or P7, as well as sham controls, were tested on a variety of behavioral tasks in both juvenile and adult periods. Results showed that P7 HI rats displayed deficits on motor learning, rapid auditory processing (RAP), and other learning/memory tasks, as well as a reduction in volume in various neuroanatomical structures. P3 HI animals showed only transient deficits on RAP tasks in the juvenile period (but not in adulthood), yet robust deficits on a visual attention task in adulthood. P3 HI animals did not show any significant reductions in brain volume that we could detect. These data suggest that: (1) behavioral deficits following neonatal HI are task-specific depending on timing of injury; (2) P3 HI rats showed transient deficits on RAP tasks; (3) the more pervasive behavioral deficits seen following P7 HI injury were associated with substantial global tissue loss; and (4) persistent deficits in attention in P3 HI subjects might be linked to neural connectivity disturbances rather than a global loss of brain volume, given that no such pathology was found. These combined

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

    PubMed Central

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

    2014-01-01

    Hypoxia-ischemia (HI) occurs when blood and/or oxygen delivery to the brain is compromised. HI injuries can occur in infants born prematurely (<37 weeks gestational age) or at very low birth weight (<1500 grams), as well as in term infants with birth complications. In both preterm and term HI populations, brain injury is associated with subsequent behavioral deficits. Neonatal HI injury can be modeled in rodents (e.g., the Rice-Vannucci method, via cautery of right carotid followed by hypoxia). When this injury is induced early in life (between postnatal day (P)1–5), neuropathologies typical of human preterm HI are modeled. When injury is induced later (P7–12), neuropathologies typical of those seen in HI term infants are modeled. The current study sought to characterize the similarities/differences between outcomes following early (P3) and late (P7) HI injury in rats. Male rats with HI injury on P3 or P7, as well as sham controls, were tested on a variety of behavioral tasks in both juvenile and adult periods. Results showed that P7 HI rats displayed deficits on motor learning, rapid auditory processing (RAP), and other learning/memory tasks, as well as a reduction in volume in various neuroanatomical structures. P3 HI animals showed only transient deficits on RAP tasks in the juvenile period (but not in adulthood), yet robust deficits on a visual attention task in adulthood. P3 HI animals did not show any significant reductions in brain volume that we could detect. These data suggest that: 1) behavioral deficits following neonatal HI are task-specific depending on timing of injury; 2) P3 HI rats showed transient deficits on RAP tasks; 3) the more pervasive behavioral deficits seen following P7 HI injury were associated with substantial global tissue loss; and 4) persistent deficits in attention in P3 HI subjects might be linked to neural connectivity disturbances rather than a global loss of brain volume, given that no such pathology was found. These combined

  11. The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

    PubMed Central

    Brault, Aaron C.; Hunsperger, Elizabeth

    2015-01-01

    Members of the genus Flavivirus are responsible for a spectrum of important neurological syndromes in humans and animals. Rodent models have been used extensively to model flavivirus neurological disease, to discover host-pathogen interactions that influence disease outcome, and as surrogates to determine the efficacy and safety of vaccines and therapeutics. In this review, we discuss the current understanding of flavivirus neuroinvasive disease and outline the host, viral and experimental factors that influence the outcome and reliability of virus infection of small-animal models. PMID:22592957

  12. 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

  13. 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

  14. 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

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

    PubMed

    Ganella, Despina E; Kim, Jee Hyun

    2014-10-01

    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.

  16. 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

  17. Molecular and cellular response of the most extensively used rodent glioma models to radiation and/or cisplatin.

    PubMed

    Bencokova, Zuzana; Pauron, Laurianne; Devic, Clément; Joubert, Aurélie; Gastaldo, Jérôme; Massart, Catherine; Balosso, Jacques; Foray, Nicolas

    2008-01-01

    Purpose Anti-glioma strategies are generally based on trials involving rodent models whose choice remains based on proliferative capacity and availability. Recently, our group obtained the most protracted survival of rats bearing F98 gliomas by combining synchrotron X-rays and intracerebral cisplatin injection (Biston et al., Cancer Res, 64:2317-2323, 2004). The response to such treatment was suggested to be dependent on BRCA1, a tumour suppressor known to be involved in the response to radiation and cisplatin. In order to verify the impact of BRCA1 functionality upon success of anti-glioma trials, radiobiological features and BRCA1-dependent stress signalling were investigated in the most extensively used rodent glioma models. Methods Cell death pathways, cell cycle arrests, DNA repair and stress signalling were evaluated in response to radiation and cisplatin in C6, 9L and F98 models. Results Rodent glioma models showed a large spectrum of cellular radiation response. Surprisingly, BRCA1 was found to be functionally impaired in C6 and F98 favouring genomic instability, tumour heterogeneity and tolerance of unrepaired DNA damage. Significance Our findings strengthened the importance of the choice of the glioma model on genetic and radiobiological bases, inasmuch as all these rat glioma models are induced by nitrosourea-mediated mutagenesis that may favour specific gene mutations. Particularly, BRCA1 status may condition the response to anti-glioma treatments. Furthermore, since BRCA1 acts as a tumour suppressor in a number of malignancies, our findings raise also the question of the implication of BRCA1 in brain tumours formation. PMID:17611717

  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.

  19. Ecdysone Receptor-based Singular Gene Switches for Regulated Transgene Expression in Cells and Adult Rodent Tissues.

    PubMed

    Lee, Seoghyun; Sohn, Kyung-Cheol; Choi, Dae-Kyoung; Won, Minho; Park, Kyeong Ah; Ju, Sung-Kyu; Kang, Kidong; Bae, Young-Ki; Hur, Gang Min; Ro, Hyunju

    2016-01-01

    Controlled gene expression is an indispensable technique in biomedical research. Here, we report a convenient, straightforward, and reliable way to induce expression of a gene of interest with negligible background expression compared to the most widely used tetracycline (Tet)-regulated system. Exploiting a Drosophila ecdysone receptor (EcR)-based gene regulatory system, we generated nonviral and adenoviral singular vectors designated as pEUI(+) and pENTR-EUI, respectively, which contain all the required elements to guarantee regulated transgene expression (GAL4-miniVP16-EcR, termed GvEcR hereafter, and 10 tandem repeats of an upstream activation sequence promoter followed by a multiple cloning site). Through the transient and stable transfection of mammalian cell lines with reporter genes, we validated that tebufenozide, an ecdysone agonist, reversibly induced gene expression, in a dose- and time-dependent manner, with negligible background expression. In addition, we created an adenovirus derived from the pENTR-EUI vector that readily infected not only cultured cells but also rodent tissues and was sensitive to tebufenozide treatment for regulated transgene expression. These results suggest that EcR-based singular gene regulatory switches would be convenient tools for the induction of gene expression in cells and tissues in a tightly controlled fashion. PMID:27673563

  20. Ecdysone Receptor-based Singular Gene Switches for Regulated Transgene Expression in Cells and Adult Rodent Tissues

    PubMed Central

    Lee, Seoghyun; Sohn, Kyung-Cheol; Choi, Dae-Kyoung; Won, Minho; Park, Kyeong Ah; Ju, Sung-Kyu; Kang, Kidong; Bae, Young-Ki; Hur, Gang Min; Ro, Hyunju

    2016-01-01

    Controlled gene expression is an indispensable technique in biomedical research. Here, we report a convenient, straightforward, and reliable way to induce expression of a gene of interest with negligible background expression compared to the most widely used tetracycline (Tet)-regulated system. Exploiting a Drosophila ecdysone receptor (EcR)-based gene regulatory system, we generated nonviral and adenoviral singular vectors designated as pEUI(+) and pENTR-EUI, respectively, which contain all the required elements to guarantee regulated transgene expression (GAL4-miniVP16-EcR, termed GvEcR hereafter, and 10 tandem repeats of an upstream activation sequence promoter followed by a multiple cloning site). Through the transient and stable transfection of mammalian cell lines with reporter genes, we validated that tebufenozide, an ecdysone agonist, reversibly induced gene expression, in a dose- and time-dependent manner, with negligible background expression. In addition, we created an adenovirus derived from the pENTR-EUI vector that readily infected not only cultured cells but also rodent tissues and was sensitive to tebufenozide treatment for regulated transgene expression. These results suggest that EcR-based singular gene regulatory switches would be convenient tools for the induction of gene expression in cells and tissues in a tightly controlled fashion. PMID:27673563

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

    PubMed

    McCormick, Cheryl M; Hodges, Travis E; Simone, Jonathan J

    2015-02-01

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

  2. 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

  3. 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

  4. Modeling combined schizophrenia-related behavioral and metabolic phenotypes in rodents.

    PubMed

    Sarnyai, Zoltán; Jashar, Cassandra; Olivier, Berend

    2015-01-01

    Schizophrenia is a chronic, debilitating disorder with a complex behavioral and cognitive phenotype underlined by a similarly complex etiology involving an interaction between susceptibility genes and environmental factors during early development. Limited progress has been made in developing novel pharmacotherapy, partly due to a lack of valid animal models. The recent recognition of the potentially causal role of central and peripheral energy metabolism in the pathophysiology of schizophrenia raises the need of research on animal models that combine both behavioral and metabolic phenotypic domains, similar to what have been identified in humans. In this review we focus on selected genetic (DBA/2J mice, leptin receptor mutants, and PSD-93 knockout mice), early neurodevelopmental (maternal protein deprivation) and pharmacological (acute phencyclidine) animal models that capture the combined behavioral and metabolic abnormalities shown by schizophrenic patients. In reviewing behavioral phenotypes relevant to schizophrenia we apply the principles established by the Research Domain Criteria (RDoC) for better translation. We demonstrate that etiologically diverse manipulations such as specific breeding, deletion of genes that are primarily involved in metabolic regulation and in synaptic plasticity, as well as early metabolic deprivation and adult pharmacological challenge of the glutamate system can lead to schizophrenia-related behavioral and metabolic phenotypes, which suggest that these pathways might be interlinked. We propose that using animal models that combine different domains of schizophrenia can be used as a translationally valid approach to capture the system-level complex interplay between peripheral and central processes in the development of psychopathology.

  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. 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.

  7. 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

    2010-06-01

    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.

  8. 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.

  9. Hippocampal theta oscillations are slower in humans than in rodents: implications for models of spatial navigation and memory.

    PubMed

    Jacobs, Joshua

    2014-02-01

    The theta oscillation is a neuroscience enigma. When a rat runs through an environment, large-amplitude theta oscillations (4-10 Hz) reliably appear in the hippocampus's electrical activity. The consistency of this pattern led to theta playing a central role in theories on the neural basis of mammalian spatial navigation and memory. However, in fact, hippocampal oscillations at 4-10 Hz are rare in humans and in some other species. This presents a challenge for theories proposing theta as an essential component of the mammalian brain, including models of place and grid cells. Here, I examine this issue by reviewing recent research on human hippocampal oscillations using direct brain recordings from neurosurgical patients. This work indicates that the human hippocampus does indeed exhibit rhythms that are functionally similar to theta oscillations found in rodents, but that these signals have a slower frequency of approximately 1-4 Hz. I argue that oscillatory models of navigation and memory derived from rodent data are relevant for humans, but that they should be modified to account for the slower frequency of the human theta rhythm.

  10. Evidence of the antiepileptic potential of amiloride with neuropharmacological benefits in rodent models of epilepsy and behavior.

    PubMed

    Ali, Atif; Ahmad, Farhan Jalees; Pillai, K K; Vohora, Divya

    2004-06-01

    Sodium-hydrogen exchangers (NHEs) in the brain play a key role in regulating neuronal pH and, hence, modulate bioelectric and seizure activity. In this study, we investigated the anticonvulsant effect of amiloride (a NHE inhibitor) on increasing current electroshock (ICES) and pentylenetetrazole (PTZ)-induced seizures in mice. Further, the effect of amiloride on mood, memory, grip strength, and rotarod performance was also evaluated. The forced swimming test (FST) and spontaneous alternation behavior (SAB) models were employed to assess the effects on mood and memory, respectively. Amiloride produced a dose-dependent increase in seizure threshold in both rodent models of epilepsy. It was observed that amiloride reduced behavioral depression in the FST in mice. In addition, it resulted in memory improvement in the SAB model. Amiloride did not affect grip strength and rotarod performance, suggesting it is devoid of behavioral impairment. The results indicate the potential antiseizure activity of amiloride along with additional neurological advantages.

  11. Network structure implied by initial axon outgrowth in rodent cortex: empirical measurement and models.

    PubMed

    Cahalane, Diarmuid J; Clancy, Barbara; Kingsbury, Marcy A; Graf, Ethan; Sporns, Olaf; Finlay, Barbara L

    2011-01-11

    The developmental mechanisms by which the network organization of the adult cortex is established are incompletely understood. Here we report on empirical data on the development of connections in hamster isocortex and use these data to parameterize a network model of early cortical connectivity. Using anterograde tracers at a series of postnatal ages, we investigate the growth of connections in the early cortical sheet and systematically map initial axon extension from sites in anterior (motor), middle (somatosensory) and posterior (visual) cortex. As a general rule, developing axons extend from all sites to cover relatively large portions of the cortical field that include multiple cortical areas. From all sites, outgrowth is anisotropic, covering a greater distance along the medial/lateral axis than along the anterior/posterior axis. These observations are summarized as 2-dimensional probability distributions of axon terminal sites over the cortical sheet. Our network model consists of nodes, representing parcels of cortex, embedded in 2-dimensional space. Network nodes are connected via directed edges, representing axons, drawn according to the empirically derived anisotropic probability distribution. The networks generated are described by a number of graph theoretic measurements including graph efficiency, node betweenness centrality and average shortest path length. To determine if connectional anisotropy helps reduce the total volume occupied by axons, we define and measure a simple metric for the extra volume required by axons crossing. We investigate the impact of different levels of anisotropy on network structure and volume. The empirically observed level of anisotropy suggests a good trade-off between volume reduction and maintenance of both network efficiency and robustness. Future work will test the model's predictions for connectivity in larger cortices to gain insight into how the regulation of axonal outgrowth may have evolved to achieve efficient

  12. Complex maze learning in rodents as a model of age-related memory impairment.

    PubMed

    Ingram, D K

    1988-01-01

    Research is reviewed concerning the age-related learning deficit observed in a 14-unit T-maze (Stone maze). Rats and mice of several strains representing different adult age groups are first trained to criterion in one-way active avoidance in a straight runway. Then training in the Stone maze is conducted which involves negotiation of five maze segments to avoid footshock. Results indicate a robust age-related impairment in acquisition observed in males and females, and in outbred, inbred, and hybrid strains. Pharmacological studies using the muscarinic antagonist, scopolamine, in young and aged rats indicate cholinergic involvement for accurate encoding during acquisition of this task. Retention aspects of storage and retrieval do not appear to be affected by scopolamine treatment. Bilateral electrolytic lesions to the fimbria-fornix of young rats also produce an acquisition deficit to implicate involvement of the septo-hippocampal cholinergic system in Stone maze learning. A salient feature of Stone maze performance is the tendency to demonstrate an alternation strategy in solving the maze. This strategy is exacerbated by impairment of cholinergic neurotransmission with either scopolamine treatment or fimbria-fornix lesions. Various models of hippocampal function are applied toward the psychological characterization of the Stone maze task without complete success. Future research is outlined to provide more thorough psychological characterization of maze performance, to analyze the specificity of cholinergic involvement in the task, and to test possible therapeutic interventions for alleviating the age-related impairments observed.

  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

    2016-08-23

    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.

  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. 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.

  17. 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

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

    PubMed

    Davies, J; Ingham, A

    2015-06-20

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

  19. 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

  20. An in vivo investigation of the initiation and progression of subchondral cysts in a rodent model of secondary osteoarthritis

    PubMed Central

    2012-01-01

    Introduction Subchondral bone cysts (SBC) have been identified in patients with knee osteoarthritis (OA) as a cause of greater pain, loss of cartilage and increased chance of joint replacement surgery. Few studies monitor SBC longitudinally, and clinical research using three-dimensional imaging techniques, such as magnetic resonance imaging (MRI), is limited to retrospective analyses as SBC are identified within an OA patient cohort. The purpose of this study was to use dual-modality, preclinical imaging to monitor the initiation and progression of SBC occurring within an established rodent model of knee OA. Methods Eight rodents underwent anterior cruciate ligament transection and partial medial meniscectomy (ACLX) of the right knee. In vivo 9.4 T MRI and micro-computed tomography (micro-CT) scans were performed consecutively prior to ACLX and 4, 8, and 12 weeks post-ACLX. Resultant images were co-registered using anatomical landmarks, which allowed for precise tracking of SBC size and composition throughout the study. The diameter of the SBC was measured, and the volumetric bone mineral density (vBMD) was calculated within the bone adjacent to SBC. At 12 weeks, the ACLX and contralateral knees were processed for histological analysis, immunohistochemistry, and Osteoarthritis Research Society International (OARSI) pathological scoring. Results At 4 weeks post-ACLX, 75% of the rodent knees had at least 1 cyst that formed in the medial tibial plateau; by 12 weeks all ACLX knees contained SBC. Imaging data revealed that the SBC originate in the presence of a subchondral bone plate breach, with evolving composition over time. The diameter of the SBC increased significantly over time (P = 0.0033) and the vBMD significantly decreased at 8 weeks post-ACLX (P = 0.033). Histological analysis demonstrated positive staining for bone resorption and formation surrounding the SBC, which were consistently located beneath the joint surface with the greatest cartilage damage

  1. Modeling depression in adult female cynomolgus monkeys (Macaca fascicularis).

    PubMed

    Willard, Stephanie L; Shively, Carol A

    2012-06-01

    Depressive disorders are prevalent, costly, and poorly understood. Male rodents in stress paradigms are most commonly used as animal models, despite the two-fold increased prevalence of depression in women and sex differences in response to stress. Although these models have provided valuable insights, new models are needed to move the field forward. Social stress-associated behavioral depression in adult female cynomolgus macaques closely resembles human depression in physiological, neurobiological, and behavioral characteristics, including reduced body mass, hypothalamic-pituitary-adrenal axis perturbations, autonomic dysfunction, increased cardiovascular disease risk, reduced hippocampal volume, altered serotonergic function, decreased activity levels, and increased mortality. In addition, behaviorally depressed monkeys also have low ovarian steroid concentrations, even though they continue to have menstrual cycles. Although this type of ovarian dysfunction has not been reported in depressed women and is difficult to identify, it may be the key to understanding the high prevalence of depression in women. Depressive behavior in female cynomolgus monkeys is naturally occurring and not induced by experimental manipulation. Different social environmental challenges, including isolation vs. subordination, may elicit the depression-like response in some animals and not others. Similarly, social subordination is stressful and depressive behavior is more common in socially subordinate monkeys. Yet, not all subordinates exhibit behavioral depression, suggesting individual differences in sensitivity to specific environmental stressors and enhanced risk of behavioral depression in some individuals. The behavior and neurobiology of subordinates is distinctly different than that of behaviorally depressed monkeys, which affords the opportunity to differentiate between stressed and depressed states. Thus, behaviorally depressed monkeys exhibit numerous physiological

  2. 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

  3. Identification of Novel Rosavirus Species That Infects Diverse Rodent Species and Causes Multisystemic Dissemination in Mouse Model

    PubMed Central

    Fan, Rachel Y. Y.; Zhang, Anna J. X.; Chan, Brandon C. C.; Lam, Carol S. F.; Yip, Cyril C. Y.; Chan, Kwok-Hung; Chen, Zhi-Wei; Yuen, Kwok-Yung

    2016-01-01

    While novel picornaviruses are being discovered in rodents, their host range and pathogenicity are largely unknown. We identified two novel picornaviruses, rosavirus B from the street rat, Norway rat, and rosavirus C from five different wild rat species (chestnut spiny rat, greater bandicoot rat, Indochinese forest rat, roof rat and Coxing's white-bellied rat) in China. Analysis of 13 complete genome sequences showed that “Rosavirus B” and “Rosavirus C” represent two potentially novel picornavirus species infecting different rodents. Though being most closely related to rosavirus A, rosavirus B and C possessed distinct protease cleavage sites and variations in Yn-Xm-AUG sequence in 5’UTR and myristylation site in VP4. Anti-rosavirus B VP1 antibodies were detected in Norway rats, whereas anti-rosavirus C VP1 and neutralizing antibodies were detected in Indochinese forest rats and Coxing's white-bellied rats. While the highest prevalence was observed in Coxing's white-bellied rats by RT-PCR, the detection of rosavirus C from different rat species suggests potential interspecies transmission. Rosavirus C isolated from 3T3 cells causes multisystemic diseases in a mouse model, with high viral loads and positive viral antigen expression in organs of infected mice after oral or intracerebral inoculation. Histological examination revealed alveolar fluid exudation, interstitial infiltration, alveolar fluid exudate and wall thickening in lungs, and hepatocyte degeneration and lymphocytic/monocytic inflammatory infiltrates with giant cell formation in liver sections of sacrificed mice. Since rosavirus A2 has been detected in fecal samples of children, further studies should elucidate the pathogenicity and emergence potential of different rosaviruses. PMID:27737017

  4. 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.

  5. 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.

  6. 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

  7. 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)

  8. Model of Adult Career Education in Corrections.

    ERIC Educational Resources Information Center

    Ryan, T. A.; And Others

    The model was designed to provide a guide for systematic planning, implementation, and evaluation of adult career education in correctional settings, utilizing a systems approach. It consists of seven chapters and a flowchart presenting seven major functions which must be carried out: (1) establishing a conceptual framework, (2) setting up an…

  9. Allometric disparity in rodent evolution

    PubMed Central

    Wilson, Laura A B

    2013-01-01

    In this study, allometric trajectories for 51 rodent species, comprising equal representatives from each of the major clades (Ctenohystrica, Muroidea, Sciuridae), are compared in a multivariate morphospace (=allometric space) to quantify magnitudes of disparity in cranial growth. Variability in allometric trajectory patterns was compared to measures of adult disparity in each clade, and dietary habit among the examined species, which together encapsulated an ecomorphological breadth. Results indicate that the evolution of allometric trajectories in rodents is characterized by different features in sciurids compared with muroids and Ctenohystrica. Sciuridae was found to have a reduced magnitude of inter-trajectory change and growth patterns with less variation in allometric coefficient values among members. In contrast, a greater magnitude of difference between trajectories and an increased variation in allometric coefficient values was evident for both Ctenohystrica and muroids. Ctenohystrica and muroids achieved considerably higher adult disparities than sciurids, suggesting that conservatism in allometric trajectory modification may constrain morphological diversity in rodents. The results provide support for a role of ecology (dietary habit) in the evolution of allometric trajectories in rodents. PMID:23610638

  10. 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.

  11. Progesterone Induces Mucosal Immunity in a Rodent Model of Human Taeniosis by Taenia solium

    PubMed Central

    Escobedo, Galileo; Camacho-Arroyo, Ignacio; Nava-Luna, Paul; Olivos, Alfonso; Pérez-Torres, Armando; Leon-Cabrera, Sonia; Carrero, J.C.; Morales-Montor, Jorge

    2011-01-01

    More than one quarter of human world's population is exposed to intestinal helminth parasites. The Taenia solium tapeworm carrier is the main risk factor in the transmission of both human neurocysticercosis and porcine cysticercosis. Sex steroids play an important role during T. solium infection, particularly progesterone has been proposed as a key immunomodulatory hormone involved in susceptibility to human taeniosis in woman and cysticercosis in pregnant pigs. Thus, we evaluated the effect of progesterone administration upon the experimental taeniosis in golden hamsters (Mesocricetus auratus). Intact female adult hamsters were randomly divided into 3 groups: progesterone-subcutaneously treated; olive oil-treated as the vehicle group; and untreated controls. Animals were treated every other day during 4 weeks. After 2 weeks of treatment, all hamsters were orally infected with 4 viable T. solium cysticerci. After 2 weeks post infection, progesterone-treated hamsters showed reduction in adult worm recovery by 80%, compared to both vehicle-treated and non-manipulated infected animals. In contrast to control and vehicle groups, progesterone treatment diminished tapeworm length by 75% and increased proliferation rate of leukocytes from spleen and mesenteric lymph nodes of infected hamsters by 5-fold. The latter exhibited high expression levels of IL-4, IL-6 and TNF-α at the duodenal mucosa, accompanied with polymorphonuclear leukocytes infiltration. These results support that progesterone protects hamsters from the T. solium adult tapeworm establishment by improving the intestinal mucosal immunity, suggesting a potential use of analogues of this hormone as novel inductors of the gut immune response against intestinal helminth infections and probably other bowel-related disorders. PMID:22110394

  12. Progesterone induces mucosal immunity in a rodent model of human taeniosis by Taenia solium.

    PubMed

    Escobedo, Galileo; Camacho-Arroyo, Ignacio; Nava-Luna, Paul; Olivos, Alfonso; Pérez-Torres, Armando; Leon-Cabrera, Sonia; Carrero, J C; Morales-Montor, Jorge

    2011-01-01

    More than one quarter of human world's population is exposed to intestinal helminth parasites. The Taenia solium tapeworm carrier is the main risk factor in the transmission of both human neurocysticercosis and porcine cysticercosis. Sex steroids play an important role during T. solium infection, particularly progesterone has been proposed as a key immunomodulatory hormone involved in susceptibility to human taeniosis in woman and cysticercosis in pregnant pigs. Thus, we evaluated the effect of progesterone administration upon the experimental taeniosis in golden hamsters (Mesocricetus auratus). Intact female adult hamsters were randomly divided into 3 groups: progesterone-subcutaneously treated; olive oil-treated as the vehicle group; and untreated controls. Animals were treated every other day during 4 weeks. After 2 weeks of treatment, all hamsters were orally infected with 4 viable T. solium cysticerci. After 2 weeks post infection, progesterone-treated hamsters showed reduction in adult worm recovery by 80%, compared to both vehicle-treated and non-manipulated infected animals. In contrast to control and vehicle groups, progesterone treatment diminished tapeworm length by 75% and increased proliferation rate of leukocytes from spleen and mesenteric lymph nodes of infected hamsters by 5-fold. The latter exhibited high expression levels of IL-4, IL-6 and TNF-α at the duodenal mucosa, accompanied with polymorphonuclear leukocytes infiltration. These results support that progesterone protects hamsters from the T. solium adult tapeworm establishment by improving the intestinal mucosal immunity, suggesting a potential use of analogues of this hormone as novel inductors of the gut immune response against intestinal helminth infections and probably other bowel-related disorders.

  13. 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.

  14. 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

  15. Translational Challenge Models in Support of Efficacy Studies: Effect of Cerebral Hypoxia on Cognitive Performances in Rodents.

    PubMed

    Deguil, Julie; Ravasi, Laura; Lanteaume, Laura; Lamberty, Yves; Bordet, Regis

    2016-01-01

    Empirical evidence currently supports the idea that neurovascular dysfunction is involved in the neurodegenerative process of Alzheimer's disease (AD). In fact, epidemiological studies report that i) vascular risk factors are directly associated with an increased incidence of AD and ii) vascular lesions are frequently co-existent with AD. The neurovascular unit is a key control system for oxygen and nutrients exchange between neurons and microvessels so the integrity of this system is essential for neuronal activity and cell survival. This suggests that hypoxia arising from various vascular injuries may participate in the pathogenesis of AD and aggravate cognitive deficit. Moreover, hypoxia appears to have a direct effect on cognitive functions, in particular memory, by inducing a transient or definitive dysfunction of synaptic transmission. The interplay of hypoxic phenomenon and the development of AD-related pathologies support the use of hypoxia as a challenge model to assess symptomatic (i.e. cognitive enhancers) AD-treatment. Such challenge should be characterized and validated with current symptomatic drugs based on different mechanisms of action before being offered as alternative models for testing new drugs. To date, symptomatic treatments of AD including anticholinesterasic- (donepezil, rivastigmine and galantamine) and antiglutamatergic- (memantine) drugs target various neurotransmission impairments occurring at different stages of the disease. The first aim of the present review is to provide an overview of the methods used to achieve experimental hypoxia in rodents and to characterize the cognitive alterations induced by each method. The second objective is to summarize the main results from studies that have tested the effect of acetylcholinesterase inhibitors on hypoxiainduced cognitive impairment. Overall, the literature research yielded only a small number of studies investigating the effect of hypoxia on cognition in rodents and the different

  16. Adult zebrafish model for pneumococcal pathogenesis.

    PubMed

    Saralahti, Anni; Piippo, Hannaleena; Parikka, Mataleena; Henriques-Normark, Birgitta; Rämet, Mika; Rounioja, Samuli

    2014-02-01

    Streptococcus pneumoniae (pneumococcus) is a leading cause of community acquired pneumonia, septicemia, and meningitis. Due to incomplete understanding of the host and bacterial factors contributing to these diseases optimal treatment and prevention methods are lacking. In the present study we examined whether the adult zebrafish (Danio rerio) can be used to investigate the pathophysiology of pneumococcal diseases. Here we show that both intraperitoneal and intramuscular injections of the pneumococcal strain TIGR4 cause a fulminant, dose-dependent infection in adult zebrafish, while isogenic mutant bacteria lacking the polysaccharide capsule, autolysin, or pneumolysin are attenuated in the model. Infection through the intraperitoneal route is characterized by rapid expansion of pneumococci in the bloodstream, followed by penetration of the blood-brain barrier and progression to meningitis. Using Rag1 mutant zebrafish, which are devoid of somatic recombination and thus lack adaptive immune responses, we show that clearance of pneumococci in adult zebrafish depends mainly on innate immune responses. In conclusion, this study provides evidence that the adult zebrafish can be used as a model for a pneumococcal infection, and that it can be used to study both host and bacterial factors involved in the pathogenesis. However, our results do not support the use of the zebrafish in studies on the role of adaptive immunity in pneumococcal disease or in the development of new pneumococcal vaccines.

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

    PubMed

    Levin, Edward D

    2011-01-01

    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 in stress-related behaviors due to the amxiolytic 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 in helping to determine the mechanisms crucial for new therapeutic treatments of neurobehavioral impairments.

  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. 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

  20. Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome.

    PubMed

    Buettner, R; Bettermann, I; Hechtl, C; Gäbele, E; Hellerbrand, C; Schölmerich, J; Bollheimer, L C

    2010-10-01

    The AMP activated kinase plays an important role in metabolic control, and pharmacologic enhancement of AMPK activity is used to improve insulin resistance. We hypothesized that high dose of folic acid supplementation might improve insulin sensitivity and hepatic inflammation and examined this by a dietary intervention in (a) the high fat fed rat model of the metabolic syndrome, which shows sole hepatic steatosis as well as (b) in rats fed with a high cholesterol, high cholate diet inducing nonalcoholic steatohepatitis (NASH). Male Wistar rats were fed with folic acid supplemented (40 mg/kg) high fat diet [based on lard, fat content 25% (wt/wt)] or NASH inducing diet (containing 15% fat, 1.25% cholesterol, 0.5% sodium cholate). Metabolic profiling was performed by measuring the animals' visceral fat pads, fasting plasma glucose, insulin, and adipokines as well as in vivo insulin tolerance tests. Hepatic steatosis and inflammation were analyzed semiquantitatively by histological analysis. Folic acid supplementation reduced visceral obesity and improved plasma adiponectin levels. In vivo insulin sensitivity was improved, and in HF-FA rats folic acid increased activation of hepatic AMPK. Further, folic acid supplementation improved hepatic inflammation in animals fed with NASH-inducing diet. Dietary folic acid improved parameters of insulin resistance and hepatic inflammation in rodent models. This might be due to an increased AMK activation.

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

    PubMed

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

    2011-09-15

    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 survival experiments 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 9.4T 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.

  2. 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

  3. 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.

  4. 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

  5. Evaluation of Hypoglycemic Efficacy of Tangningtongluo Formula, a Traditional Chinese Miao Medicine, in Two Rodent Animal Models

    PubMed Central

    Meng, Xiang-bao; Lu, Shan; Wang, Ting-ting; Liu, Yue; Sun, Gui-bo; Sun, Xiao-bo

    2014-01-01

    Traditional Chinese medicines largely lack adequate and scientifically rigorous evidence regarding efficacy and functional mechanisms. The present study was aimed to confirm the hypoglycemic effect of Tangningtongluo (TNTL) formula, a traditional Chinese Miao medicine, in two animal models: high-fat diet and streptozotocin- (STZ-) induced diabetic rats and C57BL/KsJ-db/db diabetic mice. After 4 weeks, TNTL intervention in STZ-induced diabetic rats yielded in significant improvement on the glucose tolerance test. Moreover, the islet histopathology showed that oral TNTL reduced the severity of islet necrosis in pancreases tissue. Compared with diabetic controls, a 12-week TNTL treatment regimen (dosages = 0.9, 1.8, and 3.6 g/kg) in db/db mice significantly decreased fasting glucose and HbA1c. Additionally, oral glucose tolerance in TNTL-treated mice improved significantly, compared with diabetic mice receiving metformin. Finally, tissue histopathology and biochemical index evaluations revealed significant improvement in TNTL-treated mice. Taken together, our results show that TNTL exerted a strong hypoglycemic effect in two diabetic rodent animal models, preserving β-cells in the pancreas islet and reducing the risk of diabetic retinopathy and nephropathy. PMID:25431772

  6. Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease.

    PubMed

    Ma, Wanli; Han, Weihong; Greer, Peter A; Tuder, Rubin M; Toque, Haroldo A; Wang, Kevin K W; Caldwell, R William; Su, Yunchao

    2011-11-01

    Pulmonary hypertension is a severe and progressive disease, a key feature of which is pulmonary vascular remodeling. Several growth factors, including EGF, PDGF, and TGF-β1, are involved in pulmonary vascular remodeling during pulmonary hypertension. However, increased knowledge of the downstream signaling cascades is needed if effective clinical interventions are to be developed. In this context, calpain provides an interesting candidate therapeutic target, since it is activated by EGF and PDGF and has been reported to activate TGF-β1. Thus, in this study, we examined the role of calpain in pulmonary vascular remodeling in two rodent models of pulmonary hypertension. These data showed that attenuated calpain activity in calpain-knockout mice or rats treated with a calpain inhibitor resulted in prevention of increased right ventricular systolic pressure, right ventricular hypertrophy, as well as collagen deposition and thickening of pulmonary arterioles in models of hypoxia- and monocrotaline-induced pulmonary hypertension. Additionally, inhibition of calpain in vitro blocked intracellular activation of TGF-β1, which led to attenuated Smad2/3 phosphorylation and collagen synthesis. Finally, smooth muscle cells of pulmonary arterioles from patients with pulmonary arterial hypertension showed higher levels of calpain activation and intracellular active TGF-β. Our data provide evidence that calpain mediates EGF- and PDGF-induced collagen synthesis and proliferation of pulmonary artery smooth muscle cells via an intracrine TGF-β1 pathway in pulmonary hypertension. PMID:22005303

  7. 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)

  8. 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

  9. Effect of low-level laser therapy (λ660 nm) on angiogenesis in wound healing: a immunohistochemical study in a rodent model.

    PubMed

    Colombo, Fábio; Neto, Alberto de Aguiar Pires Valença; Sousa, Ana Paula Cavalcanti de; Marchionni, Antônio Márcio Teixeira; Pinheiro, Antônio Luiz Barbosa; Reis, Silvia Regina de Almeida

    2013-01-01

    The aim of the present investigation was to evaluate the angiogenesis on dorsal cutaneous wounds in a rodent model treated with λ660 nm laser light. New vessel formation is a multistep process involving vessel sprouting, endothelial cell migration, proliferation and tube formation. Although several in vivo studies have shown that laser phototherapy influences tissue repair, a fully understanding of angiogenesis mechanisms are not yet known. Twenty-four young adult male Wistar rats weighing between 200 and 250 g were used. Under general anesthesia, one excisional wound was created on the dorsum of each animal and they were randomly distributed into two groups: one control and one treated with laser (λ660 nm, 16 mW, 10 J/cm2). Each group was subdivided into three subgroups according to the animal death timing (2, 4 and 6 days). Laser irradiation started immediately after surgery and was repeated every other day during the experiment and marked with Sirius Red, specific for collagen, and immunomarked with anti-TGF-β and anti-von Willebrand factor. Marked sections underwent histological analysis by light microscopy and the mean area of the wound of each animal was calculated and analyzed by ANOVA and Tukey's test (α=0.05). Although at some death periods, collagen expression and number of blood vessels on irradiated animals were higher than in the control ones, no significant differences were found at any time in relation to TGF-β expression (p>0.05). It was concluded that laser treatment (λ660 nm) contributed to increase angiogenesis.

  10. Sympathetic modulation of sensory nerve activity with age: human and rodent skin models.

    PubMed

    Khalil, Z; LeVasseur, S; Merhi, M; Helme, R D

    1997-11-01

    1. Sensory nerves serve an afferent role and mediate neurogenic components of inflammation and tissue repair via an axon reflex release of sensory peptides at sites of injury. Dysfunction of these nerves with age could contribute to delayed tissue healing. 2. Complementary animal and human skin models were used in the present studies to investigate changes in the modulation of sensory nerve function by sympathetic efferents during ageing. Laser Doppler flowmetry was used to monitor neurogenic skin vascular responses. 3. The animal model used skin of the hind footpad of anaesthetized rats combined with electrical stimulation of the sciatic nerve, while the human model comprised capsaicin electrophoresis to the volar surface of the forearm. Sympathetic modulation was effected by systemic phentolamine pretreatment in animals and local application in the human model. 4. The results obtained from the human model confirmed the reported decline in sensory nerve function and showed no change in sympathetic modulation with age. The results from the animal model confirm and expand results obtained from the human model. 5. The use of low (5 Hz) and high (15 Hz) frequency electrical stimulation (20 V, 2 ms for 1 min) revealed a preferential response of aged sensory nerves to low-frequency electrical stimulation parameters with differential sympathetic modulation that is dependent on the frequency of stimulation.

  11. Standard dose valproic acid does not cause additional cognitive impact in a rodent model of intractable epilepsy.

    PubMed

    Jellett, Adam P; Jenks, Kyle; Lucas, Marcella; Scott, Rod C

    2015-02-01

    Children with epilepsy face significant cognitive and behavioral impairments. These impairments are due to a poorly characterized interaction between the underlying etiology, the effect of seizures and the effect of medication. The large variation in these factors make understanding the main drivers of cognitive impairment in humans extremely difficult. Therefore, we investigated the cognitive effect of seizures and the antiepileptic drug valproic acid in a rodent model of cortical dysplasia. Rats were divided into seizure-receiving and non-receiving groups. Rats experienced frequent early life seizures using the flurothyl inhalation method: 50 seizures between postnatal day 5 and 15 and then one seizure a day following that. Rats were further divided into drug-treated and vehicle treated groups. Valproic acid treated animals were treated from 5 days preceding behavioral testing in the Morris water maze at a clinically relevant concentration. We show here that the main driver of cognitive impairments are the brain malformations, and that persistent seizures in animals with brain malformations and valproic acid caused no additional impact. These findings suggest that neither an appropriate dose of a standard antiepileptic drug or intractable seizures worsen cognition associated with a malformation of cortical development and that alternative treatment strategies to improve cognition are required.

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

    PubMed Central

    Ressler, Ilana B.; Grayson, Bernadette E.; Ulrich-Lai, Yvonne M.

    2015-01-01

    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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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

  6. Rodent Hypoxia-Ischemia Models for Cerebral Palsy Research: A Systematic Review.

    PubMed

    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

  7. 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

  8. 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

  9. 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

  10. "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…

  11. 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

  12. The Use of Perinatal 6-Hydroxydopamine to Produce a Rodent Model of Lesch-Nyhan Disease.

    PubMed

    Knapp, Darin J; Breese, George R

    2016-01-01

    Lesch-Nyhan disease is a neurologically, metabolically, and behaviorally devastating condition that has eluded complete characterization and adequate treatment. While it is known that the disease is intimately associated with dysfunction of the hypoxanthine phosphoribosyltransferase 1 (HPRT1) gene that codes for an enzyme of purine metabolism (hypoxanthine-guanine phosphoribosyltransferase) and is associated with neurological, behavioral, as well as metabolic dysfunction, the mechanisms of the neurobehavioral manifestations are as yet unclear. However, discoveries over the past few decades not only have created useful novel animal models (e.g., the HPRT-deficient mouse and the serendipitously discovered perinatal 6-hydroxydopamine (6-OHDA lesion model), but also have expanded into epigenetic, genomic, and proteomic approaches to better understand the mechanisms underlying this disease. The perinatal 6-OHDA model, in addition to modeling self-injury and dopamine depletion in the clinical condition, also underscores the profound importance of development in the differential course of maladaptive progression in the face of a common/single neurotoxic insult at different ages. Recent developments from clinical and basic science efforts attest to the fact that while the disease would seem to have a simple single gene defect at its core, the manifestations of this defect are profound and unexpectedly diverse. Future efforts employing the 6-OHDA model and others in the context of the novel technologies of genome editing, chemo- and opto-genetics, epigenetics, and further studies on the mechanisms of stress-induced maladaptations in brain all hold promise in taking our understanding of this disease to the next level. PMID:27029809

  13. 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

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

    PubMed Central

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

    2014-01-01

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

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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)

  20. 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

  1. 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

  2. Effects of morning compared with evening bright light administration to ameliorate short-photoperiod induced depression- and anxiety-like behaviors in a diurnal rodent model.

    PubMed

    Krivisky, Katy; Einat, Haim; Kronfeld-Schor, Noga

    2012-10-01

    The lack of appropriate animal models for affective disorders is a major factor hindering better understanding of the underlying pathologies and the development of more efficacious treatments. Because circadian rhythms play an important role in affective disorders, we recently suggested that diurnal rodents can be advantageous as model animals. We found that in diurnal rodents, short photoperiod induces depression- and anxiety-like behaviors, with similarities to human seasonal affective disorder. In a pilot study we also found that these behaviors are ameliorated by morning bright light administration. In the present study we further evaluated the effects of morning and evening bright light administration on short photoperiod-induced depression- and anxiety-like behaviors in diurnal fat sand rats. Animals were maintained under short (5L:19D) or neutral (12L:12D) photoperiod and treated with morning or evening bright light or red dim light as control. Morning bright light ameliorated the behavioral deficits in the elevated plus maze and social interaction tests whereas evening bright light was effective only in the social interaction test. This is the first detailed presentation of the effects of bright light treatment in an animal model and a clear demonstration to the advantages of utilizing diurnal rodents to study interactions between circadian rhythms and affect.

  3. Human Engineered Heart Muscles Engraft and Survive Long-Term in a Rodent Myocardial Infarction Model

    PubMed Central

    Riegler, Johannes; Tiburcy, Malte; Ebert, Antje; Tzatzalos, Evangeline; Raaz, Uwe; Abilez, Oscar J.; Shen, Qi; Kooreman, Nigel G.; Neofytou, Evgenios; Chen, Vincent C.; Wang, Mouer; Meyer, Tim; Tsao, Philip S.; Connolly, Andrew J.; Couture, Larry A.; Gold, Joseph D.; Zimmermann, Wolfram H.; Wu, Joseph C.

    2015-01-01

    Rational Tissue engineering approaches may improve survival and functional benefits from human embryonic stem cell-derived cardiomyocte (ESC-CM) transplantation, thereby potentially preventing dilative remodelling and progression to heart failure. Objective Assessment of transport stability, long term survival, structural organisation, functional benefits, and teratoma risk of engineered heart muscle (EHM) in a chronic myocardial infarction (MI) model. Methods and Results We constructed EHMs from ESC-CMs and released them for transatlantic shipping following predefined quality control criteria. Two days of shipment did not lead to adverse effects on cell viability or contractile performance of EHMs (n=3, P=0.83, P=0.87). After ischemia/reperfusion (I/R) injury, EHMs were implanted onto immunocompromised rat hearts at 1 month to simulate chronic ischemia. Bioluminescence imaging (BLI) showed stable engraftment with no significant cell loss between week 2 and 12 (n=6, P=0.67), preserving up to 25% of the transplanted cells. Despite high engraftment rates and attenuated disease progression (change in ejection fraction for EHMs −6.7±1.4% vs control −10.9±1.5%, n>12, P=0.05), we observed no difference between EHMs containing viable or non-viable human cardiomyocytes in this chronic xenotransplantation model (n>12, P=0.41). Grafted cardiomyocytes showed enhanced sarcomere alignment and increased connexin 43 expression at 220 days after transplantation. No teratomas or tumors were found in any of the animals (n=14) used for long-term monitoring. Conclusions EHM transplantation led to high engraftment rates, long term survival, and progressive maturation of human cardiomyocytes. However, cell engraftment was not correlated with functional improvements in this chronic MI model. Most importantly, the safety of this approach was demonstrated by the lack of tumor or teratoma formation. PMID:26291556

  4. Effect of cannabidiol in a MK-801-rodent model of aspects of schizophrenia.

    PubMed

    Gururajan, Anand; Taylor, David Alan; Malone, Daniel Thomas

    2011-09-23

    Cannabidiol is a non-psychoactive phytocannabinoid which, based on several previous preclinical and clinical reports, is purported to have antipsychotic potential. The purpose of this investigation was to further investigate if these effects would be seen using an MK-801-induced rat model of aspects of schizophrenia. MK-801 is an NMDA receptor-antagonist known to produce hyperactivity, deficits in prepulse inhibition and social withdrawal, behaviours which correlate well with some of the positive, cognitive and negative symptoms of schizophrenia. Following a 4-day acclimatisation to the holding room, rats were acclimatised to startle chambers on day 5 and their prepulse inhibition (PPI) determined on day 6 following treatment with cannabidiol or vehicle and MK-801 or vehicle. On day 9, rats were acclimatised to the social interaction testing arena and on day 10, were tested for social interaction and locomotor activity following the same treatments. Cannabidiol treatment alone disrupted PPI and produced hyperactivity but had no effect on social behaviour. Cannabidiol had no effect on MK-801-induced disruption of PPI or hyperactivity but showed potential towards inhibiting MK-801-induced social withdrawal. As a comparator, we also tested the effect of the atypical antipsychotic clozapine which only partially reversed MK-801-induced disruption of PPI but was able to reverse MK-801-induced hyperactivity and social withdrawal. In conclusion, cannabidiol showed both propsychotic activity and partial antipsychotic activity in an MK-801-induced model of aspects of schizophrenia. Further behavioural studies would be required using a range of species, strains, animal models and testing paradigms to conclusively establish the antipsychotic potential of cannabidiol.

  5. 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

  6. Quantitative relationship between axonal injury and mechanical response in a rodent head impact acceleration model.

    PubMed

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

    2011-09-01

    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 (R(2)=0.612, p<0.05), and time to surface right (R(2)=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.

  7. 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

  8. Decoding Advances in Psychiatric Genetics: A Focus on Neural Circuits in Rodent Models.

    PubMed

    Heckenast, Julia R; Wilkinson, Lawrence S; Jones, Matthew W

    2015-01-01

    Appropriately powered genome-wide association studies combined with deep-sequencing technologies offer the prospect of real progress in revealing the complex biological underpinnings of schizophrenia and other psychiatric disorders. Meanwhile, recent developments in genome engineering, including CRISPR, constitute better tools to move forward with investigating these genetic leads. This review aims to assess how these advances can inform the development of animal models for psychiatric disease, with a focus on schizophrenia and in vivo electrophysiological circuit-level measures with high potential as disease biomarkers.

  9. 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

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

    PubMed

    Sukhotinsky, Inna; Chan, Alexander M; Ahmed, Omar J; Rao, Vikram R; Gradinaru, Viviana; Ramakrishnan, Charu; Deisseroth, Karl; Majewska, Ania K; Cash, Sydney S

    2013-01-01

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

  11. Optogenetic Delay of Status Epilepticus Onset in an In Vivo Rodent Epilepsy Model

    PubMed Central

    Sukhotinsky, Inna; Chan, Alexander M.; Ahmed, Omar J.; Rao, Vikram R.; Gradinaru, Viviana; Ramakrishnan, Charu; Deisseroth, Karl; Majewska, Ania K.; Cash, Sydney S.

    2013-01-01

    Epilepsy is a devastating disease, currently treated with medications, surgery or electrical stimulation. None of these approaches is totally effective and our ability to control seizures remains limited and complicated by frequent side effects. The emerging revolutionary technique of optogenetics enables manipulation of the activity of specific neuronal populations in vivo with exquisite spatiotemporal resolution using light. We used optogenetic approaches to test the role of hippocampal excitatory neurons in the lithium-pilocarpine model of acute elicited seizures in awake behaving rats. Hippocampal pyramidal neurons were transduced in vivo with a virus carrying an enhanced halorhodopsin (eNpHR), a yellow light activated chloride pump, and acute seizure progression was then monitored behaviorally and electrophysiologically in the presence and absence of illumination delivered via an optical fiber. Inhibition of those neurons with illumination prior to seizure onset significantly delayed electrographic and behavioral initiation of status epilepticus, and altered the dynamics of ictal activity development. These results reveal an essential role of hippocampal excitatory neurons in this model of ictogenesis and illustrate the power of optogenetic approaches for elucidation of seizure mechanisms. This early success in controlling seizures also suggests future therapeutic avenues. PMID:23637949

  12. Oral efficacy of a respiratory syncytial virus inhibitor in rodent models of infection.

    PubMed

    Cianci, Christopher; Genovesi, Eugene V; Lamb, Lucinda; Medina, Ivette; Yang, Zheng; Zadjura, Lisa; Yang, Hyekyung; D'Arienzo, Celia; Sin, Ny; Yu, Kuo-Long; Combrink, Keith; Li, Zhufang; Colonno, Richard; Meanwell, Nicholas; Clark, Junius; Krystal, Mark

    2004-07-01

    BMS-433771 is a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. Mechanism of action studies have demonstrated that BMS-433771 halts virus entry through inhibition of F protein-mediated membrane fusion. BMS-433771 also exhibited in vivo efficacy following oral administration in a mouse model of RSV infection (C. Cianci, K. Y. Yu, K. Combrink, N. Sin, B. Pearce, A. Wang, R. Civiello, S. Voss, G. Luo, K. Kadow, E. Genovesi, B. Venables, H. Gulgeze, A. Trehan, J. James, L. Lamb, I. Medina, J. Roach, Z. Yang, L. Zadjura, R. Colonno, J. Clark, N. Meanwell, and M. Krystal, Antimicrob. Agents Chemother. 48:413-422, 2004). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was approximately 7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition

  13. 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

  14. 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.

  15. The Utility of a Rodent Model in Detecting Pediatric Drug-Induced Nephrotoxicity

    PubMed Central

    Espandiari, Parvaneh; Zhang, Jun; Rosenzweig, Barry A.; Vaidya, Vishal S.; Sun, Jinchun; Schnackenberg, Laura; Herman, Eugene H.; Knapton, Alan; Bonventre, Joseph V.; Beger, Richard D.; Thompson, Karol L.; Hanig, Joseph

    2009-01-01

    A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg-1 body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies. PMID:17636248

  16. The utility of a rodent model in detecting pediatric drug-induced nephrotoxicity.

    PubMed

    Espandiari, Parvaneh; Zhang, Jun; Rosenzweig, Barry A; Vaidya, Vishal S; Sun, Jinchun; Schnackenberg, Laura; Herman, Eugene H; Knapton, Alan; Bonventre, Joseph V; Beger, Richard D; Thompson, Karol L; Hanig, Joseph

    2007-10-01

    A multi-age rat model was used to identify potential age-related differences in renal injury following exposure to gentamicin (GM). In this study, 10-, 25-, 40-, and 80-day-old Sprague-Dawley rats were dosed with GM at 0, 50, or 100 mg kg(-1) body weight per day (mkd) sc for 6 or 14 days. Urine samples were collected up to 72 h after initial dosing. The maximum tolerated dose was lower in 10-day-old rats than for other ages (none survived 11 days of treatment). Eighty-day-old rats given the highest dose showed a diminished rate of growth and an increase in serum creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (Kim-1), and renal pathology. Ten- and 40-day-old rats given 100 mkd of GM for 6- or 14 days also had increased levels of serum BUN and Cr and renal pathology, whereas only mild renal alterations were found in 25-day-old rats. After 6 days of treatment with 100 mkd GM, significant increases in Havcr-1 (Kim-1) gene expression were detected only in 10- and 80-day-old rats. In urine samples, nuclear magnetic resonance and ultra performance liquid chromatography/mass spectrometry analysis detected changes related to GM efficacy (e.g., hippurate) and increases in metabolites related to antioxidant activity, which was greatest in the 80-day-old rats. The magnitude of the genomic, metabonomic, and serum chemistry changes appeared to correlate with the degree of nephropathy. These findings indicate that an experimental animal model that includes several developmental stages can detect age-related differences in drug-induced organ toxicities and may be a useful predictor of pediatric drug safety in preclinical studies.

  17. 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

  18. 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.

  19. 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

  20. Characterization of rodent models of HIV-gp120 and anti-retroviral-associated neuropathic pain.

    PubMed

    Wallace, Victoria C J; Blackbeard, Julie; Segerdahl, Andrew R; Hasnie, Fauzia; Pheby, Timothy; McMahon, Stephen B; Rice, Andrew S C

    2007-10-01

    A distal symmetrical sensory peripheral neuropathy is frequently observed in people living with Human Immunodeficiency Virus Type 1 (HIV-1). This neuropathy can be associated with viral infection alone, probably involving a role for the envelope glycoprotein gp120; or a drug-induced toxic neuropathy associated with the use of nucleoside analogue reverse transcriptase inhibitors as a component of highly active anti-retroviral therapy. In order to elucidate the mechanisms underlying drug-induced neuropathy in the context of HIV infection, we have characterized pathological events in the peripheral and central nervous system following systemic treatment with the anti-retroviral agent, ddC (Zalcitabine) with or without the concomitant delivery of HIV-gp120 to the rat sciatic nerve (gp120+ddC). Systemic ddC treatment alone is associated with a persistent mechanical hypersensitivity (33% decrease in limb withdrawal threshold) that when combined with perineural HIV-gp120 is exacerbated (48% decrease in threshold) and both treatments result in thigmotactic (anxiety-like) behaviour. Immunohistochemical studies revealed little ddC-associated alteration in DRG phenotype, as compared with known changes following perineural HIV-gp120. However, the chemokine CCL2 is significantly expressed in the DRG of rats treated with perineural HIV-gp120 and/or ddC and there is a reduction in intraepidermal nerve fibre density, comparable to that seen in herpes zoster infection. Moreover, a spinal gliosis is apparent at times of peak behavioural sensitivity that is exacerbated in gp120+ddC as compared to either treatment alone. Treatment with the microglial inhibitor, minocycline, is associated with delayed onset of hypersensitivity to mechanical stimuli in the gp120+ddC model and reversal of some measures of thigmotaxis. Finally, the hypersensitivity to mechanical stimuli was sensitive to systemic treatment with gabapentin, morphine and the cannabinoid WIN 55,212-2, but not with

  1. 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

  2. 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

  3. 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

  4. Long-lasting effects of chronic rTMS to treat chronic rodent model of depression.

    PubMed

    Feng, Shu-fang; Shi, Tian-yao; Fan-Yang; Wang, Wua-ning; Chen, Yun-chun; Tan, Qing-rong

    2012-06-15

    Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated in the pre-clinical and clinical settings to have an antidepressant effect. However, studies on the long-lasting effect of rTMS, especially when the effect is measured after treatment has ceased for a few weeks is lacking. We examined this question in a chronic unpredicted mild stress (CUMS) rat model of depression. We gave 3 weeks of high frequency (15 Hz) rTMS, venlafaxine, or these two treatments combined to a modified CUMS paradigm, and then investigated the prolonged effect of treatments. Behavioral testing (sucrose preference test, open field test, forced swimming test, novelty suppressed feeding test), plasma hormone level, hippocampal BrdU labeling, and amount of related neurotropic factors were used to assess the effects of stress and treatments. Long-term chronic rTMS significantly reversed andehonic-like behavior, increased hippocampus cell proliferation, BDNF protein level, phosphorylation of ERK1/2 compared with CUMS rats two weeks after the cessation of rTMS treatment. However, the changes in plasma hormone level were not sustained for that amount of time. Venlafaxine had no interaction with the physical stimulation. Our results suggest that high frequency rTMS has long-lasting effects, which may have some relationship with neuroplasticity.

  5. Inflammation Models of Depression in Rodents: Relevance to Psychotropic Drug Discovery

    PubMed Central

    Dantzer, Robert

    2016-01-01

    Inflammation and depression are closely inter-related; inflammation induces symptoms of depression and, conversely, depressed mood and stress favor an inflammatory phenotype. The mechanisms that mediate the ability of inflammation to induce symptoms of depression are intensively studied at the preclinical level. This review discusses how it has been possible to build animal models of inflammation-induced depression based on clinical data and to explore critical mechanisms downstream of inflammation. Namely, we focus on the ability of inflammation to increase the activity of the tryptophan-degrading enzyme, indoleamine 2,3 dioxygenase, which leads to the production of kynurenine and downstream neuroactive metabolites. By acting on glutamatergic neurotransmission, these neuroactive metabolites play a key role in the development of depression-like behaviors. An important outcome of the preclinical research on inflammation-induced depression is the identification of potential novel targets for antidepressant treatments, which include targeting the kynurenine system and production of downstream metabolites, altering transport of kynurenine into the brain, and modulating glutamatergic transmission. PMID:27026361

  6. 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

  7. 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

  8. 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.

  9. 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

  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. Gastric distention exacerbates ischemia in a rodent model of partial gastric devascularization.

    PubMed

    Urschel, J D; Antkowiak, J G; Takita, H

    1997-11-01

    Occult ischemia of the mobilized gastric fundus is an important etiologic factor for esophagogastric anastomotic leaks after esophagectomy. Postoperative gastric distention is another possible predisposing factor for anastomotic leakage. We hypothesized that gastric distention could worsen gastric ischemia. To test this hypothesis, gastric tissue perfusion was studied in 20 Sprague-Dawley rats. Baseline serosal gastric tissue perfusion was measured by laser-Doppler flowmetry at a point 10 mm distal to the gastroesophageal junction. Perfusion was measured after left gastric artery occlusion, gastric distention to 20 cm water pressure, and combined left gastric artery occlusion and gastric distention. Gastric tissue perfusion (in tissue perfusion units, TPU) was 64.2 +/- 9.1 TPU at baseline measurement, 18.6 +/- 4.3 TPU after left gastric artery occlusion, 22.0 +/- 4.1 TPU after gastric distention, and 7.8 +/- 1.8 TPU after combined left gastric artery occlusion and gastric distention. Distention (P < 0.0001) and arterial occlusion (P < 0.0001) both reduced gastric tissue perfusion; of the two, arterial occlusion produced the greatest reduction in perfusion (P < 0.021). The combination of distention and arterial occlusion caused greater reduction in gastric perfusion than either factor alone (P < 0.0001). In this model, gastric distention exacerbated the ischemia produced by partial gastric devascularization. In clinical esophageal surgery, postoperative gastric distention may similarly potentiate the ischemic effects of gastric transposition for esophageal reconstruction.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. Characterization of perforant path lesions in rodent models of memory and attention.

    PubMed

    Kirkby, D L; Higgins, G A

    1998-03-01

    Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.

  17. 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

  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. 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

  20. Nuclear factor-kappa B regulates pain and COMT expression in a rodent model of inflammation

    PubMed Central

    Hartung, Jane E.; Eskew, Olivia; Wong, Terrence; Tchivileva, Inna E.; Oladosu, Folabomi A.; O’Buckley, Sandra C.; Nackley, Andrea G.

    2015-01-01

    Nuclear factor-kappa B (NF-κB) is a ubiquitously expressed protein complex regulating the transcription of genes involved in inflammation and pain. Increased NF-κB activity in immune and nervous system cells is linked to several chronic pain conditions in humans as well as inflammation- and nerve injury-evoked pain in animals. A recent in vitro study further demonstrates that increased NF-κB activity in astrocytes decreases transcription of catechol-o-methyltransferase (COMT), an enzyme that inactivates catecholamines that cause pain. The purpose of the present study was to examine the relationship between systemic and astrocytic NF-κB activity, pain, and COMT expression in an animal model of inflammation. Results demonstrated that administration of the inflammatory stimulant complete Freund’s adjuvant (CFA) led to increased pain and decreased COMT protein expression in an NF-κB-dependent manner. Specifically, we found that rats and mice receiving intraplantar CFA exhibited increased behavioral responses to mechanical and thermal heat stimuli. CFA-evoked pain was blocked in rats receiving a pre-emptive systemic dose of the NF-κB inhibitor MG132 and exacerbated in IKKca mice with constitutive NF-κB activity in astrocytes. Furthermore, we observed NF-κB-linked reductions in COMT expression in midbrain at 6h and 1d following CFA in rats and at 1h and 1d in forebrain and midbrain following CFA in IKKca mice. Collectively, these results demonstrate that systemic and astrocytic NF-κB activity drive inflammatory pain and regulate the expression of COMT in forebrain and midbrain structures. PMID:26187567

  1. A natural model of behavioral depression in postpartum adult female cynomolgus monkeys (Macaca fascicularis)

    PubMed Central

    CHU, Xun-Xun; Rizak, Joshua Dominic; YANG, Shang-Chuan; WANG, Jian-Hong; MA, Yuan-Ye; HU, Xin-Tian

    2014-01-01

    Postpartum depression (PPD) is a modified form of major depressive disorders (MDD) that can exert profound negative effects on both mothers and infants than MDD. Within the postpartum period, both mothers and infants are susceptible; but because PPD typically occurs for short durations and has moderate symptoms, there exists challenges in exploring and addressing the underlying cause of the depression. This fact highlights the need for relevant animal models. In the present study, postpartum adult female cynomolgus monkeys (Macaca fascicularis) living in breeding groups were observed for typical depressive behavior. The huddle posture behavior was utilized as an indicator of behavioral depression postpartum (BDP) as it has been established as the core depressive-like behavior in primates. Monkeys were divided into two groups: A BDP group (n=6), which were found to spend more time huddling over the first two weeks postpartum than other individuals that formed a non-depression control group (n=4). The two groups were then further analyzed for locomotive activity, stressful events, hair cortisol levels and for maternal interactive behaviors. No differences were found between the BDP and control groups in locomotive activity, in the frequencies of stressful events experienced and in hair cortisol levels. These findings suggested that the postpartum depression witnessed in the monkeys was not related to external factors other than puerperium period. Interestingly, the BDP monkeys displayed an abnormal maternal relationship consisting of increased infant grooming. Taken together, these findings suggest that the adult female cynomolgus monkeys provide a natural model of behavioral postpartum depression that holds a number of advantages over commonly used rodent systems in PPD modeling. The cynomolgus monkeys have a highly-organized social hierarchy and reproductive characteristics without seasonal restriction—similar to humans—as well as much greater homology to

  2. A natural model of behavioral depression in postpartum adult female cynomolgus monkeys (Macaca fascicularis).

    PubMed

    Chu, Xun-Xun; Dominic Rizak, Joshua; Yang, Shang-Chuan; Wang, Jian-Hong; Ma, Yuan-Ye; Hu, Xin-Tian

    2014-05-01

    Postpartum depression (PPD) is a modified form of major depressive disorders (MDD) that can exert profound negative effects on both mothers and infants than MDD. Within the postpartum period, both mothers and infants are susceptible; but because PPD typically occurs for short durations and has moderate symptoms, there exists challenges in exploring and addressing the underlying cause of the depression. This fact highlights the need for relevant animal models. In the present study, postpartum adult female cynomolgus monkeys (Macaca fascicularis) living in breeding groups were observed for typical depressive behavior. The huddle posture behavior was utilized as an indicator of behavioral depression postpartum (BDP) as it has been established as the core depressive-like behavior in primates. Monkeys were divided into two groups: A BDP group (n=6), which were found to spend more time huddling over the first two weeks postpartum than other individuals that formed a non-depression control group (n=4). The two groups were then further analyzed for locomotive activity, stressful events, hair cortisol levels and for maternal interactive behaviors. No differences were found between the BDP and control groups in locomotive activity, in the frequencies of stressful events experienced and in hair cortisol levels. These findings suggested that the postpartum depression witnessed in the monkeys was not related to external factors other than puerperium period. Interestingly, the BDP monkeys displayed an abnormal maternal relationship consisting of increased infant grooming. Taken together, these findings suggest that the adult female cynomolgus monkeys provide a natural model of behavioral postpartum depression that holds a number of advantages over commonly used rodent systems in PPD modeling. The cynomolgus monkeys have a highly-organized social hierarchy and reproductive characteristics without seasonal restriction-similar to humans-as well as much greater homology to humans

  3. 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.

  4. 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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  8. Beyond Survival: Curriculum Models for Senior Adult Education.

    ERIC Educational Resources Information Center

    Bramwell, R. D.

    1992-01-01

    Rather than Tyler-style transmission models, process or transaction models are more appropriate for teaching older adults. Whereas Tyler models focus on achieving rigidly defined objectives, process models view education as activities worthwhile in themselves. (SK)

  9. 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

  10. Glucagon-like peptide 1 receptor stimulation reverses key deficits in distinct rodent models of Parkinson's disease

    PubMed Central

    Harkavyi, Alexander; Abuirmeileh, Amjad; Lever, Rebecca; Kingsbury, Ann E; Biggs, Christopher S; Whitton, Peter S

    2008-01-01

    Background It has recently become apparent that neuroinflammation may play a significant role in Parkinson's disease (PD). This is also the case in animal paradigms of the disease. The potential neuroprotective action of the glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 (EX-4), which is protective against cytokine mediated apoptosis and may stimulate neurogenesis, was investigated In paradigms of PD. Methods Two rodent 'models' of PD, 6-hydroxydopamine (6-OHDA) and lipopolysaccaride (LPS), were used to test the effects of EX-4. Rats were then investigated in vivo and ex vivo with a wide range of behavioural, neurochemical and histological tests to measure integrity of the nigrostriatal system. Results EX-4 (0.1 and 0.5 μg/kg) was given seven days after intracerebral toxin injection. Seven days later circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given EX-4 at both doses compared to animals given 6-OHDA/LPS and vehicle. Consistent with these observations, striatal tissue DA concentrations were markedly higher in 6-OHDA/LPS + EX-4 treated rats versus 6-OHDA/LPS + vehicle groups, whilst assay of L-DOPA production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, but this was not the case in rats co-administered EX-4. Furthermore nigral TH staining recorded in 6-OHDA/LPS + vehicle treated animals was markedly lower than in sham-operated or EX-4 treated rats. Finally, EX-4 clearly reversed the loss of extracellular DA in the striata of toxin lesioned freely moving rats. Conclusion The apparent ability of EX-4 to arrest progression of, or even reverse nigral lesions once established, suggests that pharmacological manipulation of the GLP-1 receptor system could have substantial therapeutic utility in PD. Critically, in contrast to other peptide agents that have been demonstrated to possess neuroprotective properties in pre-clinical models of PD, EX-4 is in

  11. 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…

  12. A mechanism-mediated model for carcinogenicity: Model content and prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 25 organic chemicals

    SciTech Connect

    Purdy, R.

    1996-10-01

    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 thiocontaining 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. 12 refs., 3 tabs.

  13. 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

  14. Evidence of Absorptive Function in vivo in a Neo-Formed Bio-Artificial Intestinal Segment Using a Rodent Model.

    PubMed

    Cicalese, Luca; Corsello, Tiziana; Stevenson, Heather L; Damiano, Giuseppe; Tuveri, Massimiliano; Zorzi, Daria; Montalbano, Mauro; Shirafkan, Ali; Rastellini, Cristiana

    2016-01-01

    A promising therapeutic approach for intestinal failure consists in elongating the intestine with a bio-engineered segment of neo-formed autologous intestine. Using an acellular biologic scaffold (ABS), we, and others, have previously developed an autologous bio-artificial intestinal segment (BIS) that is morphologically similar to normal bowel in rodents. This neo-formed BIS is constructed with the intervention of naïve stem cells that repopulate the scaffold in vivo, and over a period of time, are transformed in different cell populations typical of normal intestinal mucosa. However, no studies are available to demonstrate that such BIS possesses functional absorptive characteristics necessary to render this strategy a possible therapeutic application. The aim of this study was to demonstrate that the BIS generated has functional absorptive capacity. Twenty male August × Copenhagen-Irish (ACI) rats were used for the study. Two-centimeter sections of ABS were transplanted in the anti-mesenteric border of the small bowel. Animals were studied at 4, 8, and 12 weeks post-engraftment. Segments of intestine with preserved vascular supply and containing the BIS were isolated and compared to intestinal segments of same length in sham control animals (n = 10). D-Xylose solution was introduced in the lumen of the intestinal segments and after 2 h, urine and blood were collected to evaluate D-Xylose levels. Quantitative analysis was performed using ELISA. Morphologic, ultrastructural, and indirect functional absorption analyses were also performed. We observed neo-formed intestinal tissue with near-normal mucosa post-implantation as expected from our previously developed model. Functional characteristics such as morphologically normal enterocytes (and other cell types) with presence of brush borders and preserved microvilli by electron microscopy, preserved water, and ion transporters/channels (by aquaporin and cystic fibrosis transmembrane conductance regulator

  15. Quality Assurance Model for Digital Adult Education Materials

    ERIC Educational Resources Information Center

    Dimou, Helen; Kameas, Achilles

    2016-01-01

    Purpose: This paper aims to present a model for the quality assurance of digital educational material that is appropriate for adult education. The proposed model adopts the software quality standard ISO/IEC 9126 and takes into account adult learning theories, Bloom's taxonomy of learning objectives and two instructional design models: Kolb's model…

  16. 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

  17. 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

  18. Rodent-borne diseases in Thailand: targeting rodent carriers and risky habitats

    PubMed Central

    Herbreteau, Vincent; Bordes, Frédéric; Jittapalapong, Sathaporn; Supputamongkol, Yupin; Morand, Serge

    2012-01-01

    Background Comparative analysis, which aims at investigating ecological and evolutionary patterns among species, may help at targeting reservoirs of zoonotic diseases particularly in countries presenting high biodiversity. Here, we developed a simple method to target rodent reservoirs using published studies screening microparasite infections. Methods We compiled surveys of microparasites investigated in rodents trapped in Thailand. The data comprise a total of 17,358 rodents from 18 species that have been investigated for a total of 10 microparasites (viruses, bacteria and protozoans). We used residual variation of microparasite richness controlled for both rodent sample size and pathogens’ screening effort to identify major rodent reservoirs and potential risky habitats. Results Microparasite species richness was positively related to rodent sample size and pathogens’ screening effort. The investigation of the residual variations of microparasite species richness showed that several rodent species harboured more pathogens than expected by the regression model. Similarly, higher pathogen richness than expected was observed in rodents living in non-flooded lands, forests and paddy fields. Conclusion Our results suggest to target some rodent species that are not commonly investigated for pathogen screening or surveillance such as R. adamanensis or B. savilei, and that non-flooded lands and forests should be more taken into caution, whereas much surveys focused on paddy rice fields and households. PMID:22957129

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

    PubMed

    Dalle Molle, R; Portella, A K; Goldani, M Z; Kapczinski, F P; Leistner-Segal, S; 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.

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

    PubMed

    Dalle Molle, R; Portella, A K; Goldani, M Z; Kapczinski, F P; Leistner-Segal, S; 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. 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

  2. A MATHEMATICAL MODEL FOR THE ANDROGENIC REGULATION OF THE PROSTATE IN INTACT AND CASTRATE ADULT MALE RATS

    EPA Science Inventory

    An abstract that provides understanding for a mathematical model by Barton and Anderson, for the dynamics of androgenic synthesis, transport, metabolism, and regulation of the rodent ventral prostate.

  3. Chronic infection of rodents by Machupo virus.

    PubMed

    Johnson, K M; Mackenzie, R B; Webb, P A; Kuns, M L

    1965-12-17

    Machupo virus, the etiologic agent of human hemorrhagic fever in Bolivia, induced chronic asymptomatic infection in laboratory hamsters and colonized individuals of the peridomestic, wild, South American rodent, Calomys callosus. Viruria was detected for more than 500 and 150 days, respectively, in the two species. Chronic viremia was shown only for Calomys. Virus-neutralizing substances were present in parenterally infected adult animals, but not in animals born to, and in contact with, an infected female. Chronic infection in wild rodents may be an important mechanism in the natural history of Machupo and related virus infections.

  4. The generation of C-3α epimer of 25-hydroxyvitamin D and its biological effects on bone mineral density in adult rodents.

    PubMed

    Bianchini, Christina; Lavery, Paula; Agellon, Sherry; Weiler, Hope A

    2015-05-01

    The source and function of C-3α epimer of 25(OH)D (C-3 epimer) is unknown. The objectives were to (1) establish if increasing doses of vitamin D (VD) results in a proportionate dose-response in C-3 epimer; and (2) determine the biological response of bone to C-3 epimer treatment. Sprague Dawley rats (12 weeks, n = 36 female, n = 36 male) were randomized to control AIN93-M diet (1 IU VD3/g diet) or an experimental diet for 8 weeks containing VD3 at 2 or 4 IU/g diet, C-3 epimer at 0.5 or 1 IU/g diet or 25(OH)D (0.5 IU/g diet). BW and food consumption were measured weekly. Blood was sampled at week 0, 4, and 8 for assessment of VD metabolites and bone metabolism biomarkers. DXA (week 0, 4, and 8) and in vivo micro CT (μCT) (week 0 and 8) were performed in vivo plus ex vivo μCT imaging and bone biomechanics. Dietary intake and anthropometry did not differ among diet groups. The dose-response of VD generated significantly elevated C-3 epimer only in females with concentrations of 4 IU VD diet group [mean 84.6 (62.5) nmol/L] exceeding control [mean 21.4 (18.5) nmol/L, p = 0.005]. Both sexes in the 25(OH)D group did not show significant increases in C-3 epimer, whereas 0.5 and 1 IU epimer groups exceeded 100 nmol/L of C-3 epimer by 8 weeks. These data suggest C-3 epimer is endogenously generated with higher intakes of VD. Endogenous and exogenous C-3 epimer accumulates in serum without impact upon bone health outcomes in a healthy young adult model over 8 weeks.

  5. Seasonal variation in telomere length of a hibernating rodent.

    PubMed

    Turbill, Christopher; Ruf, Thomas; Smith, Steve; Bieber, Claudia

    2013-04-23

    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

  6. 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

  7. 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.

  8. 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

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

    PubMed

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

    2016-03-01

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

  10. Altered adult hippocampal neuronal maturation in a rat model of fetal alcohol syndrome.

    PubMed

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

    2011-04-12

    Exposure to ethanol during pregnancy can be devastating to the developing nervous system, leading to significant central nervous system dysfunction. The hippocampus, one of the two brain regions where neurogenesis persists into adulthood, is particularly sensitive to the teratogenic effects of ethanol. In the present study, we tested a rat model of fetal alcohol syndrome (FAS) with ethanol administered via gavage throughout all three trimester equivalents. Subsequently, we assessed cell proliferation, as well as neuronal survival, and differentiation in the dentate gyrus of the hippocampus of adolescent (35 days old), young adult (60 days old) and adult (90 days old) Sprague-Dawley rats. Using both extrinsic (bromodeoxyuridine) and intrinsic (Ki-67) markers, we observed no significant alterations in cell proliferation and survival in ethanol-exposed animals when compared with their pair-fed and ad libitum controls. However, we detected a significant increase in the number of new immature neurons in animals that were exposed to ethanol throughout all three trimester equivalents. This result might reflect a compensatory mechanism to counteract the deleterious effects of prenatal ethanol exposure or an ethanol-induced arrest of the neurogenic process at the early neuronal maturation stages. Taken together these results indicate that exposure to ethanol during the period of brain development causes a long-lasting dysregulation of the neurogenic process, a mechanism that might contribute, at least in part, to the hippocampal deficits that have been reported in rodent models of FAS.

  11. Effect of pre- and postnatal manganese exposure on brain histamine content in a rodent model of Parkinson's disease.

    PubMed

    Brus, Ryszard; Jochem, Jerzy; Nowak, Przemysław; Adwent, Marta; Boroń, Dariusz; Brus, Halina; Kostrzewa, Richard M

    2012-02-01

    Rats lesioned shortly after birth with 6-hydroxydopamine (6-OHDA; 134 μg icv) represent a near-ideal model of severe Parkinson's disease because of the near-total destruction of nigrostriatal dopaminergic fibers. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. The element manganese, an essential cofactor for many enzymatic reactions, itself in toxic amount, replicates some clinical features similar to those of Parkinson's disease. The aim of this study was to examine the effect of neonatal manganese exposure on 6-OHDA modeling of Parkinson's disease in rats, and to determine effects on histamine content in the brain of these rats in adulthood. Manganese (MnCl₂·4H₂O; 10,000 ppm) was included in the drinking water of pregnant Wistar rats from the time of conception until the 21st day after delivery, the age when neonatal rats were weaned. Control rats consumed tap water. Other groups of neonatal rat pups, on the 3rd day after birth, were pretreated with desipramine (20 mg/kg ip 1 h) prior to bilateral icv administration of 6-OHDA (60 or 134 μg) or its vehicle saline-ascorbic (0.1%) (control). At 2 months after birth, in rats lesioned with 60 or 134 μg 6-OHDA, endogenous striatal dopamine (DA) content was reduced, respectively, by 92 and 98% (HPLC/ED), while co-exposure of these groups to perinatal manganese did not magnify the DA depletion. However, there was prominent enhancement of histamine content in frontal cortex, hippocampus, hypothalamus, and medulla oblongata of adult rat brain after 6-OHDA (60 and 134 μg) injection on the day 3rd postnatal day. These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that manganese enhances effects of 6-OHDA on histamine in brain. PMID:21822760

  12. 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.

  13. 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

  14. Transplantation of GABAergic cells derived from bioreactor-expanded human neural precursor cells restores motor and cognitive behavioral deficits in a rodent model of Huntington's disease.

    PubMed

    McLeod, Marcus C; Kobayashi, Nao R; Sen, Arindom; Baghbaderani, Behnam A; Sadi, Damaso; Ulalia, Ruperto; Behie, Leo A; Mendez, Ivar

    2013-01-01

    Huntington's disease (HD) is a neurodegenerative disorder that is characterized by progressive dementia, choreiform involuntary movements, and emotional deterioration. Neuropathological features include the progressive degeneration of striatal γ-aminobutyric acid (GABA) neurons. New therapeutic approaches, such as the transplantation of human neural precursor cells (hNPCs) to replace damaged or degenerated cells, are currently being investigated. The aim of this study was to investigate the potential for utilizing telencephalic hNPCs expanded in suspension bioreactors for cell restorative therapy in a rodent model of HD. hNPCs were expanded in a hydrodynamically controlled and homogeneous environment under serum-free conditions. In vitro analysis revealed that the bioreactor-expanded telencephalic (BET)-hNPCs could be differentiated into a highly enriched population of GABAergic neurons. Behavioral assessments of unilateral striatal quinolinic acid-lesioned rodents revealed a significant improvement in motor and memory deficits following transplantation with GABAergic cells differentiated from BET-hNPCs. Immunohistochemical analysis revealed that transplanted BET-hNPCs retained a GABAergic neuronal phenotype without aberrant transdifferentiation or tumor formation, indicating that BET-hNPCs are a safe source of cells for transplantation. This preclinical study has important implications as the transplantation of GABAergic cells derived from predifferentiated BET-hNPCs may be a safe and feasible cell replacement strategy to promote behavioral recovery in HD.

  15. 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…

  16. 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…

  17. 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…

  18. 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

  19. The largest fossil rodent

    PubMed Central

    Rinderknecht, Andrés; Blanco, R. Ernesto

    2008-01-01

    The discovery of an exceptionally well-preserved skull permits the description of the new South American fossil species of the rodent, Josephoartigasia monesi sp. nov. (family: Dinomyidae; Rodentia: Hystricognathi: Caviomorpha). This species with estimated body mass of nearly 1000 kg is the largest yet recorded. The skull sheds new light on the anatomy of the extinct giant rodents of the Dinomyidae, which are known mostly from isolated teeth and incomplete mandible remains. The fossil derives from San José Formation, Uruguay, usually assigned to the Pliocene–Pleistocene (4–2 Myr ago), and the proposed palaeoenvironment where this rodent lived was characterized as an estuarine or deltaic system with forest communities. PMID:18198140

  20. Common rodent procedures.

    PubMed

    Klaphake, Eric

    2006-05-01

    Rodents are commonly owned exotic animal pets that may be seen by veterinary practitioners. Although most owners presenting their animals do care about their pets, they may not be aware of the diagnostic possibilities and challenges that can be offered by rodents to the veterinarian. Understanding clinical anatomy, proper hand-ling technique, realistic management of emergency presentations,correct and feasible diagnostic sampling, anesthesia, and humane euthanasia procedures is important to enhancing the doctor-client-patient relationship, especially when financial constraints may be imposed by the owner. PMID:16759953

  1. Therapeutic efficacy of poly (lactic-co-glycolic acid) nanoparticles encapsulated ivermectin (nano-ivermectin) against brugian filariasis in experimental rodent model.

    PubMed

    Ali, Mohammad; Afzal, Mohammad; Verma, Meenakshi; Bhattacharya, Shailja Misra; Ahmad, F J; Samim, Mohammad; Abidin, M Z; Dinda, A K

    2014-02-01

    The present study reports on the antifilarial activity of poly (lactic-co-glycolic acid) nanoparticles encapsulated ivermectin (nano-IVM) against human lymphatic filariid Brugia malayi in rodent host Mastomys coucha. Nano-IVM was prepared and optimized by nanoprecipitation method. The selected nano-IVM (F5) showed a uniform spherical shape with 96 nm diameter and 74.12 % entrapment efficiency, and when used at a suboptimal dose of 100 μg/kg body weight, completely eliminated filarial parasites from systemic circulation on 60 days post-infection in animals inflicted with B. malayi. In contrast, the coadministration of nano-IVM (F5) along with standard filaricide diethylcarbamazine (DEC) was found to be competent enough to suppress microfilarial stage of parasites and successfully eliminated microfilaria at 45 days posttreatment. However, the free form of both the drugs alone or in combination was unable to impart such suppression and followed by recurrence of the infection. Interestingly, nano-IVM (F5) was also found to be effective against adult stage parasites causing 36.67 % worm mortality and 75.89 % in combination with DEC; however, female sterilization remain almost similar. Thus, the combination of entrapped IVM with DEC exhibited enhanced microfilaricidal and marginally better macrofilaricidal efficacy than any of the single formulation or drugs combination.

  2. 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.

  3. 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

  4. 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

  5. Evidence for pyronaridine as a highly effective partner drug for treatment of artemisinin-resistant malaria in a rodent model.

    PubMed

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

    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.

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. Xenogeneic transfer of fetal liver and adult bone marrow-derived haemopoietic cells in rodents: changes in spleen colony differentials with increased doses of cells.

    PubMed

    Gulya, E; Gábor Szabó, L; Kelemen, E

    1997-01-01

    The effect of very high haemopoietic cell doses were investigated on the composition of splenic cell colonies/clusters in irradiated animals under xenogeneic circumstances. Differential cluster/colony counts from serial histological sections of the spleen were investigated before, and 9-12 days after transplantation of fetal liver- or adult bone marrow-derived haemopoietic cells following 5.0 to 8.5 Gy total body irradiation. Syngeneic as well as xenogeneic (mouse to rat and rat to mouse) transplantations were carried out. Cluster/colony differentials changed with the increase of the injected cell mass from 10(5) to 10(6) and 10(7) or more, i.e. the overwhelming erythroid pattern became trilinear even with xenogeneic transplants.

  12. 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…

  13. 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)

  14. Activity of and effect of subcutaneous treatment with the broad-spectrum antiviral lectin griffithsin in two laboratory rodent models.

    PubMed

    Barton, Christopher; Kouokam, J Calvin; Lasnik, Amanda B; Foreman, Oded; Cambon, Alexander; Brock, Guy; Montefiori, David C; Vojdani, Fakhrieh; McCormick, Alison A; O'Keefe, Barry R; Palmer, Kenneth E

    2014-01-01

    Griffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections. PMID:24145548

  15. Developmental regulation of group I metabotropic glutamate receptors in the premature brain and their protective role in a rodent model of periventricular leukomalacia.

    PubMed

    Jantzie, Lauren L; Talos, Delia M; Selip, Debra B; An, Li; Jackson, Michele C; Folkerth, Rebecca D; Deng, Wenbin; Jensen, Frances E

    2010-11-01

    Cerebral white matter injury in premature infants, known as periventricular leukomalacia (PVL), is common after hypoxia-ischemia (HI). While ionotropic glutamate receptors (iGluRs) can mediate immature white matter injury, we have previously shown that excitotoxic injury to premyelinating oligodendrocytes (preOLs) in vitro can be attenuated by group I metabotropic glutamate receptor (mGluR) agonists. Thus, we evaluated mGluR expression in developing white matter in rat and human brain, and tested the protective efficacy of a central nervous system (CNS)-penetrating mGluR agonist on injury to developing oligodendrocytes (OLs) in vivo. Group I mGluRs (mGluR1 and mGluR5) were strongly expressed on OLs in neonatal rodent cerebral white matter throughout normal development, with highest expression early in development on preOLs. Specifically at P6, mGluR1 and mGLuR5 were most highly expressed on GalC-positive OLs compared to neurons, axons, astrocytes and microglia. Systemic administration of (1S,3R) 1-aminocyclopentane-trans-1,3,-dicarboxylic acid (ACPD) significantly attenuated the loss of myelin basic protein in the white matter following HI in P6 rats. Assessment of postmortem human tissue showed both mGluR1 and mGluR5 localized on immature OLs in white matter throughout development, with mGluR5 highest in the preterm period. These data indicate group I mGluRs are highly expressed on OLs during the peak period of vulnerability to HI and modulation of mGluRs is protective in a rodent model of PVL. Group I mGluRs may represent important therapeutic targets for protection from HI-mediated white matter injury.

  16. 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.

  17. The Adults and Older Adults Functional Assessment Inventory: A Rasch Model Analysis.

    PubMed

    Sousa, Liliana B; Prieto, Gerardo; Vilar, Manuela; Firmino, Horácio; Simões, Mário R

    2015-11-01

    Functional assessment methods are an important element in multidimensional neuropsychological evaluations, particularly in older adults. The Adults and Older Adults Functional Assessment Inventory is a new measure of basic and instrumental activities of daily living. Rasch model analyses were used to analyze the psychometric characteristics of the instrument in a sample of 803 participants. The original categories did not provide an optimal assessment of functional incapacity. The scale was dichotomized to achieve a better reliability score and item fit. The final 50 items revealed a moderately high variability in item difficulty, acceptable fits to items and persons, and a good Person Separation Reliability score. The scores were able to discriminate between normal controls and clinical patients. None of the items showed Differential Item Functioning associated with age, gender, or education. The instrument is able to achieve measures of functional incapacity with the useful properties of the Rasch model.

  18. The Adults and Older Adults Functional Assessment Inventory: A Rasch Model Analysis.

    PubMed

    Sousa, Liliana B; Prieto, Gerardo; Vilar, Manuela; Firmino, Horácio; Simões, Mário R

    2015-11-01

    Functional assessment methods are an important element in multidimensional neuropsychological evaluations, particularly in older adults. The Adults and Older Adults Functional Assessment Inventory is a new measure of basic and instrumental activities of daily living. Rasch model analyses were used to analyze the psychometric characteristics of the instrument in a sample of 803 participants. The original categories did not provide an optimal assessment of functional incapacity. The scale was dichotomized to achieve a better reliability score and item fit. The final 50 items revealed a moderately high variability in item difficulty, acceptable fits to items and persons, and a good Person Separation Reliability score. The scores were able to discriminate between normal controls and clinical patients. None of the items showed Differential Item Functioning associated with age, gender, or education. The instrument is able to achieve measures of functional incapacity with the useful properties of the Rasch model. PMID:25651593

  19. 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

  20. 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…

  1. 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...

  2. Immunotoxicity risks associated with land-treatment of petrochemical wastes revealed using an in situ rodent model.

    PubMed

    Rafferty, D P; Lochmiller, R L; McBee, K; Qualls, C W; Basta, N T

    2001-01-01

    Land-treatment of petrochemical wastes is a widely used method to dispose of hazardous and non-hazardous waste by biodegradation. However, no comprehensive assessment of the impact of such disposal techniques on terrestrial ecosystems has been conducted. Despite the presence of suspected immunotoxicants in the soil, wild rodents frequently reside on these waste sites after closure or abandonment. We explored the seasonal sensitivity of the immune system of the hispid cotton rat (Sigmodon hispidus) to in situ exposures on sites land-treated with petrochemical wastes. Animals were monitored on five contaminated land-treatment sites and five ecologically matched-reference sites in Oklahoma, USA, over two seasons (summer and winter). Most hematological parameters were not adversely affected by land-treatment; however, platelet counts were 26% greater in cotton rats from land-treatment sites compared to reference sites in winter. Significant treatment-related differences were observed in total serum protein concentrations, organ mass and organ cellularity, but these differences were not consistent across the five land-treatment units. Lymphoproliferative responses of cotton rat splenocytes stimulated in vitro were elevated for a T-cell mitogen and depressed for a B-cell mitogen in animals from land-treatment compared to reference sites. The ability of splenocytes to proliferate in response to interleukin-2 receptor-binding was not influenced by treatment. Total yields of peritoneal cells, yield of peritoneal macrophages, and yield of peritoneal lymphocytes were influenced to varying degrees by land-treatment. Functionally, in vitro metabolic activity of peritoneal macrophages was 114% greater in cotton rats from land-treatment sites compared to reference sites during summer. These results indicate that petrochemical wastes applied to soils on these five land-treatment sites had variable immunomodulatory effects in resident cotton rats. Immune alterations for some assays

  3. 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

  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. 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".

  6. The Healthy Ageing Model: health behaviour change for older adults.

    PubMed

    Potempa, Kathleen M; Butterworth, Susan W; Flaherty-Robb, Marna K; Gaynor, William L

    2010-01-01

    Proposed is a model of primary care for older adults with chronic health conditions that focuses on active engagement in health care. The Healthy Ageing Model is anchored in established theory on motivation and health behaviour change. The model draws on empirical and applied clinical underpinnings in such diverse areas as health promotion and education, treatment of addictions or obesity, management of chronic diseases, goal-setting, and coaching techniques. The conceptual foundation for the Healthy Ageing Model is described first, followed by a brief description of the key characteristics of the model. In conclusion, suggestions are offered for the clinical application and for further developing the model.

  7. 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

  8. 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

  9. 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.

  10. 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

  11. Role modeling clinical judgment for an unfolding older adult simulation.

    PubMed

    Lasater, Kathie; Johnson, Elizabeth A; Ravert, Patricia; Rink, Doris

    2014-05-01

    Nurse educators must foster development of clinical judgment in students to help them provide the best care for the increasing population of older adult patients. This article reports qualitative findings from a mixed-methods study that focused on clinical judgment in the simulated perioperative care of an older adult. The sample was composed of treatment and control groups of prelicensure students (N = 275) at five sites. The treatment group watched a video of an expert nurse role model caring for a patient similar to the simulation patient, whereas the control group did not watch the video. Four weeks after simulation, participants cared for real-life, older adult perioperative patients. After the simulated and real-life care experiences, participants completed questionnaires related to clinical judgment dimensions. These two data sets revealed rich findings about the students' simulation learning, affirming the value of expert role models. Transferability of simulation learning to practice was also explored. PMID:24716674

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. 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…

  17. 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

  18. Individual differences in the effects of prenatal stress exposure in rodents

    PubMed Central

    Boersma, Gretha J.; Tamashiro, Kellie L.

    2014-01-01

    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. Geomagnetic field detection in rodents

    SciTech Connect

    Olcese, J.; Reuss, S.; Semm, P.

    1988-01-01

    In addition to behavioral evidence for the detection of earth-strength magnetic fields (MF) by rodents, recent investigations have revealed that electrophysiological and biochemical responses to MF occur in the pineal organ and retina of rodents. In addition, ferrimagnetic deposits have been identified in the ethmoidal regions of the rodent skull. These findings point to a new sensory phenomenon, which interfaces with many fields of biology, including neuroscience, psychophysics, behavioral ecology, chronobiology and sensory physiology.

  20. 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

  1. 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

  2. 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.

  3. 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

  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.

  5. 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.

  6. 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

  7. 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

  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. 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

  10. 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

  11. 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

  12. Environmental enrichment for laboratory rodents.

    PubMed

    Hutchinson, Eric; Avery, Anne; Vandewoude, Sue

    2005-01-01

    Modernization of housing and husbandry techniques for rodents has minimized confounding variables. The result has been vastly improved health maintenance and reproducibility of research findings, advances that have decreased the numbers of animals needed to attain statistically significant results. Even though not all aspects of rodent manipulation have been strictly defined, as housing and handling procedures have become increasingly standardized, many animal care personnel have recognized the lack of complexity of the rodents' environment. Concern for this aspect of animal well-being has led many research facilities to provide "environmental enrichment" for rodents. Additionally, regulatory agencies in the United States and Europe have also been increasingly concerned about this issue relative to laboratory animal husbandry. However, little is known about the influence such husbandry modifications may have on biological parameters. In this article, laws and guidelines relating to rodent enrichment are reviewed, the natural behaviors of select rodent species are discussed, and an overview of widely used types of enrichment in laboratory rodent management is provided. The literature evaluating effects of rodent enrichment is reviewed both in terms of neurological development and as an experimental variable, and results of a study evaluating the effect of enrichment on immune and physiological parameters are reported. Survey data on current enrichment practices in a large multi-institutional organization are presented, and practical aspects requiring consideration when devising a rodent enrichment program are discussed.

  13. 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

  14. 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

  15. 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

  16. 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.

  17. 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

  18. 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

  19. Comparative evaluation of forced swim test and tail suspension test as models of negative symptom of schizophrenia in rodents.

    PubMed

    Chatterjee, Manavi; Jaiswal, Manoj; Palit, Gautam

    2012-01-01

    Previous studies have shown that the administration of NMDA antagonist can induce negative symptoms of schizophrenia which can be tested through the enhanced immobility observed in the forced swim test (FST). In the present study, we have compared the effects of acute as well as chronic administration of a noncompetitive NMDA receptor antagonist, ketamine on FST, and another behaviour despair model, tail suspension test (TST). Our observations suggest that chronic ketamine administration induced a state of enhanced immobility in FST, but such findings were not replicated in the TST model. Further, in FST, treatment with clozapine reverses the ketamine-induced immobility in mice, whereas it enhances the immobility duration in the TST model. However, haloperidol showed no protective effects in both models. The data suggests that although both of these tests show common behavioural measure of feeling despair, however, the underlying pathophysiology seems to be different. Hence, forced swim test but not tail suspension test can be used as a model of negative symptom of psychosis in mice.

  20. 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.

  1. 1-[2-(4-Benzyloxyphenoxy)Ethyl]Imidazole inhibits monoamine oxidase B and protects against neuronal loss and behavioral impairment in rodent models of Parkinson's disease.

    PubMed

    Chung, Jin Yong; Lee, Ji Won; Ryu, Choon Ho; Min, Hye Kyung; Yoon, Yeo Jin; Lim, Mi Jung; Park, Cheol Hyoung

    2015-08-01

    Monoamine oxidase B (MAO-B) is well known as a therapeutic target for Parkinson's disease (PD). MAO-B inhibitors retain antiparkinsonism abilities to improve motor function and prevent neuronal loss by decreasing dopamine metabolism and oxidative stress in the brain. From the study to find novel antiparkinsonism drugs that can inhibit MAO-B activity, neuronal loss, and behavioral deficits in the mouse model of PD, we identified that 1-[2-(4-benzyloxyphenoxy)ethyl]imidazole (BPEI) or safinamide strongly and selectively inhibited MAO-B activities in a dose-dependent manner (IC50 of BPEI and safinamide for MAO-B were 0.016 and 0.0021 µM and for MAO-A were 70.0 and 370 µM, respectively). In ex vivo studies after an administration (30 mg/kg, i.p.) of BPEI or safinamide to normal mice, the MAO-B activity in the brain was reduced by up to 90.6% or 82.4% at 1.0 hr. BPEI (20 mg/kg, i.p.) or safinamide (20 mg/kg, i.p.) significantly reversed the behavioral impairments, dopamine levels in the striatum, and neuronal loss in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice compared with the MPTP-alone-treated group. In the 6-hydroxydopamine-induced PD rat model, behavioral improvement by levodopa sparing activity was observed in the BPEI- or safinamide-treated (20 mg/kg, i.p.) rats. Moreover, BPEI revealed additional curative activities for nonmotor symptoms of PD such as pain, anxiety, epilepsy, and depression in rodent disease models. Therefore, BPEI has broad therapeutic potential for treating motor symptoms via strong and selective inhibitory effects on MAO-B, with additional benefits for comorbid symptoms in PD.

  2. 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.

  3. Rodent carcinogens: Setting priorities

    SciTech Connect

    Gold, L.S.; Slone, T.H.; Stern, B.R.; Manley, N.B.; Ames, B.N. )

    1992-10-09

    The human diet contains an enormous background of natural chemicals, such as plant pesticides and the products of cooking, that have not been a focus of carcinogenicity testing. A broadened perspective that includes these natural chemicals is necessary. A comparison of possible hazards for 80 daily exposures to rodent carcinogens from a variety of sources is presented, using an index (HERP) that relates human exposure to carcinogenic potency in rodents. A similar ordering would be expected with the use of standard risk assessment methodology for the same human exposure values. Results indicate that, when viewed against the large background of naturally occurring carcinogens in typical portions of common foods, the residues of synthetic pesticides or environmental pollutants rank low. A similar result is obtained in a separate comparison of 32 average daily exposures to natural pesticides and synthetic pesticides residues in the diet. Although the findings do not indicate that these natural dietary carcinogens are important in human cancer, they cast doubt on the relative importance for human cancer of low-dose exposures to synthetic chemicals.

  4. 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.

  5. 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

  6. 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…

  7. 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

  8. Antinociceptive effects of the selective CB2 agonist MT178 in inflammatory and chronic rodent pain models.

    PubMed

    Vincenzi, Fabrizio; Targa, Martina; Corciulo, Carmen; Tabrizi, Mojgan Aghazadeh; Merighi, Stefania; Gessi, Stefania; Saponaro, Giulia; Baraldi, Pier Giovanni; Borea, Pier Andrea; Varani, Katia

    2013-06-01

    Cannabinoid CB(2) receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory, neuropathic, and bone cancer pain. In this study the effect of a novel CB(2)agonist (MT178) was evaluated in different animal models of pain. First of all, in vitro competition binding experiments performed on rat, mouse, or human CB receptors revealed a high affinity, selectivity, and potency of MT178. The analgesic properties of the novel CB(2) agonist were evaluated in various in vivo experiments, such as writhing and formalin assays, showing a good efficacy comparable with that produced by the nonselective CB agonist WIN 55,212-2. A dose-dependent antiallodynic effect of the novel CB(2) compound in the streptozotocin-induced diabetic neuropathy was found. In a bone cancer pain model and in the acid-induced muscle pain model, MT178 was able to significantly reduce mechanical hyperalgesia in a dose-related manner. Notably, MT178 failed to provoke locomotor disturbance and catalepsy, which were observed following the administration of WIN 55,212-2. CB(2) receptor mechanism of action was investigated in dorsal root ganglia where MT178 mediated a reduction of [(3)H]-d-aspartate release. MT178 was also able to inhibit capsaicin-induced substance P release and NF-κB activation. These results demonstrate that systemic administration of MT178 produced a robust analgesia in different pain models via CB(2) receptors, providing an interesting approach to analgesic therapy in inflammatory and chronic pain without CB(1)-mediated central side effects.

  9. Alleviation of thermoregulatory dysfunction with the new serotonin and norepinephrine reuptake inhibitor desvenlafaxine succinate in ovariectomized rodent models.

    PubMed

    Deecher, Darlene C; Alfinito, Peter D; Leventhal, Liza; Cosmi, Scott; Johnston, Grace H; Merchenthaler, Istvan; Winneker, Richard

    2007-03-01

    Hot flushes and night sweats, referred to as vasomotor symptoms (VMS), are presumed to be a result of declining hormone levels and are the principal menopausal symptoms for which women seek medical treatment. To date, estrogens and/or some progestins are the most effective therapeutics for alleviating VMS; however, these therapies may not be appropriate for all women. Therefore, nonhormonal therapies are being evaluated. The present study investigated a new reuptake inhibitor, desvenlafaxine succinate (DVS), in animal models of temperature dysfunction. Both models used are based on measuring changes in tail-skin temperature (TST) in ovariectomized (OVX) rats. The first relies on naloxone-induced withdrawal in morphine-dependent (MD) OVX rats, resulting in an acute rise in TST. The second depends on an OVX-induced loss of TST decreases during the dark phase as measured by telemetry. An initial evaluation demonstrated abatement of the rise in TST with long-term administration of ethinyl estradiol or with a single oral dose of DVS (130 mg/kg) in the MD model. Further evaluation showed that orally administered DVS acutely and dose dependently (10-100 mg/kg) abated a naloxone-induced rise in TST of MD rats and alleviated OVX-induced temperature dysfunction in the telemetry model. Oral administration of DVS to OVX rats caused significant increases in serotonin and norepinephrine levels in the preoptic area of the hypothalamus, a key region of the brain involved in temperature regulation. These preclinical studies provide evidence that DVS directly impacts thermoregulatory dysfunction in OVX rats and may have utility in alleviating VMS associated with menopause.

  10. A Rodent Model of Chikungunya Virus Infection in RAG1 -/- Mice, with Features of Persistence, for Vaccine Safety Evaluation.

    PubMed

    Seymour, Robert L; Adams, A Paige; Leal, Grace; Alcorn, Maria D H; Weaver, Scott C

    2015-01-01

    Chikungunya virus (CHIKV) is a positive sense, single stranded RNA virus in the genus Alphavirus, and the etiologic agent of epidemics of severe arthralgia in Africa, Asia, Europe and, most recently, the Americas. CHIKV causes chikungunya fever (CHIK), a syndrome characterized by rash, fever, and debilitating, often chronic arthritis. In recent outbreaks, CHIKV has been recognized to manifest more neurologic signs of illness in the elderly and those with co-morbidities. The syndrome caused by CHIKV is often self-limited; however, many patients develop persistent arthralgia that can last for months or years. These characteristics make CHIKV not only important from a human health standpoint, but also from an economic standpoint. Despite its importance as a reemerging disease, there is no licensed vaccine or specific treatment to prevent CHIK. Many studies have begun to elucidate the pathogenesis of CHIKF and the mechanism of persistent arthralgia, including the role of the adaptive immune response, which is still poorly understood. In addition, the lack of an animal model for chronic infection has limited studies of CHIKV pathogenesis as well as the ability to assess the safety of vaccine candidates currently under development. To address this deficiency, we used recombination activating gene 1 (RAG1-/-) knockout mice, which are deficient in both T and B lymphocytes, to develop a chronic CHIKV infection model. Here, we describe this model as well as its use in evaluating the safety of a live-attenuated vaccine candidate.

  11. DHA effect on chemotherapy-induced body weight loss: an exploratory study in a rodent model of mammary tumors.

    PubMed

    Hajjaji, Nawale; Couet, Charles; Besson, Pierre; Bougnoux, Philippe

    2012-01-01

    Body weight loss during the course of cancer disease has been associated with poor prognosis. Beside cancer-associated cachexia, weight loss can also result from chemotherapy. This work explored whether a model of mammary tumors in female Sprague Dawley rats could be appropriate to study the effect of doxorubicin on body weight, described weight change in this model, and assessed the effect of DHA on weight during chemotherapy. After tumor induction, rats were randomly assigned to a control or a DHA-enriched diet, and treated with doxorubicin or placebo twice a week for 2.5 wk (n = 6 in each group). Body weight, food intake, and tumor growth were monitored. Neither the induction of tumors nor their initial development impaired body weight gain. No reduction in food intake was observed. Tumor growth was similar between groups from day 1 to day 11. Although doxorubicin induced body weight loss from day 4 compared to placebo (P< 0.01) in rats fed the control diet, it did not induce body weight loss in rats fed the DHA-enriched diet (P = 0.02), indicating that DHA had a protective effect. These results indicate that doxorubicin can induce body weight loss in this model and that a DHA-enriched diet can prevent this effect.

  12. A PPAR-β/δ agonist is neuroprotective and decreases cognitive impairment in a rodent model of Parkinson's disease.

    PubMed

    Das, Nihar R; Gangwal, Rahul P; Damre, Mangesh V; Sangamwar, Abhay T; Sharma, Shyam S

    2014-05-01

    Parkinson's disease (PD) is associated with higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of GW0742, a PPAR-β/δ agonist in rat model of cognitive impairment associated with PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) (100 µg/1 µl/side) produced significant cognitive dysfunctions. PPAR-β/δ agonist GW0742 at a dose of 30 and 100 µg/kg showed significant improvement in cognitive impairments caused by MPTP in rat model of PD as evident from passive avoidance and Morris water maze test. MPTP-induced massive oxidative damage and DNA fragmentation was ameliorated by GW0742 treatment as observed after MDA and GSH estimation and TUNEL assay. Tyrosine hydroxylase positive neurons were decreased by 25% of normal control in MPTP group and GW0742 treatment restored tyrosine hydroxylase levels showing neuroprotective nature. Further, we performed physiologically based pharmacokinetic (PBPK) modeling study using GastroPlus to characterize the kinetics of GW0742 in the brain. The predicted amounts of GW0742 in brain suggest that it has the ability to cross the blood brain barrier. This study implicates the involvement of PPAR-β/δ in PD induced cognitive impairment. PMID:24635117

  13. A PPAR-β/δ agonist is neuroprotective and decreases cognitive impairment in a rodent model of Parkinson's disease.

    PubMed

    Das, Nihar R; Gangwal, Rahul P; Damre, Mangesh V; Sangamwar, Abhay T; Sharma, Shyam S

    2014-05-01

    Parkinson's disease (PD) is associated with higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of GW0742, a PPAR-β/δ agonist in rat model of cognitive impairment associated with PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) (100 µg/1 µl/side) produced significant cognitive dysfunctions. PPAR-β/δ agonist GW0742 at a dose of 30 and 100 µg/kg showed significant improvement in cognitive impairments caused by MPTP in rat model of PD as evident from passive avoidance and Morris water maze test. MPTP-induced massive oxidative damage and DNA fragmentation was ameliorated by GW0742 treatment as observed after MDA and GSH estimation and TUNEL assay. Tyrosine hydroxylase positive neurons were decreased by 25% of normal control in MPTP group and GW0742 treatment restored tyrosine hydroxylase levels showing neuroprotective nature. Further, we performed physiologically based pharmacokinetic (PBPK) modeling study using GastroPlus to characterize the kinetics of GW0742 in the brain. The predicted amounts of GW0742 in brain suggest that it has the ability to cross the blood brain barrier. This study implicates the involvement of PPAR-β/δ in PD induced cognitive impairment.

  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. 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

  16. 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

  17. Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study.

    PubMed

    Perlis, Roy H; Moorjani, Priya; Fagerness, Jesen; Purcell, Shaun; Trivedi, Madhukar H; Fava, Maurizio; Rush, A John; Smoller, Jordan W

    2008-11-01

    Recent rodent models of antidepressant response implicate a novel set of genes in mechanisms of antidepressant action. The authors examined variants in four such genes (KCNK2 (TREK1), SLC18A2 (VMAT2), S100A10, and HDAC5) for association with remission in a large effectiveness trial of antidepressant treatments. Subjects were drawn from the Sequenced Treatment Alternatives to Relieve Depression (STAR(*)D) study, a multicenter, prospective, effectiveness trial in major depressive disorder (MDD). Outpatients with nonpsychotic MDD were initially treated with citalopram for up to 14 weeks; those who did not remit with citalopram were sequentially randomized to a series of next-step treatments, each for up to 12 weeks. Single-nucleotide polymorphisms in four genes were examined for association with remission, defined as a clinician-rated Quick Inventory of Depressive Symptomatology (QIDS-C(16)) score < or =5. Of 1554 participants for whom DNA was available, 565 (36%) reached remission with citalopram treatment. No association with any of the four genes was identified. However, among the 751 who entered next-step treatment, variants in KCNK2 were associated with treatment response (Bonferroni-corrected, gene-based empirical p<0.001). In follow-up analyses, KCNK2 was also associated with effects of similar magnitude for third-step treatment among those with unsatisfactory benefit to both citalopram and one next-step pharmacotherapy (n=225). These findings indicate that genetic variation in KCNK2 may identify individuals at risk for treatment resistance. More broadly, they indicate the utility of animal models in identifying genes for pharmacogenetic studies of antidepressant response.

  18. Comprehensive Evaluation of Peripheral Nerve Regeneration in t