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Sample records for adult cd-1 mice

  1. Persistent conditioned place preference to aggression experience in adult male sexually-experienced CD-1 mice.

    PubMed

    Golden, S A; Aleyasin, H; Heins, R; Flanigan, M; Heshmati, M; Takahashi, A; Russo, S J; Shaham, Y

    2017-01-01

    We recently developed a conditioned place preference (CPP) procedure, commonly used to study rewarding drug effects, to demonstrate that dominant sexually-experienced CD-1 male mice form CPP to contexts previously associated with defeating subordinate male C57BL/6J mice. Here we further characterized conditioned and unconditioned aggression behavior in CD-1 mice. In Exp. 1 we used CD-1 mice that displayed a variable spectrum of unconditioned aggressive behavior toward younger subordinate C57BL/6J intruder mice. We then trained the CD-1 mice in the CPP procedure where one context was intruder-paired, while a different context was not. We then tested for aggression CPP 1 day after training. In Exp. 2, we tested CD-1 mice for aggression CPP 1 day and 18 days after training. In Exp. 3-4, we trained the CD-1 mice to lever-press for palatable food and tested them for footshock punishment-induced suppression of food-reinforced responding. In Exp. 5, we characterized unconditioned aggression in hybrid CD-1 × C57BL/6J D1-Cre or D2-Cre F1 generation crosses. Persistent aggression CPP was observed in CD-1 mice that either immediately attacked C57BL/6J mice during all screening sessions or mice that gradually developed aggressive behavior during the screening phase. In contrast, CD-1 mice that did not attack the C57BL/6J mice during screening did not develop CPP to contexts previously paired with C57BL/6J mice. The aggressive phenotype did not predict resistance to punishment-induced suppression of food-reinforced responding. CD-1 × D1-Cre or D2-Cre F1 transgenic mice showed strong unconditioned aggression. Our study demonstrates that aggression experience causes persistent CPP and introduces transgenic mice for circuit studies of aggression.

  2. Pharmacokinetics of bisphenol A in serum and adipose tissue following intravenous administration to adult female CD-1 mice.

    PubMed

    Doerge, Daniel R; Twaddle, Nathan C; Vanlandingham, Michelle; Fisher, Jeffrey W

    2012-06-01

    Bisphenol A (BPA) is an important industrial chemical used as the monomer for polycarbonate plastic and in epoxy resins for use in food can liners. Worldwide biomonitoring studies consistently find high prevalence of BPA conjugates in urine consistent with pervasive exposure at levels typically below 1 μg/kg bw/day. The current study used LC/MS/MS to measure serum pharmacokinetics of unconjugated (active) and conjugated (inactive) BPA in adult female CD-1 mice following intravenous (IV) injection, which produces higher serum levels by circumventing the processes of absorption from the GI tract and presystemic metabolism that occur after oral administration. Deuterated BPA (100 μg/kg bw) was used to avoid interference by background contamination from trace amounts of native BPA. Additionally, the pharmacokinetics of unconjugated BPA were determined in adipose tissue, a proposed site of action and "depot" for BPA. After IV injection, unconjugated BPA rapidly distributed out of the circulation (t(1/2)=0.2 h) and terminal elimination also proceeded rapidly (t(1/2)=0.8 h). Consistent with the degree of aqueous solubility, lipid/water solubility ratio, and partitioning from blood into adipose tissue in vivo, the levels of unconjugated BPA in mouse adipose tissue rapidly reached a maximal level (0.25 h) that did not exceed the serum maximum at the initial sampling time (0.08 h). Terminal elimination of unconjugated BPA from adipose tissue (t(1/2)=7.0 h) was similar to that for conjugated BPA in serum (t(1/2)=6.6 h) and <0.01% of the administered dose remained in adipose tissue after 24 h. These plasma and tissue kinetics are consistent with rapid equilibria and underscore the non-persistent nature of BPA, particularly when compared with slowly metabolized lipophilic organic pollutants like halogenated dibenzodioxins.

  3. Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CD1 Mice

    EPA Science Inventory

    Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the bi...

  4. Perinatal exposure to the xenoestrogen bisphenol-A induces mammary intraductal hyperplasias in adult CD-1 mice

    PubMed Central

    Vandenberg, Laura N.; Maffini, Maricel V.; Schaeberle, Cheryl M.; Ucci, Angelo A.; Sonnenschein, Carlos; Rubin, Beverly S.; Soto, Ana M.

    2014-01-01

    Humans are routinely exposed to bisphenol-A (BPA), an estrogenic compound that leaches from consumer products. Given the sensitivity of the developing organism to hormones, exposure of fetuses and infants is a concern. Here, CD-1 mice were exposed to environmentally relevant doses of BPA during gestation and the lactational period (gestational day 8 through postnatal day 16). At 3, 9 and 12–15 months of age, mammary glands from exposed offspring were examined for structural changes. BPA-exposed females demonstrated altered mammary phenotypes including the appearance of alveolar buds. Additionally, intraductal hyperplasias were observed exclusively in BPA–exposed females. These lesions had the appearance of “beaded” ducts, with epithelial cells present inside the ductal lumen and increased proliferation indexes compared to normal ducts. Similar structures have also been observed following exposure to other estrogens. These results are further evidence that perinatal BPA exposure can alter the morphology of the rodent mammary gland in adulthood. PMID:18938238

  5. EFFECTS OF GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE IN CD-1 MICE: MICROTIA AND PRELIMINARY HEARING TESTS

    EPA Science Inventory

    Microtia is a reduction in pinna size, usually seen in humans in conjunction with other medical conditions. Here we report microtia in CD-1 mice following gestational exposure to ethane dimethanesulfonate (EDS), an alkylating agent and adult rat Leydig cell toxicant. Methods...

  6. Acute and Chronic Kudzu Improves Plasma Glucose Tolerance in Non-Diabetic CD-1 Mice.

    PubMed

    Carlson, Scott; Prasain, Jeevan K; Peng, Ning; Dai, Yanying; Wyss, J Michael

    2014-01-01

    Previous studies demonstrate that kudzu root extract and its major isoflavone (puerarin) improve glucose metabolism in animal models of insulin resistance and type 2 diabetes; however, these beneficial effects have not been investigated in normal glycemic mice. The present study investigates the effect of acute and chronic kudzu root extract supplementation on glucose tolerance in normoglycemic CD-1 mice. Male, adult CD-1 mice were fed a phytoestrogen-free diet containing 0.2% or 0.0% kudzu root extract for 6 weeks. Thereafter, they were acutely administered kudzu root extract (75 mg/kg BW; oral) or vehicle followed by a glucose challenge (2 g/kg BW; oral). In control fed mice, the acute glucose challenge increased blood glucose ~300% after 30 minutes, and acute kudzu root extract administration significantly blunted this response by ~50%. In mice chronically fed a kudzu-supplemented diet, glucose tolerance was improved, and acute treatment caused no additional improvement. Irrespective of treatment, all mice were normoglycemic at the start of each glucose challenge. Administration of insulin resulted in a larger decrease in blood glucose in chronic kudzu-supplemented compared to control mice. Co-administration of phloridzin (a specific inhibitor of SGLT-mediated glucose uptake), improved glucose tolerance in acutely kudzu-treated mice but had no significant effect on glucose tolerance in chronically treated mice. These results indicate that both acute and chronic administration of kudzu root extract improves glucose tolerance in a normal glycemic mouse strain and that the effects of chronic kudzu feeding may be mediated, in part, by enhanced insulin sensitivity (chronic) and inhibition of sodium dependent glucose transport.

  7. Acute and Chronic Kudzu Improves Plasma Glucose Tolerance in Non-Diabetic CD-1 Mice

    PubMed Central

    Carlson, Scott; Prasain, Jeevan K.; Peng, Ning; Dai, Yanying; Wyss, J. Michael

    2016-01-01

    Previous studies demonstrate that kudzu root extract and its major isoflavone (puerarin) improve glucose metabolism in animal models of insulin resistance and type 2 diabetes; however, these beneficial effects have not been investigated in normal glycemic mice. The present study investigates the effect of acute and chronic kudzu root extract supplementation on glucose tolerance in normoglycemic CD-1 mice. Male, adult CD-1 mice were fed a phytoestrogen-free diet containing 0.2% or 0.0% kudzu root extract for 6 weeks. Thereafter, they were acutely administered kudzu root extract (75 mg/kg BW; oral) or vehicle followed by a glucose challenge (2 g/kg BW; oral). In control fed mice, the acute glucose challenge increased blood glucose ~300% after 30 minutes, and acute kudzu root extract administration significantly blunted this response by ~50%. In mice chronically fed a kudzu-supplemented diet, glucose tolerance was improved, and acute treatment caused no additional improvement. Irrespective of treatment, all mice were normoglycemic at the start of each glucose challenge. Administration of insulin resulted in a larger decrease in blood glucose in chronic kudzu-supplemented compared to control mice. Co-administration of phloridzin (a specific inhibitor of SGLT-mediated glucose uptake), improved glucose tolerance in acutely kudzu-treated mice but had no significant effect on glucose tolerance in chronically treated mice. These results indicate that both acute and chronic administration of kudzu root extract improves glucose tolerance in a normal glycemic mouse strain and that the effects of chronic kudzu feeding may be mediated, in part, by enhanced insulin sensitivity (chronic) and inhibition of sodium dependent glucose transport.

  8. IMMMUNOPHENOTYPE OF SPONTANEOUS HEMATOLYMPHOID TUMORS OCCURRING IN YOUNG AND AGING FEMALE CD-1 MICE

    PubMed Central

    Rehg, Jerold E.; Rahija, Richard; Bush, Dorothy; Bradley, Alys; Ward, Jerrold M.

    2015-01-01

    A few reports indicated the incidence of hematolymphoid neoplasms in old CD-1 mice, but the cellular lineage of CD-1 mouse neoplasms has not be published. In this study, immunohistochemistry (IHC) was used to characterize the cellular lineage of spontaneous hematolymphoid neoplasms arising in young female CD-1 mice used as health monitoring sentinels and aging female CD-1 mice used as controls in 80 wk carcinogenesis studies. Lymphoblastic lymphomas of T-cell and B-cell lineage were common in mice 12 mo or less of age, whereas a wide range of non-lymphoblastic B-cell lymphomas and lymphoblastic T-cell lymphomas were common in mice > 12 mo old. Renal hyaline droplets positive for lysozyme were observed in aged mice with a histiocytic-associated large B-cell lymphoma (HA-BCL) and a myeloid leukemia. Endogenous ecotropic MuLV genes have been recovered from CD-1 mice, but MuLV protein expression has not been previously demonstrated. We reported for the first time the expression of MuLV protein by IHC in lymphomas and some normal tissues of both young and aging CD-1 mice. This report should help to differentiate spontaneous lymphomas and leukemias in CD-1 mice from those induced by chemicals and other methods. PMID:26224701

  9. Neurobehavioural Effects of Hypergravity Exposure in CD-1 Mice

    NASA Astrophysics Data System (ADS)

    Santucci, Daniela; Francia, Nadia; Aloe, Luigi; Enrico, Alleva

    The effects of spaceflight on the nervous system physiology could have important implications for the prolonged stay outside Earth's gravitational field. In this view, both ground-based and space research using animal models represent useful tools to investigate the impact of gravity (hypergravity, microgravity and weightlessness) on the nervous system and behaviour. Data coming from these studies, besides acquisition of knowledge relevant for spaceflights and pro-longed permanence of both humans and animals in space, could provide insight into basic bio-logical phenomena underlying the plasticity of the nervous system and its adaptive responses to a changing environment. Most ground experiments employing animal models use the paradigm of hypergravity exposure with the expectation that behavioural and physiological reactions to this environment might help to explain reactions to the microgravity challenge faced by or-biting animals. An overview of ground-based experiments set up to investigate the effects of changes of gravitational environment on the neurobehavioural responses of CD-1 mouse will be reported, and will illustrate the short-, medium-and long-term behavioural and neurobiological consequences of hypergravity exposure both at adulthood and during early and late postnatal development. Moreover, since mother-pup interaction is critical for the survival and the devel-opment of neonatal rodents, especially in an extreme environment such as that of space, we characterized, exploiting ethological methods, changes in maternal behaviour of CD-1 outbred mouse dams exposed to mild hypergravity. The results of these experiments will be discussed.

  10. 17β-estradiol enhances memory duration in the main olfactory bulb in CD-1 mice.

    PubMed

    Dillon, T Samuel; Fox, Laura C; Han, Crystal; Linster, Christiane

    2013-12-01

    Rodents rely heavily on odor detection, discrimination, and memory to locate food, find mates, care for pups, and avoid predators. Estrogens have been shown to increase memory retention in rodents performing spatial memory and object placement tasks. Here we evaluate the extent to which 17β-estradiol modulates memory formation and duration in the olfactory system. Adult CD-1 mice were gonadectomized and given either systemic 17β-estradiol replacement, local 17β-estradiol in the main olfactory bulb, or no replacement. Before performing the behavioral task the mice were given saline or PHTPP (an estrogen receptor β [ER-β] antagonist) via bilateral infusion into the main olfactory bulb. As the beta-type estrogen receptor (ER-β) is more abundant than the alpha-type estrogen receptor in the murine main olfactory bulb, the current study focuses on 17β-estradiol and its interactions with ERβ. Habituation, a simple, nonassociative learning task in which an animal is exposed to the same odor over successive presentations, was used to evaluate the animals' ability to detect odors and form an olfactory memory. To evaluate memory duration, we added a final trial of intertrial interval time (30 or 60 min) in which we presented the habituated odor. Neither surgical nor drug manipulation affected the ability of mice to detect or habituate to an odor. After habituation, gonadectomized 17β-estradiol-treated mice retained memory of an odor for 30 min, whereas non-estradiol-treated, 17β-estradiol+ERβ antagonist (PHTPP), and untreated male mice did not remember an odor 30 min after habituation. The results show that both systemic and local bulbar infusions of 17β-estradiol enhance odor memory duration in mice.

  11. PERIODS OF VERTEBRAL COLUMN SENSITIVITY TO BORIC ACID TREATMENT IN CD-1 MICE IN UTERO

    EPA Science Inventory

    Periods of vertebral column sensitivity to boric acid treatment in CD-1 mice in utero.

    Cherrington JW, Chernoff N.

    Department of Toxicology, North Carolina State University, Raleigh, NC 27695, USA. jana_cherrington@hotmail.com

    Boric acid (BA) has many uses as...

  12. Effects of Differing Response-Force Requirements on Food-Maintained Responding in CD-1 Mice

    ERIC Educational Resources Information Center

    Zarcone, Troy J.; Chen, Rong; Fowler, Stephen C.

    2007-01-01

    The effect of force requirements on response effort was examined using outbred (CD-1) mice trained to press a disk with their snout. Lateral peak forces greater than 2 g were defined as threshold responses (i.e., all measured responses). Different force requirements were used to define criterion responses (a subclass of threshold responses) that…

  13. CD1d-restricted peripheral T cell lymphoma in mice and humans

    PubMed Central

    Bachy, Emmanuel; Urb, Mirjam; Chandra, Shilpi; Robinot, Rémy; Bricard, Gabriel; de Bernard, Simon; Traverse-Glehen, Alexandra; Gazzo, Sophie; Blond, Olivier; Khurana, Archana; Baseggio, Lucile; Heavican, Tayla; Ffrench, Martine; Crispatzu, Giuliano; Mondière, Paul; Schrader, Alexandra; Taillardet, Morgan; Thaunat, Olivier; Martin, Nadine; Dalle, Stéphane; Le Garff-Tavernier, Magali; Salles, Gilles; Lachuer, Joel; Hermine, Olivier; Asnafi, Vahid; Roussel, Mikael; Lamy, Thierry; Herling, Marco; Iqbal, Javeed; Buffat, Laurent; Marche, Patrice N.; Gaulard, Philippe; Kronenberg, Mitchell; Defrance, Thierry

    2016-01-01

    Peripheral T cell lymphomas (PTCLs) are a heterogeneous entity of neoplasms with poor prognosis, lack of effective therapies, and a largely unknown pathophysiology. Identifying the mechanism of lymphomagenesis and cell-of-origin from which PTCLs arise is crucial for the development of efficient treatment strategies. In addition to the well-described thymic lymphomas, we found that p53-deficient mice also developed mature PTCLs that did not originate from conventional T cells but from CD1d-restricted NKT cells. PTCLs showed phenotypic features of activated NKT cells, such as PD-1 up-regulation and loss of NK1.1 expression. Injections of heat-killed Streptococcus pneumonia, known to express glycolipid antigens activating NKT cells, increased the incidence of these PTCLs, whereas Escherichia coli injection did not. Gene expression profile analyses indicated a significant down-regulation of genes in the TCR signaling pathway in PTCL, a common feature of chronically activated T cells. Targeting TCR signaling pathway in lymphoma cells, either with cyclosporine A or anti-CD1d blocking antibody, prolonged mice survival. Importantly, we identified human CD1d-restricted lymphoma cells within Vδ1 TCR-expressing PTCL. These results define a new subtype of PTCL and pave the way for the development of blocking anti-CD1d antibody for therapeutic purposes in humans. PMID:27069116

  14. DEVELOPMENTAL TOXICITY OF METHANOL: PATHOGENESIS IN CD-1 AND C57BL/6J MICE EXPOSED IN WHOLE EMBRYO CULTURE

    EPA Science Inventory

    BACKGROUND: Methanol causes axial skeleton and craniofacial defects in both CD-1 and C57BL/6J mice during gastrulation, but C57BL/6J embryos are more severely affected. We evaluated methanol-induced pathogenesis in CD-1 and C57BL/6J embryos exposed during gastrulation in whole em...

  15. Strain dependent differences in glucocorticoid-induced bone loss between C57BL/6J and CD-1 mice

    PubMed Central

    Ersek, Adel; Santo, Ana I. Espirito; Vattakuzhi, Youridies; George, Saumya; Clark, Andrew R.; Horwood, Nicole J.

    2016-01-01

    We have investigated the effect of long-term glucocorticoid (GC) administration on bone turnover in two frequently used mouse strains; C57BL/6J and CD1, in order to assess the influence of their genetic background on GC-induced osteoporosis (GIO). GIO was induced in 12 weeks old female C57BL/6J and CD1 mice by subcutaneous insertion of long-term release prednisolone or placebo pellets. Biomechanical properties as assessed by three point bent testing revealed that femoral elasticity and strength significantly decreased in CD1 mice receiving GC, whereas C57BL/6J mice showed no differences between placebo and prednisolone treatment. Bone turnover assessed by microcomputer tomography revealed that contrary to C57BL/6J mice, prednisolone treated CD1 mice developed osteoporosis. In vitro experiments have underlined that, at a cellular level, C57BL/6J mice osteoclasts and osteoblasts were less responsive to GC treatment and tolerated higher doses than CD1 cells. Whilst administration of long-term release prednisolone pellets provided a robust GIO animal model in 12 weeks old CD1 mice, age matched C57BL/6J mice were not susceptible to the bone changes associated with GIO. This study indicates that for the induction of experimental GIO, the mouse strain choice together with other factors such as age should be carefully evaluated. PMID:27812009

  16. Inhibitory avoidance in CD1 mice: sex matters, as does the supplier.

    PubMed

    Parra, Andrés; Rama, Encarnación; Vinader-Caerols, Concepción; Monleón, Santiago

    2013-11-01

    The purpose of the present work was to study possible differences in the learning of inhibitory avoidance (also called passive avoidance) in male and female CD1 mice acquired from three different suppliers, for which a one-trial step-through version of the paradigm was employed. Ninety-six mice from Charles River (France), Janvier (France) and Harlan (The Netherlands) laboratories were divided by sex and assigned to group C, J or H, respectively (n=16). The animals were tested in the training phase (foot-shock: 0.3mA, 5s) and again for avoidance (no foot-shock delivered) one week later. Inhibitory avoidance learning (test latencies significantly higher than training latencies) was observed in every one of the six groups of animals. The variable Supplier was statistically significant, showing better to worse avoidance in C, J and H mice (in that order). A post hoc analysis showed differences between groups C and H. Females tended to exhibit avoidance learning to a greater extent than males. Our results suggest that inhibitory avoidance learning in CD1 mice varies depending on the breeding facilities from which they originate, and that females should be included in inhibitory avoidance studies.

  17. Dietary phytoestrogens accelerate the time of vaginal opening in immature CD-1 mice.

    PubMed

    Thigpen, Julius E; Haseman, Joseph K; Saunders, Hannah E; Setchell, Kenneth D R; Grant, Mary G; Forsythe, Diane B

    2003-12-01

    The purpose of the study reported here was to determine the effects of dietary phytoestrogens on the time of vaginal opening (VO) in immature CD-1 mice, and to correlate it with phytoestrogen and total metabolizable energy (ME) contents of the diet in an effort to determine the most appropriate diets(s) for comparing or evaluating the estrogenic or antiestrogenic activity of endocrine disruptor compounds (EDC). Mice were weaned at postnatal day (PND) 15 and fed the test diets from PND 15 to 30. Vaginal opening was recorded from PND 20 to 30. The phytoestrogen content of the diet was highly predictive (P < 0.0001) of the proportion of mice with VO at PND 24. Total ME content also was significantly (P < 0.01) correlated with time of VO, although this variable was somewhat less predictive than was phytoestrogen content. Time of VO in mice was significantly (P < 0.05) accelerated in mice fed diets high in phytoestrogens, compared with those containing low phytoestrogen content. It was concluded that: dietary daidzein and genistein can significantly (P < 0.01) accelerate the time of VO in CD-1 mice; the advancement in time of VO is more highly correlated with daidzein and genistein contents of the diets than with total ME content; advancement in the time of VO is a sensitive end point for evaluating the estrogenic activity of EDCs, and should be part of the standard protocol for evaluating EDCs. Phytoestrogen-free diet(s) containing the same amount of ME should be used in bioassays that compare the time of VO, or increases in uterine weight as end points for evaluating the estrogenic activity of an EDC.

  18. Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice

    PubMed Central

    Satoh, Masashi; Hoshino, Miyuki; Fujita, Koki; Iizuka, Misao; Fujii, Satoshi; Clingan, Christopher S.; Van Kaer, Luc; Iwabuchi, Kazuya

    2016-01-01

    It has been shown that CD1d expression and glycolipid-reactive, CD1d-restricted NKT cells exacerbate the development of obesity and insulin resistance in mice. However, the relevant CD1d-expressing cells that influence the effects of NKT cells on the progression of obesity remain incompletely defined. In this study, we have demonstrated that 3T3-L1 adipocytes can present endogenous ligands to NKT cells, leading to IFN-γ production, which in turn, stimulated 3T3-L1 adipocytes to enhance expression of CD1d and CCL2, and decrease expression of adiponectin. Furthermore, adipocyte-specific CD1d deletion decreased the size of the visceral adipose tissue mass and enhanced insulin sensitivity in mice fed a high-fat diet (HFD). Accordingly, NKT cells were less activated, IFN-γ production was significantly reduced, and levels of adiponectin were increased in these animals as compared with control mice on HFD. Importantly, macrophage recruitment into the adipose tissue of adipocyte-specific CD1d-deficient mice was significantly blunted. These findings indicate that interactions between NKT cells and CD1d-expressing adipocytes producing endogenous NKT cell ligands play a critical role in the induction of inflammation and functional modulation of adipose tissue that leads to obesity. PMID:27329323

  19. Chronic pain causes a persistent anxiety state leading to increased ethanol intake in CD1 mice.

    PubMed

    González-Sepúlveda, Marta; Pozo, Oscar J; Marcos, Josep; Valverde, Olga

    2016-02-01

    Mood disorders and chronic pain are closely linked, but limited progress has been made in understanding the role of chronic and neuropathic pain in the aetiopathogenesis of depression. To explore the pathological mechanisms that mediate the association between pain and depressive-like behaviours, we studied the time-dependent effect of neuropathic pain on the development of anxiety-like and despair behaviours in CD1 mice. We analysed behavioural data, neuroinflammation reactions and changes in neurotransmitter (glutamate and serotonin) levels in the mouse prefrontal cortex. Sciatic-operated mice displayed long-lasting anxiety-like and despair behaviours, starting 5 and 20 days after partial sciatic nerve ligation, respectively. Glutamatergic neurotransmission and IL-1β cytokine expression were enhanced in the prefrontal cortex of mice with neuropathic pain. We found no change in serotonin metabolism, cytokine IL-6 or brain-derived neurotrophic factor levels. While sciatic-operated mice exposed to intermittent ethanol intake (20% v/v) using the drinking in the dark procedure consumed higher amounts of ethanol than sham-operated mice, thermal allodynia and despair behaviour were not attenuated by ethanol consumption. Our findings reveal an association between glutamatergic neurotransmission and pain-induced mood disorders, and indicate that moderate ethanol consumption does not relieve nociceptive and depressive behaviours associated with chronic pain in mice.

  20. Group housing of male CD1 mice: reflections from toxicity studies.

    PubMed

    Annas, A; Bengtsson, C; Törnqvist, E

    2013-04-01

    Owing to their naturally aggressive behaviour, male mice are often housed individually in toxicity studies. However, several publications advocate group-housing of mice to enable normal social behaviour and interactions between the animals. This refinement project aimed at facilitate group-housing in toxicity studies. A handling procedure, including key factors such as allocation into groups before sexual maturation, transfer of used nesting material into clean cages and avoidance of external changes, that makes group-housing of male CD-1 mice possible in long-term toxicity studies has been developed at Safety Assessment within AstraZeneca, Sweden. Observations on the effect on aggression/fighting in group-housed male mice following different procedures performed in toxicity studies have shown that temporary removal of animals from the group for blood or urine sampling does not affect the group dynamics. However, temporary removal of animals for mating leads to fighting if the animals are taken back to the original group. Treatment with test compound might affect the general condition of the animals and the social hierarchy could be changed. In such cases aggression/fighting might occur and the animals have to be separated. Our experience clearly indicates that group housing of male mice in long-term studies leads to more easily handled animals, as compared with individually housed mice.

  1. Reproductive toxicity of ethylene glycol monoethyl ether tested by continuous breeding of CD-1 mice

    SciTech Connect

    Lamb, J.C. IV; Gulati, D.K.; Russell, V.S.; Hommel, L.; Sabharwal, P.S.

    1984-08-01

    The reproductive toxicity of ethylene glycol monoethyl ether (EGEE) was evaluated in the Fertility Assessment by Continuous Breeding protocol. Both male and female CD-1 mice were given 0, 0.5, 1.0 or 2% EGEE in the drinking water and were housed as breeding pairs continuously for 14 weeks. Significant adverse effects on fertility were seen at 1 and 2% but not at 0.5%. After the continuous breeding phase of this test was completed, treated males were housed with control females and treated females with control males and fertility and reproduction were compared to the corresponding pairs of control male and control female mice. Both males and females from the 1 and 2% groups were affected. Testicular atrophy decreased sperm motility and increased abnormal sperm were noted in the treated males, but no specific anomalies were detected in the females. 7 references, 1 figure, 7 tables.

  2. Pulmonary toxicity and metabolic activation of dauricine in CD-1 mice.

    PubMed

    Jin, Hua; Dai, Jieyu; Chen, Xiaoyan; Liu, Jia; Zhong, Dafang; Gu, Yansong; Zheng, Jiang

    2010-03-01

    Dauricine is the major bioactive component isolated from the roots of Menispermum dauricum D.C. and has shown promising pharmacological activities with a great potential for clinic use. However, the adverse effects and toxicity of the alkaloid are unfortunately ignored. The objective of the current study was to evaluate the toxicity of dauricine in vitro and in vivo. Mice (CD-1) were treated intraperitoneally with dauricine at various doses, and sera and lung lavage fluids were collected after 24 h of treatment. No changes in serum aspartate aminotransferase, alanine aminotransferase, and blood urea nitrogen were noticed, whereas a dose-dependent increase in lactate dehydrogenase activity was observed in lung lavage fluids. Ethidium-based staining studies showed that remarkable cells lost membrane integrity in the lungs of the animals treated with dauricine at 150 mg/kg. Histopathological evaluation of lungs of mice showed that dauricine at the same dose caused significant alveolar edema and hemorrhage. Exposure to dauricine at 40 muM for 24 h resulted in up to 60% cell death in human lung cell lines BEAS-2B, WI-38, and A549. Ketoconazole showed protective effect on the pulmonary injury in mice given dauricine. A quinone methide metabolite of dauricine was identified in mouse lung microsomal incubations, and the presence of ketoconazole in the microsomal incubations suppressed the formation of the quinone methide metabolite. In conclusion, dauricine produced pulmonary injury in CD-1 mice. The pulmonary toxicity appears to depend on the metabolism of dauricine mediated by CYP3A. The electrophilic quinone methide metabolite probably plays an important role in the pulmonary toxicity induced by dauricine.

  3. Behavioural phenotypic characterization of CD-1 mice lacking the neuropeptide S receptor.

    PubMed

    Ruzza, C; Pulga, A; Rizzi, A; Marzola, G; Guerrini, R; Calo', G

    2012-04-01

    Neuropeptide S (NPS) is the endogenous ligand of a previously orphan receptor now named NPSR. In the brain NPS regulates several biological functions including anxiety, arousal, locomotion, food intake, learning and memory, pain and drug abuse. Mice lacking the NPSR gene (NPSR(-/-)) represent an useful tool to investigate the neurobiology of the NPS/NPSR system. NPSR(-/-) mice have been generated in a 129S6/SvEv genetic background. In the present study we generated CD-1 congenic NPSR(+/+) and NPSR(-/-) mice and investigated their phenotype and sensitivity to NPS in various behavioural assays. The phenotype analysis revealed no locomotor differences between NPSR(+/+) and NPSR(-/-) mice. The behaviour of NPSR(+/+) and NPSR(-/-) mice in the righting reflex test was superimposable. No differences were recorded between the two genotypes in the elevated plus maze, open field and stress-induced hyperthermia tests, with the exception of rearing behaviour that was reduced in knockout animals. Moreover the behaviour of NPSR(+/+) and NPSR(-/-) mice in the forced swimming, novel object recognition and formalin assays was similar. The stimulatory effects of NPS in the locomotor activity test and its anxiolytic-like actions in the elevated plus maze and open field assays were evident in NPSR(+/+) but not NPSR(-/-) animals. In conclusion, the present study indicates that the NPS/NPSR system does not tonically control locomotion, sensitivity to diazepam, anxiety, depressive-like behaviours, memory and pain transmission in mice. Furthermore our results clearly show that the product of the NPSR gene represents the mandatory protein for all the NPS biological effects so far described.

  4. Maternal restraint stress-enhanced teratogenicity of all-trans-retinoic acid in CD-1 mice.

    PubMed

    Rasco, J F; Hood, R D

    1995-02-01

    The present study combined maternal restraint stress with a teratogenic agent, all-trans-retinoic acid (tRA). Five treatment groups were used initially: (1) vehicle (corn oil) control [C], (2) food/water-deprived [FWD], (3) tRA only [tRA], (4) restraint only [R], and (5) tRA plus restraint [tRA+R]. Mated CD-1 mice in groups 3 and 5 were given 20 mg/kg tRA po. Mice in groups 4 and 5 were restrained in the supine position for 12 hr (9:00 a.m. to 9:00 p.m.), and the FWD group mice were deprived during the same time period. The tRA+R mice were dosed immediately prior to the 12-hr restraint period. All treatments were administered on gestation day (GD) 9 (copulation plug = day 1). On GD 18, all females were killed and subjected to teratological examination. The incidences of resorptions, short tails, bent tails, fused ribs, and fused vertebrae were significantly increased in the tRA+R group, in comparison with all other groups. Spina bifida was observed only in the tRA+R group. The current results, combined with those of earlier studies with other agents, support the likelihood that maternal stress can exacerbate adverse effects of chemical teratogens on mouse development.

  5. Kidney antioxidant status, biochemical parameters and histopathological changes induced by methomyl in CD-1 mice.

    PubMed

    El-Demerdash, Fatma; Dewer, Youssef; ElMazoudy, Reda H; Attia, Azza A

    2013-09-01

    The widespread of pesticide in public health and agriculture has caused severe environmental pollution and health hazards. Methomyl is used worldwide in agriculture and health programs. Besides its advantages in the agriculture, it causes several toxic effects. In this study, we aimed to investigate the effects of methomyl at different time intervals on lipid peroxidation, reduced glutathione (GSH), total sulfhydryl group (T-SH), antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and histopathological changes in mice kidney. Ten CD-1 mice per group were assigned to one of four treatment groups. Group one served as control while groups 2, 3 and 4 were orally treated with 1mgmethomyl/kg BW for 10, 20 and 30 days, respectively. Methomyl significantly increased lipid peroxidation in kidney as compared to control group. Levels of GSH and T-SH and activities of SOD, CAT and GST were found to be decreased. On the other hand, methomyl significantly increased the levels of urea, uric acid and creatinine in serum. The histological examination of kidney revealed damage involving the entire renal nephrons in both 20 and 30 days of methomyl exposure. Severe dilatation of the cortical tissue, congested glomerulus with swelling of the endothelial cells and degeneration of the epithelium cells lining the tubules were observed. In conclusion, the results suggest that methomyl exposure can cause renal damage, oxidative stress, perturbations in antioxidant defense system and histopathologic changes in mice kidney in a time dependent manner.

  6. Investigating the effects of nanoparticles on reproduction and development in Drosophila melanogaster and CD-1 mice

    NASA Astrophysics Data System (ADS)

    Philbrook, Nicola Anne

    Manufactured nanoparticles (NPs) are a class of small (≤ 100 nm) materials that are being used for a variety of purposes, including industrial lubricants, food additives, antibacterial agents, as well as delivery systems for drug and gene therapies. Their unique characteristics due to their small size as well as their parent materials allow them to be exploited in convenience applications; however, some of these properties also allow them to interact with and invade biological systems. Few studies have been performed to determine the potential harm that NPs can inflict on reproductive and developmental processes in organisms. In this study, Drosophila melanogaster and CD-1 mice were orally exposed to varying doses of titanium dioxide (TiO 2) NPs, silver (Ag) NPs, or hydroxyl-functionalized carbon nanotubes (fCNTs) and Drosophila were also exposed to microparticles (MPs) as a control for particle size. The subsequent effect of these materials on reproduction and development were evaluated. Strikingly, each type of NP studied negatively affected either reproduction or development in one or both of the two model systems. TiO2 NPs significantly negative effected both CD-1 mouse development (100 mg/kg or 1000 mg/kg) as well as Drosophila female fecundity (0.005%-0.5% w/v). Ag NPs significantly reduced mouse fetus viability after prenatal exposure to10 mg/kg. Ag NPs also significantly decreased the developmental success of Drosophila when they were directly exposed to these NPs (0.05% - 0.5% w/v) compared to both the vehicle and MP controls. fCNTs significantly increased the presence of morphological defects, resorptions and skeletal abnormalities in CD-1 mice, but had little effect on Drosophila. We speculate that the differences seen in the effects of NP types may be partially due to differences in reproductive physiology as well as each organism's ability to internalize these NPs. Whereas the differing response of each organism to a NP type was likely due in part to

  7. Olfactory Sensitivity for Six Predator Odorants in CD-1 Mice, Human Subjects, and Spider Monkeys

    PubMed Central

    Sarrafchi, Amir; Odhammer, Anna M. E.; Hernandez Salazar, Laura Teresa; Laska, Matthias

    2013-01-01

    Using a conditioning paradigm, we assessed the olfactory sensitivity of six CD-1 mice (Mus musculus) for six sulfur-containing odorants known to be components of the odors of natural predators of the mouse. With all six odorants, the mice discriminated concentrations <0.1 ppm (parts per million) from the solvent, and with five of the six odorants the best-scoring animals were even able to detect concentrations <1 ppt (parts per trillion). Four female spider monkeys (Ateles geoffroyi) and twelve human subjects (Homo sapiens) tested in parallel were found to detect the same six odorants at concentrations <0.01 ppm, and with four of the six odorants the best-scoring animals and subjects even detected concentrations <10 ppt. With all three species, the threshold values obtained here are generally lower than (or in the lower range of) those reported for other chemical classes tested previously, suggesting that sulfur-containing odorants may play a special role in olfaction. Across-species comparisons showed that the mice were significantly more sensitive than the human subjects and the spider monkeys with four of the six predator odorants. However, the human subjects were significantly more sensitive than the mice with the remaining two odorants. Human subjects and spider monkeys significantly differed in their sensitivity with only two of the six odorants. These comparisons lend further support to the notion that the number of functional olfactory receptor genes or the relative or absolute size of the olfactory bulbs are poor predictors of a species’ olfactory sensitivity. Analysis of odor structure–activity relationships showed that in both mice and human subjects the type of alkyl rest attached to a thietane and the type of oxygen moiety attached to a thiol significantly affected olfactory sensitivity. PMID:24278296

  8. Behavioral Responses of CD-1 Mice to Six Predator Odor Components.

    PubMed

    Sievert, Thorbjörn; Laska, Matthias

    2016-06-01

    Mammalian prey species are able to detect predator odors and to display appropriate defensive behavior. However, there is only limited knowledge about whether single compounds of predator odors are sufficient to elicit such behavior. Therefore, we assessed if predator-naïve CD-1 mice (n = 60) avoid sulfur-containing compounds that are characteristic components of natural predator odors and/or display other indicators of anxiety. A 2-compartment test arena was used to assess approach/avoidance behavior, general motor activity, and the number of fecal pellets excreted when the animals were presented with 1 of 6 predator odor components in one compartment and a blank control in the other compartment. We found that 2 of the 6 predator odor components (2-propylthietane and 3-methyl-1-butanethiol) were significantly avoided by the mice. The remaining 4 predator odor components (2,2-dimethylthietane, 3-mercapto-3-methylbutan-1-ol, 3-mercapto-3-methylbutyl-1-formate, and methyl-2-phenylethyl sulphide) as well as a nonpredator-associated fruity odor (n-pentyl acetate) were not avoided. Neither the general motor activity nor the number of excreted fecal pellets, both widely used measures of stress- or anxiety-related behavior, were systematically affected by any of the odorants tested. Further, we found that small changes in the molecular structure of a predator odor component can have a marked effect on its behavioral significance as 2-propylthietane was significantly avoided by the mice whereas the structurally related 2,2-dimethylthietane was not. We conclude that sulfur-containing volatiles identified as characteristic components of the urine, feces, and anal gland secretions of mammalian predators can be, but are not necessarily sufficient to elicit defensive behaviors in a mammalian prey species.

  9. Neonatal exposure to daidzein, genistein, or the combination modulates bone development in female CD-1 mice.

    PubMed

    Kaludjerovic, Jovana; Ward, Wendy E

    2009-03-01

    Neonatal exposure to genistein (GEN), an isoflavone abundant in soy, favorably modulates bone mineral density (BMD) and bone strength in mice at adulthood. The study objective was to determine whether early exposure to a combination of the soy isoflavones daidzein (DAI) and GEN that naturally exists in soy protein-based infant formula results in greater benefits to bone at adulthood than either treatment alone. Male and female CD-1 mice (n = 8-16 pups per group per gender) were randomized to subcutaneous injections of DAI (2 mg x kg body weight(-1) x d(-1)), GEN (5 mg x kg body weight(-1) x d(-1)), DAI+GEN (7 mg x kg body weight(-1) x d(-1)), diethylstilbesterol (DES; positive control) (2 mg x kg body weight(-1) x d(-1)), or control (CON) from postnatal d 1-5 and were studied to 4 mo of age. BMD, biomechanical bone strength, and bone microarchitecture were assessed at the femur and lumbar vertebrae (LV). Females treated with DAI, GEN, DAI+GEN, or DES had greater (P < 0.05) BMD at the LV compared with CON and vertebra in the DAI and DES group were more resistant to compression fractures. Microstructural analyses demonstrated that treatment with DAI and GEN resulted in greater (P < 0.05) trabecular connectivity and trabecular thickness, respectively, than the CON. In conclusion, neonatal exposure to DAI and/or GEN had a positive effect on the skeleton of female mice at adulthood, but, compared with individual treatments, DAI+GEN did not have a greater benefit to bone in females or males.

  10. Assessment of ethylene glycol monobutyl and monophenyl ether reproductive toxicity using a continuous breeding protocol in Swiss CD-1 mice.

    PubMed

    Heindel, J J; Gulati, D K; Russell, V S; Reel, J R; Lawton, A D; Lamb, J C

    1990-11-01

    A continuous breeding reproduction study design was utilized to examine the reproductive toxicity of ethylene glycol monobutyl ether (EGBE) and ethylene glycol monophenyl ether (EGPE). Swiss CD-1 mice were administered EGBE in drinking water (0, 0.5, 1.0, and 2.0%, i.e., 0.7, 1.3, and 2.1 g/kg body wt/day) and EGPE was administered via the feed (0, 0.25, 1.25, and 2.5%, i.e., 0, 0.4, 2.0, and 4 g/kg body wt/day). Both male and female mice were dosed for 7 days prior to and during a 98-day cohabitation period. EGBE was toxic at the high (2%) and mid dose (1%) to adult F0 female mice: 13 out of 22 females at the high dose and 6 out of 20 at the mid dose died during the cohabitation period. Both the high- and mid-dose animals produced fewer litters/pair, fewer pups/litter, with decreased pup weight. These effects occurred in the presence of decreased body weight, decreased water consumption, and increased kidney weight. A crossover mating trial indicated that the reproductive effects could be attributed primarily to an effect on the female. This was substantiated at necropsy where testes and epididymis weights were normal as were sperm number and motility. Fertility of the offspring of the 0.5% group was normal in the presence of increased liver weights. With respect to EGPE, there was no change in the ability to produce five litters during the continuous breeding period. There was, however, a significant but small (10-15%) decrease in the number of pups/litter and in pup weight in the high-dose group. A crossover mating trial suggested a female component of the reproductive toxicity of EGPE. While fertility was only minimally compromised, severe neonatal toxicity was observed. By Day 21 there were only 8 out of 40 litters in the mid- and high-dose groups which had at least one male and female/litter. Second generation reproductive performance of the mid-dose group (1.25%) was unaffected except for a small decrease in live pup weight. In summary the reproductive

  11. Toxicity and bio-accumulation of inhaled cerium oxide nanoparticles in CD1 mice.

    PubMed

    Aalapati, Srinivas; Ganapathy, Selvam; Manapuram, Saikumar; Anumolu, Goparaju; Prakya, Balakrishna Murthy

    2014-11-01

    Male CD1 mice were subjected to nose-inhalation exposure of CeO2 nanoparticles (NPs) for 0, 7, 14 or 28 days with 14 or 28 days of recovery time at an aerosol concentration of 2 mg/m(3). Markers of lung injury and pro-inflammatory cytokines (interleukin-1beta, tumour necrosis factor-alpha, interleukin-6 and macrophage inflammatory protein-2) in bronchoalveolar lavage fluid (BALF), oxidative stress in lungs, bio-accumulation, and histopathology of pulmonary and extrapulmonary tissues were assessed. BALF analysis revealed the induction of pulmonary inflammation, as evident by an increase in the influx of neutrophils with a significant secretion of pro-inflammatory cytokines that lead to generation of oxidative stress and cytotoxicity, as is evident by induction of lipid peroxidation, depletion of glutathione and increased BALF lactate dehydrogenase and protein. The histopathological examination revealed that these inhaled CeO2 NPs were located all over the pulmonary parenchyma, inducing a severe, chronic, active inflammatory response characterised by necrosis, proteinosis, fibrosis and well-formed discrete granulomas in the pulmonary tissue and tubular degeneration leading to coagulative necrosis in kidneys. Inductively coupled plasma optical emission spectrometer results showed a significant bio-accumulation of these particles in the pulmonary and extrapulmonary tissues, even after one month of post-inhalation exposure. Together, these findings suggest that inhalation exposure of CeO2 NPs can induce pulmonary and extrapulmonary toxicity.

  12. Investigating the effects of in utero benzene exposure on epigenetic modifications in maternal and fetal CD-1 mice.

    PubMed

    Philbrook, Nicola A; Winn, Louise M

    2015-11-15

    Exposure to the ubiquitous environmental pollutant benzene is positively correlated with leukemia in adults and may be associated with childhood leukemia following in utero exposure. While numerous studies implicate oxidative stress and DNA damage as playing a role in benzene-mediated carcinogenicity, emerging evidence suggests that alterations in epigenetic regulations may be involved. The present study aimed to determine whether DNA methylation and/or various histone modifications were altered following in utero benzene exposure in CD-1 mice. Global DNA methylation and promoter-specific methylation of the tumor suppressor gene, p15, were assessed. Additionally, levels of acetylated histones H3, H4, and H3K56, as well as methylated histones H3K9 and H3K27 were assessed by Western blotting. A significant decrease in global DNA methylation of maternal bone marrow was observed following benzene exposure; however no effect on global DNA methylation was detected in fetal livers. Additionally, no effect of benzene exposure was observed on p15 promoter methylation or any measured histone modifications in both maternal bone marrow and fetal livers. These results suggest that the methodology used in the present study did not reveal alterations in DNA methylation and histone modifications following in utero exposure to benzene; however further experimentation investigating these modifications at the whole genome/epigenome level, as well as at later stages of benzene-induced carcinogenesis, are warranted.

  13. The Effects of Perioperative Analgesia on Litter Size in Crl:CD1(ICR) Mice Undergoing Embryo Transfer

    PubMed Central

    Goulding, David R; Myers, Page H; Goulding, Eugenia H; Blankenship, Terry L; Grant, Mary F; Forsythe, Diane B

    2010-01-01

    The objective of this study was to evaluate the effect on litter size of 2 analgesics used perioperatively during mouse embryo transfer surgery. Day 2.5 pseudopregnant CD1 mice (n = 96) were divided equally into 2 analgesic treatment groups and a saline control group. Each mouse received a single, subcutaneous dose of buprenorphine hydrochloride (0.1 mg/kg), flunixin meglumine (2.5 mg/kg), or saline immediately after induction of anesthesia with 2.5% isoflurane. Each mouse then was prepared for aseptic surgery. Blastocysts had previously been collected from C57BL/6NCrl female mice that were synchronized and superovulated by using pregnant mare serum gonadotropin and human chorionic gonadotropin and mated with C57BL/6NTac male mice 3.5 d before collection. Viable blastocysts were pooled, and 8 were selected arbitrarily and transplanted into the right uterine horn of each pseudopregnant CD1 mouse. Mice were monitored throughout pregnancy, and the number of pups at birth was documented. No statistically significant difference was found between the 3 groups. These results indicate that perioperative analgesic treatment with buprenorphine or flunixin in the CD1 mouse undergoing embryo transfer is not associated with increased embryonic loss. PMID:20819387

  14. Pituitary-dependent masculinization of hepatic hexobarbital hydroxylase in Crl:CD-1(ICR)BR mice.

    PubMed

    Shapiro, B H

    1985-03-25

    The sexual dimorphism in hepatic drug metabolism found in Crl:CD-1 mice is due to the normally repressive effects of testicular androgens on the activities of hepatic monooxygenases. The ability of testosterone to elevate the Michaelis constant (Km) and reduce the maximum velocity (Vmax) of hepatic hexobarbital hydroxylase is dependent upon the pituitary, so that in the hypophysectomized mouse androgens have no repressive effects on the activities of hepatic monooxygenases.

  15. Assessment of the effect of prolonged forced swimming on CD-1 mice sperm morphology with and without antioxidant supplementation.

    PubMed

    Rodriguez, I; Diaz, A; Vaamonde, D

    2016-04-01

    As physical exercise has been shown to negatively affect sperm morphology, this study was undertaken to assess the effect of a 3-min forced swimming protocol during 50 days, with and without administration of antioxidants [N-acetylcysteine (NAC) and trans-resveratrol], on sperm morphology in CD-1 mice. Forty-four 13-week-old CD-1 mice were randomly allocated to four different groups: mice not submitted to exercise, control group (CG), mice submitted to swimming without administration of antioxidants (EX), mice submitted to swimming that received trans-resveratrol supplementation [exercise group (EX)+Resv] and mice submitted to swimming exercise that received NAC supplementation (EX+NAC). The EX showed 30.5% of spermatozoa with normal morphology, showing significant differences with regard to the CG, which showed 58.5%. The groups receiving antioxidant supplements showed significantly higher percentages of spermatozoa with normal morphology in comparison with the EX group (EX+Resv: 64.1%, EX+NAC: 48.2%). The imposed model of forced swimming caused alterations in sperm morphology. The antioxidants employed seem to be suitable antioxidants for avoiding exercise-associated sperm morphology anomalies in prolonged forced swimming exercise. Trans-resveratrol has proven to be more efficient for this purpose.

  16. Gene expression profiling in the liver of CD-1 mice to characterize the hepatotoxicity of triazole fungicides

    SciTech Connect

    Goetz, Amber K.; Bao, Wenjun; Ren, Hongzu; Schmid, Judith E.; Tully, Douglas B.; Wood, Carmen; Rockett, John C.; Narotsky, Michael G.; Sun, Guobin; Lambert, Guy R.; Thai, S.-F.; Wolf, Douglas C.; Nesnow, Stephen; Dix, David J. . E-mail: dix.david@epa.gov

    2006-09-15

    Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and hypotheses on potential mechanisms of action for this class of chemicals. Adult male CD-1 mice were exposed daily for 14 days to fluconazole, myclobutanil, propiconazole, or triadimefon at three dose levels by oral gavage. Doses were based on previous studies that resulted in liver hypertrophy or hepatotoxicity. All four triazoles caused hepatocyte hypertrophy, and all except triadimefon increased relative liver/body weight ratios at the middle and high dose levels. CYP enzyme activities were also induced by all four triazoles at the middle and high doses as measured by the dealkylations of four alkoxyresorufins, although some differences in substrate specificity were observed. Consistent with this common histopathology and biochemistry, several CYP and xenobiotic metabolizing enzyme (XME) genes were differentially expressed in response to all four (Cyp2d26 and Cyp3a11), or three of the four (Cyp2c40, Cyp2c55, Ces2, Slco1a4) triazoles. Differential expression of numerous other CYP and XME genes discriminated between the various triazoles, consistent with differences in CYP enzyme activities, and indicative of possible differences in mechanisms of hepatotoxicity or dose response. Multiple isoforms of Cyp1a, 2b, 2c, 3a, and other CYP and XME genes regulated by the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were differentially expressed following triazole exposure. Based on these results, we expanded on our original hypothesis that triazole hepatotoxicity was mediated by CYP induction, to include additional XME genes, many of which are modulated by CAR and PXR.

  17. Rearing conditions and domestication background determine regulation of hippocampal cell proliferation and survival in adulthood-laboratory CD1 and C57Bl/6 mice versus wild house mice.

    PubMed

    Schaefers, A T U

    2013-01-03

    Brain development is sensitive to an individual's interaction with its environment. Deprivation of natural environmental stimulation especially in the phase after weaning has long-lasting consequences on neuroplasticity. However, previous findings concerning the effects of rearing environment on adult hippocampal cell proliferation and neurogenesis in rodents remain contradictory. To address the question, whether the variability of hippocampal plasticity in response to environmental conditions is a unique feature at least in mice, the present study examined the effects of social and physical deprivation during brain development on hippocampal cell production and survival in adults of three mouse strains (Mus musculus) with different domestication background: outbred CD1, inbred C57Bl/6 and the F2-descendants of wild-caught house mice. Wheel running increased cell proliferation rates in the dentate gyrus of CD1 and C57Bl/6 mice reared under socially and physically deprived conditions, but not from enriched conditions. In wild house mice, neither the rearing conditions nor the wheel-running challenge did affect proliferative activity. This indicates, on the one hand, that wild house mice are more robust in their regulation of hippocampal cell proliferation against environmental influences and, on the other hand, that domestication and rearing background of laboratory animals impact neuroplastic potentials and responsiveness to external stimuli in adulthood.

  18. Ultra-high olfactory sensitivity for the human sperm-attractant aromatic aldehyde bourgeonal in CD-1 mice.

    PubMed

    Larsson, Linda; Laska, Matthias

    2011-12-01

    Recent studies have shown that certain aromatic aldehydes are ligands for olfactory receptors expressed in mammalian sperm cells and induce sperm chemotaxis. Using a conditioning paradigm, the olfactory sensitivity of five CD-1 mice for seven aromatic aldehydes was investigated. With all seven stimuli, the mice discriminated concentrations as low as 0.01 ppm (parts per million) from the solvent, and with bourgeonal the animals even detected concentrations as low as 0.1 ppq (parts per quadrillion) which constitutes the lowest olfactory detection threshold value reported in this species so far. The presence of a tertiary butyl group in para-position (relative to the functional aldehyde group) combined with a lack of an additional alkyl group next to the functional aldehyde group may be responsible for the extraordinary sensitivity of the mice for bourgeonal.

  19. Compared plasma and brain pharmacokinetics of clomipramine and its metabolite demethylclomipramine in two strains of mice (NMRI and CD1).

    PubMed

    Marty, H; Varoquaux, O; Fialip, J; Cordonnier, P; Duroux, E; Bulach, C; Eschalier, A; Advenier, C; Pays, M; Bastide, P

    1992-01-01

    The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CD1) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmax CMI = 14 min), metabolism prompt (tmax DCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasma t1/2 = 53 min against 165 min in the CD1 mice). Both values were well below that reported for man (mean plasma t1/2 = 24 h). The data presented can serve as a basis for designing true chronic administration protocol in animals.

  20. Detailed analysis of the behavior and memory performance of middle-aged male and female CD-1 mice in a 3D maze.

    PubMed

    Ennaceur, A; Michalikova, S; van Rensburg, R; Chazot, P L

    2008-03-05

    Fifty percent of CD-1 mice from both sex die by the end of 2 years. The survival rate is higher in females than in males. This high mortality rate is associated to the high susceptibility of this strain of mice to some immuno-pathologies and the high incidence of systemic amyloidosis. It is therefore possible that premature cognitive deficits can be observed in CD-1 mice. In the present study, we describe a novel method for assessing emotional responses and memory performance of young (4 months) and middle-aged (12 months) CD-1 mice of both sexes in a 3D spatial navigation task. Animals are introduced to the maze without preliminary habituation and trained in a working memory test. As expected CD-1 mice have a low number of entries to arms on their first exposure to the maze which confirm our previous report on the anxious trait of this strain compared to C57/BL6 mice. The measure of arm/bridge ratio suggests that anxiety induced by exposure to the maze persists much longer in middle-aged male mice compared to middle-aged female mice and compared to both young male and female mice. The measure of memory revealed that young female mice made significantly less arm repeats and more unique arm visits before first arm repeat than middle-aged female and male mice. There are also significant differences between young female and young male mice with the former committing fewer errors than the latter.

  1. Scratching Responses to Epidermal Injury in C57BL/6, DBA/2, BALB/c, and CD1 Mice

    PubMed Central

    Sargent, Jennifer L; Löhr, Christiane V; Diggs, Helen E

    2016-01-01

    Whereas early investigations into ulcerative dermatitis (UD) focused on the possibility of a primary dermatopathology, several recent studies have advocated scratching behavior as a primary driver for UD. The aim of this study was to assess whether B6 mice exhibit excessive scratching under resting conditions or when provoked by epidermal barrier disruption. We hypothesized that B6 mice would exhibit more spontaneous scratching behavior and that B6 mice would be more pruritic after mild epidermal barrier injury compared with the other strains and stock tested. The behavior of the retired breeder female C57BL/6J, DBA/2J, BALB/cByJ, and Crl:CD1 mice was videotaped for 60 min. Behavior filming occurred at 17:15 and at 07:00 the next morning prior to (baseline) and after tape-stripping to initiate epidermal barrier disruption. Scratching duration was recorded as brief (less than 3 s) or prolonged (3 s or longer), on the basis of observations during a pilot study. In contrast to the hypothesis, B6 mice did not scratch significantly more frequently, have more long-duration scratching events, nor have a higher median scratching duration of prolonged scratching as compared with the other types of mice tested. In fact, B6 mice showed the lowest average scratching frequency and duration under both conditions. B6 mice demonstrated increased scratching behavior after epidermal barrier disruption, but the increased scratching did not surpass the rate or duration of scratching in the other types of mice tested. These findings do not support the idea that a strain-related tendency toward exaggerated scratching behavior under resting or epidermal barrier disruption conditions predisposes B6 mice to UD. PMID:27298245

  2. Maternal behavior, paternal behavior, and pup survival in CD-1 albino mice (Mus musculus) in three different housing conditions.

    PubMed

    Wright, S L; Brown, R E

    2000-06-01

    Parental behavior, food consumption, and pup development in litters of CD-1 albino mice (Mus musculus) with single mothers or paired mothers in 3 different housing conditions were compared. Fewer pups survived when parents were required to run in a wheel to obtain food, and these pups had lower weights than pups in the wheel-noncontingent and no-wheel groups. The presence of the male facilitated pup survival in the wheel-contingent group but had no effect on pup growth. Mice in the wheel-contingent group ran more revolutions than those in the wheel-noncontingent group and spent less time in parental care. In the wheel-contingent group, males spent more time running and ate less food than females, suggesting that males may indirectly facilitate pup development by providing food for the mother. The results suggest that the presence of the male increases pup care and may facilitate maternal behavior under appropriate environmental conditions.

  3. Dominant lethal study in CD-1 mice following inhalation exposure to 1,3-butadiene: Final technical report

    SciTech Connect

    Hackett, P.L.; Mast, T.J.; Brown, M.G.; Clark, M.L.; Evanoff, J.J.; Rowe, S.E.; McClanahan, B.J.; Buschbom, R.L.; Decker, J.R.; Rommereim, R.L.; Westerberg, R.B.

    1988-04-01

    The effects of whole-body inhalation exposures to 1,3-butadiene on the reproductive system was evaluated. The results of dominant lethality in CD-1 male mice that were exposed to 1,3-butadiene are described. Subsequent to exposure, males were mated with two unexposed females. Mating was continued for 8 weeks with replacement of two females each week. Gravid uteri were removed, and the total number, position and status of implantations were determined. The mice were weighed prior to exposure and at 0, 1, 2, 3, 4, 5, 6, 7, and 8 weeks after exposure and at sacrifice. The animals were observed for mortality, morbidity and signs of toxicity throughout the study. 19 refs., 5 figs., 9 tabs.

  4. Copper-Induced Spermatozoa Head Malformation Is Related to Oxidative Damage to Testes in CD-1 Mice.

    PubMed

    Zhang, Zhuo-Wei; Zhi-GangTan; Qiao, Na; Kang, Zhen-Long; Chen, Zhi-Ling; Hu, Lian-Mei; Yang, Zeng-Ming; Li, Ying

    2016-10-01

    The molecular mechanism for copper toxicity on spermatozoa quality in mice is not well understood. In a 4-week experiment, we challenged 24, 6-week-old male CD-1 mice with twice-a-week intraperitoneal copper chloride injections and evaluated spermatozoa quality, copper levels in the testes, serum testosterone, the expression of key antioxidant glutathione peroxidase 5 (GPx5), and the regulated androgen receptor (AR) in the mice testes. We compared these outcomes for four groups of six mice given doses of 0, 1.25, 2.5, 5.0 mg/kg weight copper chloride twice a week for 4 weeks. The mice demonstrated a copper increase spermatozoa head malformation in a dose-response manner. However, we observed no changes in spermatozoa viability and acrosome integrity in the ratio of mouse body weight to testes weight or in the histomorphology of the testes as the average copper level increased. Results of our RT-PCR assays, immunohistochemical tests, ELISA, and histochemistry analyses indicated that testis GPx5 expression was increased, AR expression in the testes was decreased, serum testosterone was decreased, and the activity of 3β-hydroxysteroid dehydrogenase was decreased as the copper dose increased. In conclusion, these data show that sublethal exposure to copper induces spermatozoa head malformation and influences both mRNA and protein levels of GPx5 and AR which is related to copper resides in the testes.

  5. Disposition of Perfluorooctanoic Acid (PFOA) in Pregnant and Lactating CD-1 Mice and Their Pups

    EPA Science Inventory

    Previous studies in mice prenatally-exposed to PFOA demonstrate growth and developmental effects, including impaired body weight gain and mammary gland development, delayed eye opening, and increased mortality. Those dose dependent effects appeared to worsen if offspring exposed ...

  6. Dietary supplementation of β-guanidinopropionic acid (βGPA) reduces whole-body and skeletal muscle growth in young CD-1 mice.

    PubMed

    Baumgarner, Bradley L; Nagle, Alison M; Quinn, Meagan R; Farmer, A Elaine; Kinsey, Stephen T

    2015-05-01

    Increased AMP-activated protein kinase (AMPK) activity leads to enhanced fatty acid utilization, while also promoting increased ubiquitin-dependent proteolysis (UDP) in mammalian skeletal muscle. β-guanidinopropionic acid (βGPA) is a commercially available dietary supplement that has been shown to promote an AMPK-dependent increase in fatty acid utilization and aerobic capacity in mammals by compromising creatine kinase function. However, it remains unknown if continuous βGPA supplementation can negatively impact skeletal muscle growth in a rapidly growing juvenile. The current study was conducted to examine the effect of βGPA supplementation on whole-body and skeletal muscle growth in juvenile and young adult mice. Three-week old, post weanling CD-1 mice were fed a standard rodent chow that was supplemented with either 2% (w/w) α-cellulose (control) or βGPA. Control and βGPA-fed mice (n = 6) were sampled after 2, 4, and 8 weeks. Whole-body and hindlimb muscle masses were significantly (P < 0.05) reduced in βGPA-fed mice by 2 weeks. The level of AMPK (T172) phosphorylation increased significantly (P < 0.05) in the gastrocnemius of βGPA-fed versus control mice at 2 weeks, but was not significantly different at the 4- and 8-week time points. Further analysis revealed a significant (P < 0.05) increase in the skeletal muscle-specific ubiquitin ligase MAFbx/Atrogin-1 protein and total protein ubiquitination in the gastrocnemius of βGPA versus control mice at the 8-week time point. Our data indicate that feeding juvenile mice a βGPA-supplemented diet significantly reduced whole-body and skeletal muscle growth that was due, at least in part, to an AMPK-independent increase in UDP.

  7. The Effect of Cage Space on Behavior and Reproduction in Crl:CD1(Icr) and C57BL/6NCrl Laboratory Mice

    PubMed Central

    Gaskill, Brianna N.; Pritchett-Corning, Kathleen R.

    2015-01-01

    Recommendations for the amount of cage space required for female mice with litters were first made in the 2011 Guide for the Care and Use of Laboratory Animals. We hypothesized that if a difference in mouse behavior and reproduction exists within the limits of commercially available caging, this difference would be detected between the smallest and largest cages. C57BL/6NCrl and Crl:CD1(Icr) breeding mice were randomly assigned to a cage treatment: LP 18790 (226cm2); A RC1 (305cm2); A N10 (432cm2); T 1291 (800cm2) and a breeding configuration: single (male removed after birth); pair (1 male + 1 female); or trio (1 male + 2 females) in a factorial design for 12 weeks. All cages received 8-10g of nesting material and nests were scored weekly. Pups were weaned between post-natal day 18 and 26 and were weighed at weaning. Adult behavior and location in the cage were recorded by scan samples every 30 min over 48 hr of video recorded on PND 0-8 and PND 14-21 when pups were in the cage. Press posture and play behavior were recorded by 1/0 sampling method. Cage space did not significantly alter typical reproductive measures. Pups in the smallest cage played less than in the other cages. Adults in the smallest cage displayed more press posture than in the two largest cages. Mice in the largest cage spent more time under the feeder than in other areas of the cage. Nest score was also the highest in the largest cage. Housing breeding groups of mice in a range of commercially available cage sizes does not affect reproduction but behavioral measures suggest that the smallest cage tested, LP 18790, may be stressful for outbred mice when pups are present. PMID:26020792

  8. Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice

    SciTech Connect

    Dawson, Jennifer E.; Raymond, Angela M.; Winn, Louise M. . E-mail: winnl@biology.queensu.ca

    2006-03-01

    In utero exposure to valproic acid (VPA) during pregnancy is associated with an increased risk of neural tube defects (NTDs). Although the mechanism by which VPA mediates these effects is unknown, VPA-initiated changes in embryonic protein levels have been implicated. The objectives of this study were to investigate the effect of in utero VPA exposure on embryonic protein levels of p53, NF-{kappa}B, Pim-1, c-Myb, Bax, and Bcl-2 in the CD-1 mouse. We also evaluated the protective effects of folic acid and pantothenic acid on VPA-induced NTDs and VPA-induced embryonic protein changes in this model. Pregnant CD-1 mice were administered a teratogenic dose of VPA prior to neural tube closure and embryonic protein levels were analyzed. In our study, VPA (400 mg/kg)-induced NTDs (24%) and VPA-exposed embryos with an NTD showed a 2-fold increase in p53, and 4-fold decreases in NF-{kappa}B, Pim-1, and c-Myb protein levels compared to their phenotypically normal littermates (P < 0.05). Additionally, VPA increased the ratio of embryonic Bax/Bcl-2 protein levels (P < 0.05). Pretreatment of pregnant dams with either folic acid or pantothenic acid prior to VPA significantly protected against VPA-induced NTDs (P < 0.05). Folic acid also reduced VPA-induced alterations in p53, NF-{kappa}B, Pim-1, c-Myb, and Bax/Bcl-2 protein levels, while pantothenic acid prevented VPA-induced alterations in NF-{kappa}B, Pim-1, and c-Myb. We hypothesize that folic acid and pantothenic acid protect CD-1 embryos from VPA-induced NTDs by independent, but not mutually exclusive mechanisms, both of which may be mediated by the prevention of VPA-induced alterations in proteins involved in neurulation.

  9. Folic acid and pantothenic acid protection against valproic acid-induced neural tube defects in CD-1 mice.

    PubMed

    Dawson, Jennifer E; Raymond, Angela M; Winn, Louise M

    2006-03-01

    In utero exposure to valproic acid (VPA) during pregnancy is associated with an increased risk of neural tube defects (NTDs). Although the mechanism by which VPA mediates these effects is unknown, VPA-initiated changes in embryonic protein levels have been implicated. The objectives of this study were to investigate the effect of in utero VPA exposure on embryonic protein levels of p53, NF-kappaB, Pim-1, c-Myb, Bax, and Bcl-2 in the CD-1 mouse. We also evaluated the protective effects of folic acid and pantothenic acid on VPA-induced NTDs and VPA-induced embryonic protein changes in this model. Pregnant CD-1 mice were administered a teratogenic dose of VPA prior to neural tube closure and embryonic protein levels were analyzed. In our study, VPA (400 mg/kg)-induced NTDs (24%) and VPA-exposed embryos with an NTD showed a 2-fold increase in p53, and 4-fold decreases in NF-kappaB, Pim-1, and c-Myb protein levels compared to their phenotypically normal littermates (P<0.05). Additionally, VPA increased the ratio of embryonic Bax/Bcl-2 protein levels (P<0.05). Pretreatment of pregnant dams with either folic acid or pantothenic acid prior to VPA significantly protected against VPA-induced NTDs (P<0.05). Folic acid also reduced VPA-induced alterations in p53, NF-kappaB, Pim-1, c-Myb, and Bax/Bcl-2 protein levels, while pantothenic acid prevented VPA-induced alterations in NF-kappaB, Pim-1, and c-Myb. We hypothesize that folic acid and pantothenic acid protect CD-1 embryos from VPA-induced NTDs by independent, but not mutually exclusive mechanisms, both of which may be mediated by the prevention of VPA-induced alterations in proteins involved in neurulation.

  10. Inhalation reproductive toxicology studies: Male dominant lethal study of n-hexane in Swiss (CD-1) mice: Final report

    SciTech Connect

    Mast, T.J.; Rommereim, R.L.; Evanoff, J.J.; Sasser, L.B.; Decker, J.R.; Stoney, K.H.; Weigel, R.J.; Westerberg, R.B.

    1988-08-01

    The straight-chain hydrocarbon, n-hexane, is a volatile, ubiquitous solvent routinely used in industrial environments; consequently, the opportunity for industrial, environmental or accidental exposure to hexane vapors is significant. Although myelinated nerve tissue is the primary target organ of hexane, the testes have also been identified as being sensitive to hexacarbon exposure. The objective of this study was to evaluate male dominant lethal effects in Swiss (CD-1) mice after exposure to 0, 200, 1000, or 5000 ppM n-hexane, 20 h/day for 5 consecutive days. Each exposure concentration consisted of 30 randomly selected, proven male breeders; 4 groups. The mice were weighed just prior to the first day of exposure and at weekly intervals until sacrifice. Ten males in each dose group were sacrificed one day after the cessation of exposure, and their testes and epididymides were removed for evaluation of the germinal epithelium. The remaining male mice, 20 per group, were individually housed in hanging wire-mesh breeding cages where they were mated with unexposed, virgin females for eight weekly intervals; new females were provided each week. The mated females were sacrificed 12 days after the last day of cohabitation and their reproductive status and the number and viability of the implants were recorded. The appearance and behavior of the male mice were unremarkable throughout the study period and no evidence of n-hexane toxicity was observed. 18 refs., 3 figs., 11 tabs.

  11. Effects of postweaning social and physical deprivation on locomotor activity patterns and explorative behavior in female CD-1 mice.

    PubMed

    Haupt, Moritz; Schaefers, Andrea T U

    2010-05-01

    Social and physical deprivation during adolescence has detrimental consequences for brain maturation and cognitive functions. To test the hypothesis that social and physical deprivation during mouse adolescence would disrupt activity and exploration behavior, we exposed mice either to deprived or enriched rearing (postnatal days 21-60) and assessed activity and exploration of adult mice individually or in mixed treatment groups. In automated group compartments, deprived-reared mice displayed higher locomotor activity, reduced explorative behavior and shifted activity timing compared to enriched-reared mice. Contrastingly, distance and timing of wheel running were largely unaffected by deprived rearing. Our results demonstrate that postweaning social and physical deprivation has measurable effects on mouse locomotor and exploratory behavior, and that such effects may be discernable depending on the activity type studied. Our results further emphasize the importance of the sensitive postweaning period for shaping adult behavioral profiles.

  12. The effect of fenbuconazole on cell proliferation and enzyme induction in the liver of female CD1 mice

    SciTech Connect

    Juberg, Daland R.; Mudra, Daniel R.; Hazelton, George A.; Parkinson, Andrew

    2006-07-15

    Fenbuconazole, a triazole fungicide, has been associated with an increase in the incidence of liver adenomas in female mice following long-term dietary exposure. The aim of this study was to evaluate whether the mode of action for liver tumor formation by fenbuconazole is similar to that of phenobarbital. Treatment of CD1 mice with 0, 20, 60, 180 or 1300 ppm fenbuconazole for up to 4 weeks caused a dose-dependent increase in liver weight that was associated with centrilobular hepatocellular hypertrophy, cytoplasmic eosinophilia and panlobular hepatocellular vacuolation, as well as an initial increase in the cell proliferation labeling index. Fenbuconazole also caused a dose-dependent increase in liver microsomal cytochromes b{sub 5} and P450 and the levels of immunoreactive CYP2B10 and its associated activity 7-pentoxyresorufin O-dealkylation (PROD). Treatment of mice with 1000 ppm phenobarbital elicited the same effects as treatment of mice with 1300 ppm fenbuconazole, except that phenobarbital was more effective than fenbuconazole at inducing PROD activity, even though fenbuconazole induced CYP2B10 to the same extent as did phenobarbital. This difference was attributed to the ability of fenbuconazole to bind tightly to CYP2B10 and partially mask its catalytic activity in liver microsomes, which is characteristic of several azole-containing drugs. All hepatocellular changes and induced enzyme activity returned to control levels within 4 weeks of discontinuing treatment with fenbuconazole or phenobarbital, indicating that the observed changes were fully reversible. We conclude that fenbuconazole is a phenobarbital-type inducer of mouse liver cytochrome P450, and the mode of action by which fenbuconazole induces liver adenomas in mice is similar to that of phenobarbital.

  13. Evaluation of the developmental toxicity of ethylene glycol aerosol in CD-1 mice by nose-only exposure.

    PubMed

    Tyl, R W; Ballantyne, B; Fisher, L C; Fait, D L; Dodd, D E; Klonne, D R; Pritts, I M; Losco, P E

    1995-08-01

    Ethylene glycol (EG; CAS No. 107-21-1) is teratogenic to mice by whole-body (WB) exposure to aerosol (1000-2500 mg/m3). The WB results were confounded by possible exposure from ingestion after grooming and/or from percutaneous absorption. Therefore, CD-1 mice were exposed to EG aerosol (MMAD 2.6 +/- 1.7 microns) on Gestational Days (GD) 6 through 15, 6 hr/day, by nose-only (NO) (0, 500, 1000, or 2500 mg/m3) or WB exposures (0 or 2100 mg/m3, as positive control), 30/group. Five additional "satellite" females each at 2500 mg/m3 NO and 2100 mg/m3 WB were exposed on GD 6 for measurement of EG on fur. Control environments were water aerosol (4200 mg/m3 for NO; 2700 mg/m3 for WB). Females were weighed and evaluated for clinical signs and water consumption throughout gestation. On GD 18, maternal uterus, liver, and kidneys (2) were weighed, with kidneys examined microscopically. Corpora lutea and implantation sites were recorded. Live fetuses were weighed, sexed, and examined for structural alterations. For NO dams, kidney weights were increased at 1000 and 2500 mg/m3; no renal lesions and no other treatment-related maternal toxicity were observed. There were no effects on pre- or postimplantation loss; fetal body weights/litter were reduced at 2500 mg/m3. At 2500 mg/m3, incidences of fused ribs and skeletal variations were increased. The 2500 mg/m3 NO satellite animals had approximately 330 mg/kg extractable EG. The WB group exhibited maternal and developmental toxicity including increased fetal skeletal malformations and variations, confirming previous results, with 1390 mg/kg extractable EG on fur. Therefore, exposure of CD-1 mice to a respirable EG aerosol during organogenesis by NO inhalation resulted in minimal maternal toxicity at 1000 and 2500 mg/m3 and developmental toxicity at 2500 mg/m3. The NOAEL was 500 mg/m3 NO for maternal and 1000 mg/m3 NO for developmental toxicity. This study supports the interpretation of the initial EG WB results as due to systemic

  14. Effects of a 28-Day Cage-Change Interval on Intracage Ammonia Levels, Nasal Histology, and Perceived Welfare of CD1 Mice

    PubMed Central

    Vogelweid, Catherine M; Zapien, Kathleen A; Honigford, Matthew J; Li, Linghui; Li, Hua; Marshall, Heather

    2011-01-01

    We measured daily intracage ammonia levels and performed weekly assessments of CD1 male, female, and breeder mice housed within disposable, ventilated cages that remained unchanged for 28 d. We tested housing groups comprising 1, 3, or 5 sex-matched mice per cage and breeder pairs with litters. Mice housed in cages with higher concentrations of ammonia developed degeneration and inflammatory lesions in the nasal passages. Mean ammonia exposure levels that caused rhinitis were 181 ppm for 18 d. Ammonia exposures of 93 ppm for 16 d caused necrosis of the olfactory epithelium, whereas 52 ppm for 13 d caused epithelial degeneration. Observers could not detect visible signs of rhinitis or identify cages with elevated ammonia levels, nor did they identify any sick or distressed mice. Observers consistently assigned poorer welfare scores as cages became dirtier. We conclude that we can extend the cage-change interval to at least 28 d for disposable, ventilated caging housing a single CD1 mouse. Cages containing 3 CD1 mice of either sex should be changed biweekly, and cages containing 5 CD1 mice or breeder pairs should be changed at least once weekly. PMID:22330779

  15. Fatal placental hemorrhage in pregnant CD-1 mice following one oral dose of T-2 toxin.

    PubMed Central

    Rousseaux, C G; Nicholson, S; Schiefer, H B

    1985-01-01

    Forty-eight hours after oral administration of a single dose (3.0 mg/kg BW) of T-2 toxin to mice on days 7, 8, 10, 11 and 12 of pregnancy, 17% maternal mortality following vaginal hemorrhage was encountered. Necropsy examination of the dead females revealed that massive hemorrhages originating from the placental regions had occurred into the reproductive tract. This observation supports the studies in which hemorrhagic disease has been described as characteristic for intoxications with T-2 toxin. The results suggest that fatal hemorrhage during pregnancy can occur in hemochorial and hemoendotheliochorial placental mammals as a result of T-2 toxin administration. Images Fig. 1. Fig. 2. PMID:3986684

  16. Anabolic steroid- and exercise-induced cardio-depressant cytokines and myocardial β1 receptor expression in CD1 mice.

    PubMed

    Fineschi, Vittorio; Di Paolo, Marco; Neri, Margherita; Bello, Stefania; D'Errico, Stefano; Dinucci, Dinuccio; Parente, Ruggero; Pomara, Cristoforo; Rabozzi, Roberto; Riezzo, Irene; Turillazzi, Emanuela

    2011-02-01

    Few animal model studies have been conducted in order to evaluate the impact of androgenic anabolic steroids (AAS) supraphysiological doses on the cardiovascular system and myocardial injury. Twenty-five male CD1 mice (8-10 weeks old; 35g initial body weight) were randomized into three AAS treated groups and two control groups. The AAS mice received intramuscular Nandrolone Decanoate (DECA-DURABOLIN), vehicled in arachidis oil, for 42 days, twice per week, with different dosages, studying plasma lipid analysis, cardiac histopathological features, cardiac β (1) adrenergic receptor expression, and the effects of the myocardial expression of inflammatory mediators (IL-1β, TNF-α) on the induction of cardiomyocytes apoptosis (HSP 70, TUNEL), using proteomic and immunohistochemical analysis. The mice had free movements in their animal rooms (two groups) or exercised by running on a motor-driven treadmill the others three groups. Recurring high dose AAS administration and physical training in mice produce significant increase in body weight and for total cholesterol. A moderate increase of the heart weight, cardiac hypertrophy and wide colliquative myocytolysis, were observed in high dose AAS administration and physical training group. The expression of HSP70 and inflammatory cytokine IL-1β, increased in the three AAS-treated groups. TNF- α showed a more extensive expression in the AAS-high dose group. A significant apoptotic process randomly sparse in the myocardium was described. Our data support the hypothesis that the combined effects of vigorous training, anabolic steroid abuse and stimulation of the sympathetic nervous system, may predispose to myocardial injury.

  17. In vivo assessment of bone marrow toxicity by gold nanoparticle-based bioconjugates in Crl:CD1(ICR) mice

    PubMed Central

    Berce, Cristian; Lucan, Ciprian; Petrushev, Bobe; Boca, Sanda; Miclean, Mirela; Sarpataki, Orsolya; Astilean, Simion; Buzoianu, Anca; Tomuleasa, Ciprian; Bojan, Anca

    2016-01-01

    Introduction The present study aimed at evaluating the biodistribution of Tween® 20-gold nanoparticle (GNP) conjugates and their potential toxicity on the bone marrow before moving on to Phase I clinical trials. Materials and methods Tween® 20-conjugated GNPs were injected intravenously for 21 days in male Crl:CD1(ICR) mice. Body weight of the mice was evaluated each day. After the sub-chronic Tween® 20-GNPs administration, blood samples were harvested, and a full blood count was done individually. Total Au quantity from all major organs was assessed using inductively coupled plasma mass spectrometry. One femur and the sternum obtained from each animal were used for histological assessment. Results Our data showed that the Tween® 20-GNP conjugates were found in large quantities in the bladder. Au was shown to accumulate in the hematopoietic bone tissue, with significant side effects such as leucopoiesis and megakaryopoiesis. The mice had a higher white blood cell and platelet count as opposed to the control group. This suggested that the previously described leukopenic effects of isoflurane were overridden by the leucopoietic effects of Tween® 20-GNPs. Conclusion It was uncertain whether the mice were reactive to Au as it is a foreign substance to the tissues or whether the side effects observed were a precursor condition of a more severe hematological condition. Au was found to be hepatotoxic, urging the need for further studies in order to achieve better in vivo compliance and exploit the immense potential of GNPs in cancer pharmacology. PMID:27621620

  18. Hepatic mitochondrial alteration in CD1 mice associated with prenatal exposures to low doses of perfluorooctanoic acid (PFOA)

    PubMed Central

    Quist, Erin M.; Filgo, Adam J.; Cummings, Connie A.; Kissling, Grace E.; Hoenerhoff, Mark J.; Fenton, Suzanne E.

    2014-01-01

    Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPARs), PFOA exposure can induce defects in fatty acid oxidation, lipid transport, and inflammation. Here, pregnant CD-1 mice were orally gavaged with 0, 0.01, 0.1, 0.3 and 1 mg/kg of PFOA from gestation days (GD) 1 through 17. On postnatal day (PND) 21, histopathologic changes in the livers of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND 91 in an apparent dose-dependent response. Transmission electron microscopy (TEM) of selected liver sections from PND 91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. Within hypertrophied hepatocytes, mitochondria were not only increased in number, but also exhibited altered morphologies suggestive of increased and/or uncontrolled fission and fusion reactions. These findings suggest that peroxisome proliferation is not a component of PFOA-induced hepatic toxicity in animals that are prenatally exposed to low doses of PFOA. PMID:25326589

  19. Chlorination byproducts induce gender specific autistic-like behaviors in CD-1 mice.

    PubMed

    Guariglia, Sara Rose; Jenkins, Edmund C; Chadman, Kathryn K; Wen, Guang Y

    2011-10-01

    In 2000, the Agency for Toxic Substances and Disease Registry (ATSDR) released a report concerning elevated autism prevalence and the presence water chlorination byproducts in the municipal drinking water supply in Brick Township, New Jersey. The ATSDR concluded that it was unlikely that these chemicals, specifically chloroform, bromoform (Trihalomethanes; THMs) and tetrachloroethylene (Perchloroethylene; PCE) had contributed to the prevalence of autism in this community based upon correlations between timing of exposure and/or concentration of exposure. The ATSDR conclusion may have been premature, as there is no conclusive data evidencing a correlation between a particular developmental time point that would render an individual most susceptible to toxicological insult with the development of autism. Therefore, it was our aim to determine if these chemicals could contribute to autistic like behaviors. We found that males treated with THMs and PCE have a significant reduction in the number of ultrasonic vocalizations (USVs) emitted in response to maternal separation, which are not attributed to deficits in vocal ability to or to lesser maternal care. These same males also show significantly elevated anxiety, an increase in perseverance behavior and a significant reduction in sociability. The sum of our data suggests that male, but not female mice, develop autistic like behaviors after gestational and postnatal exposure to the aforementioned chemical triad via drinking water. We believe development of such aberrant behaviors likely involves GABAergic system development.

  20. Prolonged prenatal exposure to low-level ozone affects aggressive behaviour as well as NGF and BDNF levels in the central nervous system of CD-1 mice.

    PubMed

    Santucci, Daniela; Sorace, Alberto; Francia, Nadia; Aloe, Luigi; Alleva, Enrico

    2006-01-06

    The long-term effects on isolation-induced aggressive behaviour and central NGF and BDNF levels of gestational exposures to ozone (O(3)) were evaluated in adult CD-1 mice. Females were exposed to O(3), at the dose of 0.0, 0.3 or 0.6 ppm from 30 days prior the formation of breeding pairs until gestational day 17. Litters were fostered at birth to untreated dams and, at adulthood, male offspring underwent five successive daily encounters (15 min each) with a standard opponent of the same strain, sex, weight and age. The encounters on day 1, 3 and 5 were videotaped and agonistic and non-agonistic behavioural items finely scored. O(3)-exposed mice showed a significant increase in freezing and defensive postures, a decrease in nose-sniffing behaviour and reduced progressively the aggressive behavioural profile displayed on day 1. Reduced NGF levels in the hippocampus and increased BDNF in the striatum were also found upon O(3) exposure.

  1. Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice.

    PubMed

    Terse, Pramod; Engelke, Kory; Chan, Kenneth; Ling, Yonghua; Sharpnack, Douglas; Saunthararajah, Yogen; Covey, Joseph M

    2014-01-01

    Decitabine (5-aza-2'-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and β-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on 2 consecutive days/week for up to 9 weeks followed by a 28-day recovery to support its clinical trials up to 9-week duration. Tetrahydrouridine, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. End points evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry, or urinalysis parameters. Dose- and gender-dependent changes in plasma DAC levels were observed with a Cmax within 1 hour. At the 1 mg/kg dose tested, THU increased DAC plasma concentration (∼ 10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high-dose 1 mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes and decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils, and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis, and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoiesis, and genotoxicity. Following the recovery period, a complete or trend toward resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity

  2. Long-term betamethasone 21-phosphate disodium treatment has distinct effects in CD1 and DBA/2 mice on animal behavior accompanied by opposite effects on neurogenesis.

    PubMed

    Aiello, Rossana; Crupi, Rosalia; Leo, Antonio; Chimirri, Serafina; Rispoli, Vincenzo; Marra, Rosario; Citraro, Rita; Cuzzocrea, Salvatore; De Sarro, Giovambattista; Russo, Emilio

    2015-02-01

    One of the most peculiar characteristics of the stress response is the pronounced inter-individual and inter-strain variability both in behavioral and neurochemical outcomes. Several studies confirm that rodents belonging to the same or different strain and/or gender, when exposed to a stressor, may show behavioral and cognitive differences. We compared the effects of long-term betamethasone 21-phosphate disodium (BTM), a widely clinically used corticosteroid, on animal behavior and neurogenesis in CD1 and DBA/2 mice. BTM treatment, in CD1 mice, increased body weight gain and anxiety parameters while having pro-depressant effects. Furthermore, BTM significantly reduced neurogenesis in the dentate gyrus of the hippocampus. Finally, BTM treatment induced a significant impairment in memory and learning performance in the Morris water maze. At odds, BTM administration, in DBA/2 mice, caused a significant reduction in the body weight while not modifying anxiety parameters. In addition, both an increased synaptogenesis and neurogenesis were found. Similarly to CD1 mice, also in DBA/2 mice, memory and learning were impaired. Our data confirm that long-term exposure to corticosteroids can generate or aggravate psychiatric/neurologic disorders such as depression, anxiety, memory and learning. Our study did not reveal significant differences between corticosterone and BTM treatment in CD1 mice. In contrast, BTM treatment in mice with an anxious phenotype (DBA/2 mice) revealed some contrasting results indicating that genetic factors can influence corticosteroids dependent effects. Finally, our data further underline the need for a re-evaluation of neurogenesis role; the increased neurogenesis observed in DBA/2 mice and behavioral effects might be distinguished phenomena.

  3. THE EMBRYOLETHALITY OF LIPOPOLYSACCHARIDE IN CD-1 AND METALLOTHIONEIN I-II NULL MICE: LACK OF A ROLE FOR INDUCED ZINC DEFICIENCY OR METALLOTHIONEIN INDUCTION

    EPA Science Inventory

    ABSTRACT

    Lipopolysaccharide (LPS) is embryolethal in CD-1 mice. LPS induces metallothionein (MT) via cytokines, including TNF-, IL-1 and IL-6, which initiate and maintain the acute phase response. Maternal hepatic MT induction in pregnant rats, by diverse toxicants, can ...

  4. EFFECT OF GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE (EDS), BROMOCHLOROACETIC ACID (BCA) AND MOLINATE ON REPRODUCTIVE FUNCTION IN CD-1 MALE MICE

    EPA Science Inventory

    EFFECT OF GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE (EDS), BROMOCHLOROACETIC ACID (BCA) AND MOLINATE ON REPRODUCTIVE FUNCTION IN CD-1 MALE MICE. D.K. Tarka1,2 , G.R. Klinefelter2, J.C. Rockett2, J.D. Suarez2, N.L. Roberts2 and J.M. Rogers1,2. 1 University of North Carol...

  5. In utero exposure to benzene increases embryonic c-Myb and Pim-1 protein levels in CD-1 mice

    SciTech Connect

    Wan, Joanne; Winn, Louise M.

    2008-05-01

    Benzene is a known human leukemogen, but its role as an in utero leukemogen remains controversial. Epidemiological studies have correlated parental exposure to benzene with an increased incidence of childhood leukemias. We hypothesize that in utero exposure to benzene may cause leukemogenesis by affecting the embryonic c-Myb/Pim-1 signaling pathway and that this is mediated by oxidative stress. To investigate this hypothesis, pregnant CD-1 mice were treated with either 800 mg/kg of benzene or corn oil (i.p.) on days 10 and 11 of gestation and in some cases pretreated with 25 kU/kg of PEG-catalase. Phosphorylated and total embryonic c-Myb and Pim-1 protein levels were assessed using Western blotting and maternal and embryonic oxidative stress were assessed by measuring reduced to oxidized glutathione ratios. Our results show increased oxidative stress at 4 and 24 h after exposure, increased phosphorylated Pim-1 protein levels 4 h after benzene exposure, and increased Pim-1 levels at 24 and 48 h after benzene exposure. Embryonic c-Myb levels were elevated at 24 h after exposure. PEG-catalase pretreatment prevented benzene-mediated increases in embryonic c-Myb and Pim-1 protein levels, and benzene-induced oxidative stress. These results support a role for ROS in c-Myb and Pim-1 alterations after in utero benzene exposure.

  6. Effect of Cage-Induced Stereotypies on Measures of Affective State and Recurrent Perseveration in CD-1 and C57BL/6 Mice

    PubMed Central

    Novak, Janja; Bailoo, Jeremy D.; Melotti, Luca; Würbel, Hanno

    2016-01-01

    Stereotypies are abnormal repetitive behaviour patterns that are highly prevalent in laboratory mice and are thought to reflect impaired welfare. Thus, they are associated with impaired behavioural inhibition and may also reflect negative affective states. However, in mice the relationship between stereotypies and behavioural inhibition is inconclusive, and reliable measures of affective valence are lacking. Here we used an exploration based task to assess cognitive bias as a measure of affective valence and a two-choice guessing task to assess recurrent perseveration as a measure of impaired behavioural inhibition to test mice with different forms and expression levels of stereotypic behaviour. We trained 44 CD-1 and 40 C57BL/6 female mice to discriminate between positively and negatively cued arms in a radial maze and tested their responses to previously inaccessible ambiguous arms. In CD-1 mice (i) mice with higher stereotypy levels displayed a negative cognitive bias and this was influenced by the form of stereotypy performed, (ii) negative cognitive bias was evident in back-flipping mice, and (iii) no such effect was found in mice displaying bar-mouthing or cage-top twirling. In C57BL/6 mice neither route-tracing nor bar-mouthing was associated with cognitive bias, indicating that in this strain these stereotypies may not reflect negative affective states. Conversely, while we found no relation of stereotypy to recurrent perseveration in CD-1 mice, C57BL/6 mice with higher levels of route-tracing, but not bar-mouthing, made more repetitive responses in the guessing task. Our findings confirm previous research indicating that the implications of stereotypies for animal welfare may strongly depend on the species and strain of animal as well as on the form and expression level of the stereotypy. Furthermore, they indicate that variation in stereotypic behaviour may represent an important source of variation in many animal experiments. PMID:27145080

  7. Evaluation of toluene exposure via drinking water on levels of regional brain biogenic monoamines and their metabolites in CD-1 mice

    SciTech Connect

    Hsieh, G.C.; Sharma, R.P.; Parker, R.D.; Coulombe, R.A. Jr. )

    1990-10-01

    Toluene, a potentially neurotoxic substance, is found in trace amounts in groundwater. Adult male CD-1 mice were continuously fed drinking water ad libitum containing 0, 17, 80, and 405 mg/liter toluene. After a 28-day treatment, animals were tested for endogenous levels of the biogenic monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and their respective metabolites, 3-methoxy-4-hydroxymandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), in six discrete brain regions. The maximum toluene-induced increases of biogenic amines and their metabolites generally occurred at a toluene concentration of 80 mg/liter. In the hypothalamus, a major NE-containing compartment, the concentrations of NE significantly increased by 51, 63, and 34% in groups dosed with 17, 80, and 405 mg/liter, respectively. Significant increases of NE were also observed in the medulla oblongata and midbrain. Concomitantly, concentrations of VMA increased in various brain regions. Concentrations of DA were significantly higher in the corpus striatum and hypothalamus. Alterations in levels of DA metabolites, DOPAC and HVA, were marginal. Toluene significantly increased concentrations of 5-HT in all dissected brain regions, except cerebellum, and increased the 5-HIAA levels in the hypothalamus, corpus striatum, and cerebral cortex.

  8. Susceptibility of germfree or antibiotic-treated adult mice to Cryptosporidium parvum.

    PubMed

    Harp, J A; Wannemuehler, M W; Woodmansee, D B; Moon, H W

    1988-08-01

    Adult mice are more resistant than neonatal mice to intestinal colonization with the protozoan parasite Cryptosporidium parvum. Development of a mature intestinal flora may play a role in this resistance. We compared susceptibilities to colonization with C. parvum in adult conventional mice, adult germfree mice, and adult conventional mice treated with oral antibiotics to deplete the intestinal flora. Germfree mice of both CD1 and BALB/c strains were colonized at day 7 following inoculation with C. parvum oocysts isolated from the feces of an infected, diarrheic calf. Age-matched conventional mice of the same strains were comparatively resistant to colonization. Conventional mice treated with antibiotics remained resistant to colonization. These results suggest that the microflora in the intestine was not the sole determinant of resistance or susceptibility to colonization. The germfree adult mouse as an experimental model of cryptosporidiosis is discussed.

  9. A new easy accessible and low-cost method for screening olfactory sensitivity in mice: behavioural and nociceptive response in male and female CD-1 mice upon exposure to millipede aversive odour.

    PubMed

    Capone, Francesca; Puopolo, Maria; Branchi, Igor; Alleva, Enrico

    2002-06-01

    In a previous study, mice were found to be repelled by the odour emitted by the millipede (Ommatoiulus sabulosus) as a defensive strategy against predators [Physiol. Behav. 74 (2001) 305-311]. To develop a standardised test for screening olfactory capabilities in rodents, we have characterised the behavioural response displayed by adult male and female CD-1 mice when exposed to a Stimulus Object (SO) consisting of a millipede-shaped sponge previously soaked either in a Toluquinone (TQ) solution (5g/100ml; Fluka), a chemical component of the exudate secreted by the millipede, or in distilled water. In Experiment 1, behaviours performed when exposed to the SO were scored (15min for 5 consecutive days). TQ exposure suppressed nearly completely Catching and Eating the SO, and increased general activity in a sex-dependent fashion. In Experiment 2, performances in a hot-plate test (50+/-0.5 degrees C, cut-off 60s) were assessed immediately after a 15-min exposure to the SO. Toluquinone-exposed mice showed a subtle yet significant decrease of pain threshold. TQ exposure assay is a new, easily testable, and low-cost method for measuring rodents olfactory sensitivity relevant for the analysis of the pharmacological agents, lesions and transgenesis.

  10. Emotional responses and memory performance of middle-aged CD1 mice in a 3D maze: effects of low infrared light.

    PubMed

    Michalikova, S; Ennaceur, A; van Rensburg, R; Chazot, P L

    2008-05-01

    Non-thermal near infra-red (IR) has been shown to have many beneficial photobiological effects on a range of cell types, including neurons. In the present study, a pretreatment with a daily 6 min exposure to IR1072 for 10 days yielded a number of significant behavioral effects on middle-aged female CD-1 mice (12-months) tested in a 3D-maze. Middle-aged mice show significant deficits in a working memory test and IR treatment reversed this deficit. Interestingly, the IR treated middle-aged group despite making less memory errors than sham middle-aged group spent longer time in different parts of the maze than both the young group (3-months) and sham-middle-aged group (12-months). Young mice appeared more anxious than middle-aged mice in the first sessions of the test. Exposure to IR appeared to have no significant effects upon exploratory activity or anxiety responses. However, it elicited significant effects on working memory, with the IR middle-aged mice being more considerate in their decision making, which results in an overall improved cognitive performance which is comparable to that of young CD-1 mice. The present study describes a novel method for assessing emotional responses and memory performance in a 3D spatial navigation task and demonstrates the validity of our new all-in-one test and its sensitivity to ageing and non-invasive beneficial IR treatment.

  11. The combination of ethanol with mephedrone increases the signs of neurotoxicity and impairs neurogenesis and learning in adolescent CD-1 mice.

    PubMed

    Ciudad-Roberts, Andrés; Duart-Castells, Leticia; Camarasa, Jorge; Pubill, David; Escubedo, Elena

    2016-02-15

    A new family of psychostimulants, under the name of cathinones, has broken into the market in the last decade. In light of the fact that around 95% of cathinone consumers have been reported to combine them with alcoholic drinks, we sought to study the consequences of the concomitant administration of ethanol on mephedrone -induced neurotoxicity. Adolescent male Swiss-CD1 mice were administered four times in one day, every 2h, with saline, mephedrone (25mg/kg), ethanol (2; 1.5; 1.5; 1g/kg) and their combination at a room temperature of 26±2°C. The combination with ethanol impaired mephedrone-induced decreases in dopamine transporter and tyrosine hydroxylase in the frontal cortex; and in serotonin transporter and tryptophan hydroxylase in the hippocampus by approximately 2-fold, 7days post-treatment. Furthermore, these decreases correlated with a 2-fold increase in lipid peroxidation, measured as concentration of malondialdehyde (MDA), 24h post-treatment, and were accompanied by changes in oxidative stress-related enzymes. Ethanol also notably potentiated mephedrone-induced negative effects on learning and memory, as well as hippocampal neurogenesis, measured through the Morris water maze (MWM) and 5-bromo-2'-deoxyuridine staining, respectively. These results are of special significance, since alcohol is widely co-abused with amphetamine derivatives such as mephedrone, especially during adolescence, a crucial stage in brain maturation. Given that the hippocampus is greatly involved in learning and memory processes, normal brain development in young adults could be affected with permanent behavioral consequences after this type of drug co-abuse.

  12. Preference for high-fat diet is developed by young Swiss CD1 mice after short-term feeding and is prevented by NMDA receptor antagonists.

    PubMed

    Buttigieg, Angie; Flores, Osvaldo; Hernández, Alejandro; Sáez-Briones, Patricio; Burgos, Héctor; Morgan, Carlos

    2014-01-01

    Obesity is a worldwide epidemic that is increasing at an alarming rate. One of its causes is the increased availability and consumption of diets rich in fat. In the present study, we investigated the effects of short-term consumption of a high fat diet (HFD) on dietary preferences in Swiss CD1 mice and its relation in time to specific metabolic effects. Mice that were weaned 21days postpartum and fed a chow diet for one week were afterward subjected to a diet preference test for 5days, exposed to both a regular diet (RD) and HFD. We found that mice did not show any preferences. In a second experiment, two groups of mice that were weaned 21days postpartum and subjected to a chow diet for one week were fed either RD or HFD for 18days, and a diet preference test was performed for 5days. After this short-term consumption of HFD, mice preferred HFD, while mice subjected to RD did not show any preference. Importantly, no differences in blood glucose levels were found between the groups prior to and after the experiments. The results support our hypothesis that the preference for HFD is not a spontaneous behavior in CD1 mice, but it can be observed after short-term consumption; additionally, this preference develops before metabolic effects appear. Finally, this preference for HFD could not be observed when the mice were i.p. injected daily with low doses of the NMDA receptor antagonists, ketamine, ifenprodil or MK-801 during the HFD feeding period. These data suggest that acquisition of dietary preference for HFD is a NMDA receptor-dependent learning process.

  13. The effects of chronic exposure to common bedding materials on the metabolic rate and overall health of male CD-1 mice.

    PubMed

    Becker, Corey E; Mathur, Carolyn F; Rehnberg, Bradley G

    2010-01-01

    Anecdotes and personal Web pages claim that cedar and pine beddings cause respiratory distress in rodents, although no previous research could be found to support these claims. There have, however, been published studies of respiratory distress in cedar and pine mill workers. That research links exposure to wood dust to asthma and to bronchial and alveolar damage in humans. This study looks at the effects of 3 types of bedding (CareFRESH Original, cedar, and pine) on the growth, food intake, oxygen consumption, IgE antibody concentrations, and general appearance and behavior in male CD-1 mice. Mice who were housed on these beddings for approximately 4 months did not show significant differences in any of these variables. This suggests that these 3 materials provide equally healthy substrates for long-term rearing of mice and possibly other rodents.

  14. Final report on the reproductive toxicity of n,n'-methylenebisacrylamide (BACR) (CAS No. 110-26-9) in CD-1 (trade name) swiss mice. Laboratory supplement. Report for 1 May 1990-31 March 1991

    SciTech Connect

    Not Available

    1993-01-01

    The laboratory supplement for developmental toxicity testing of N,N'-methylbisacrylamide in CD1 Swiss mice describes experimental protocols and chemical analysis of the compound and contains an overview of the published literature on the subject.

  15. Final report on the reproductive toxicity of acrylamide (ACRL) (CAS No. 79-06-1) CD-1 (trade name) swiss mice. Laboratory supplement. Report for 1 February-30 December 1990

    SciTech Connect

    Not Available

    1993-01-01

    The document is the laboratory supplement to the Final Report on the Reproductive Toxicity of Acrylamide in CD-1 Swiss Mice. It provides a review of previous studies, experimental protocols, and data on the chemical analyses of the compound used.

  16. Brucella abortus S19 and RB51 vaccine immunogenicity test: Evaluation of three mice (BALB/c, Swiss and CD-1) and two challenge strains (544 and 2308).

    PubMed

    Miranda, Karina Leite; Dorneles, Elaine Maria Seles; Pauletti, Rebeca Barbosa; Poester, Fernando Padilla; Lage, Andrey Pereira

    2015-01-15

    The aim of the present study was to evaluate the use of different mouse strains (BALB/c, Swiss and CD-1) and different challenge strains (Brucella abortus 544 and 2308) in the study of B. abortus vaccine (S19 and RB51) immunogenicity test in the murine model. No significant difference in B. abortus vaccine potency assay was found with the use of B. abortus 544 or B. abortus 2308 as challenge strain. Results of variance analysis showed an interaction between treatment and mouse strain; therefore these parameters could not be compared separately. When CD-1 groups were compared, those vaccinated showed significantly lower counts than non-vaccinated ones (P<0.05), independently of the vaccine received (S19 or RB51). Similar results were observed on BALB/c groups. However, in Swiss mouse groups, S19 was more protective than RB51 (P<0.05), which showed protection when compared to the non-vaccinated group (P<0.05). In summary, data from the present study showed that CD-1, BALB/c and Swiss mice strains, as well as both challenge strains, B. abortus strains 544 and 2308, can be used in immunogenicity tests of S19 and RB51 vaccines.

  17. Final report on the reproductive toxicity of acrylamide (ACRL) (CAS No. 79-06-1) in CD-1 (trade name) swiss mice

    SciTech Connect

    Not Available

    1993-01-01

    Acrylamide (ACRL), known to cause reproductive toxicity, neurotoxicity, and induce dominant lethal mutations, was tested in a modified Reproductive Assessment by Continuous Breeding (RACB) Protocol in Swiss CD-1 mice. Exposure to ACRL in water at dose levels of 30 ppm (9.2 mg/kg) resulted in slight reproductive toxicity (decreased pups/litter and spermatid head counts) and increased postimplantation loss (dominant lethal effect) in the absence of demonstrable neurotoxicity for the F0 animals. F1 animals dosed with 30 ppm ACRL were more severely affected than the F0 animals exhibiting a more profound effect on fertility in the presence of slight neurotoxicity (decreased grip strength in males).

  18. Chronic nandrolone administration promotes oxidative stress, induction of pro-inflammatory cytokine and TNF-α mediated apoptosis in the kidneys of CD1 treated mice

    SciTech Connect

    Riezzo, Irene; Turillazzi, Emanuela; Bello, Stefania; Cantatore, Santina; Cerretani, Daniela; Di Paolo, Marco; Fiaschi, Anna Ida; Frati, Paola; Neri, Margherita; Pedretti, Monica; Fineschi, Vittorio

    2014-10-01

    Nandrolone decanoate administration and strenuous exercise increase the extent of renal damage in response to renal toxic injury. We studied the role played by oxidative stress in the apoptotic response caused by nandrolone decanoate in the kidneys of strength-trained male CD1 mice. To measure cytosolic enzyme activity, glutathione peroxidase (GPx), glutathione reductase (GR) and malondialdehyde (MDA) were determined after nandrolone treatment. An immunohistochemical study and Western blot analysis were performed to evaluate cell apoptosis and to measure the effects of renal expression of inflammatory mediators (IL-1β, TNF-α) on the induction of apoptosis (HSP90, TUNEL). Dose-related oxidative damage in the kidneys of treated mice is shown by an increase in MDA levels and by a reduction of antioxidant enzyme GR and GPx activities, resulting in the kidney's reduced radical scavenging ability. Renal specimens of the treated group showed relevant glomeruli alterations and increased immunostaining and protein expressions, which manifested significant focal segmental glomerulosclerosis. The induction of proinflammatory cytokine expression levels was confirmed by Western blot analysis. Long-term administration of nandrolone promotes oxidative injury in the mouse kidneys. TNF-α mediated injury due to nandrolone in renal cells appears to play a role in the activation of both the intrinsic and extrinsic apoptosis pathways. - Highlights: • We analyze abuse of nandrolone decanoate in strength-trained male CD1 mice. • Nandrolone decanoate administration increases oxidative stress. • Increased cytokine expressions were observed. • Renal apoptosis was described. • Long-term administration of nandrolone promotes oxidative injury in mice kidney.

  19. Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice

    PubMed Central

    Rodriguez, Karina F.; Ungewitter, Erica K.; Crespo-Mejias, Yasmin; Liu, Chang; Nicol, Barbara; Kissling, Grace E.; Yao, Humphrey Hung-Chang

    2015-01-01

    Background Mice exposed to high levels of arsenic in utero have increased susceptibility to tumors such as hepatic and pulmonary carcinomas when they reach adulthood. However, the effects of in utero arsenic exposure on general physiological functions such as reproduction and metabolism remain unclear. Objectives We evaluated the effects of in utero exposure to inorganic arsenic at the U.S. Environmental Protection Agency (EPA) drinking water standard (10 ppb) and at tumor-inducing levels (42.5 ppm) on reproductive end points and metabolic parameters when the exposed females reached adulthood. Methods Pregnant CD-1 mice were exposed to sodium arsenite [none (control), 10 ppb, or 42.5 ppm] in drinking water from gestational day 10 to birth, the window of organ formation. At birth, exposed offspring were fostered to unexposed dams. We examined reproductive end points (age at vaginal opening, reproductive hormone levels, estrous cyclicity, and fertility) and metabolic parameters (body weight changes, hormone levels, body fat content, and glucose tolerance) in the exposed females when they reached adulthood. Results Arsenic-exposed females (10 ppb and 42.5 ppm) exhibited early onset of vaginal opening. Fertility was not affected when females were exposed to the 10-ppb dose. However, the number of litters per female was decreased in females exposed to 42.5 ppm of arsenic in utero. In both 10-ppb and 42.5-ppm groups, arsenic-exposed females had significantly greater body weight gain, body fat content, and glucose intolerance. Conclusion Our findings revealed unexpected effects of in utero exposure to arsenic: exposure to both a human-relevant low dose and a tumor-inducing level led to early onset of vaginal opening and to obesity in female CD-1 mice. Citation Rodriguez KF, Ungewitter EK, Crespo-Mejias Y, Liu C, Nicol B, Kissling GE, Yao HH. 2016. Effects of in utero exposure to arsenic during the second half of gestation on reproductive end points and metabolic

  20. Enhanced urinary bladder and liver carcinogenesis in male CD1 mice exposed to transplacental inorganic arsenic and postnatal diethylstilbestrol or tamoxifen

    SciTech Connect

    Waalkes, Michael P. . E-mail: waalkes@niehs.nih.gov; Liu Jie; Ward, Jerrold M.; Diwan, Bhalchandra A.

    2006-09-15

    Pregnant CD1 mice received 85 ppm arsenite in the drinking water from gestation day 8 to 18, groups (n = 35) of male offspring were subsequently injected on postpartum days 1 through 5 with diethylstilbestrol (DES; 2 {mu}g/pup/day) or tamoxifen (TAM; 10 {mu}g/pup/day), and tumor formation was assessed over 90 weeks. Arsenic alone increased hepatocellular carcinoma (14%), adenoma (23%) and total tumors (31%) compared to control (0, 2 and 2%, respectively). Arsenic alone also increased lung adenocarcinoma, adrenal cortical adenoma and renal cystic tubular hyperplasia compared to control. Compared to arsenic alone, arsenic plus DES increased liver tumor incidence in mice at risk 2.2-fold and increased liver tumor multiplicity (tumors/liver) 1.8-fold. The treatments alone did not impact urinary bladder carcinogenesis, but arsenic plus TAM significantly increased formation of urinary bladder transitional cell tumors (papilloma and carcinoma; 13%) compared to control (0%). Urinary bladder proliferative lesions (combined tumors and hyperplasia) were also increased by arsenic plus TAM (40%) or arsenic plus DES (43%) compared to control (0%) or the treatments alone. Urinary bladder proliferative lesions occurred in the absence of any evidence of uroepithelial cytotoxic lesions. Urinary bladder lesions and hepatocellular carcinoma induced by arsenic plus TAM and/or DES overexpressed estrogen receptor-{alpha}, indicating that aberrant estrogen signaling may have been a factor in the enhanced carcinogenic response. Thus, in male CD1 mice, gestational arsenic exposure alone induced liver adenoma and carcinoma, lung adenocarcinoma, adrenal adenoma and renal cystic hyperplasia. Furthermore, DES enhanced transplacental arsenic-induced hepatocarcinogenesis. In utero arsenic also initiated urinary bladder tumor formation when followed by postnatal TAM and uroepithelial proliferative lesions when followed by TAM or DES.

  1. A disruption of ctpA encoding carboxy-terminal protease attenuates Burkholderia mallei and induces partial protection in CD1 mice.

    PubMed

    Bandara, Aloka B; DeShazer, David; Inzana, Thomas J; Sriranganathan, Nammalwar; Schurig, Gerhardt G; Boyle, Stephen M

    2008-09-01

    Burkholderia mallei is the etiologic agent of glanders in solipeds (horses, mules and donkeys), and incidentally in carnivores and humans. Little is known about the molecular mechanisms of B. mallei pathogenesis. The putative carboxy-terminal processing protease (CtpA) of B. mallei is a member of a novel family of endoproteases involved in the maturation of proteins destined for the cell envelope. All species and isolates of Burkholderia carry a highly conserved copy of ctpA. We studied the involvement of CtpA on growth, cell morphology, persistence, and pathogenicity of B. mallei. A sucrose-resistant strain of B. mallei was constructed by deleting a major portion of the sacB gene of the wild type strain ATCC 23344 by gene replacement, and designated as strain 23344DeltasacB. A portion of the ctpA gene (encoding CtpA) of strain 23344DeltasacB was deleted by gene replacement to generate strain 23344DeltasacBDeltactpA. In contrast to the wild type ATCC 23344 or the sacB mutant 23344DeltasacB, the ctpA mutant 23344DeltasacBDeltactpA displayed altered cell morphologies with partially or fully disintegrated cell envelopes. Furthermore, relative to the wild type, the ctpA mutant displayed slower growth in vitro and less ability to survive in J774.2 murine macrophages. The expression of mRNA of adtA, the gene downstream of ctpA was similar among the three strains suggesting that disruption of ctpA did not induce any polar effects. As with the wild type or the sacB mutant, the ctpA mutant exhibited a dose-dependent lethality when inoculated intraperitoneally into CD1 mice. The CD1 mice inoculated with a non-lethal dose of the ctpA mutant produced specific serum immunoglobulins IgG1 and IgG2a and were partially protected against challenge with wild type B. mallei ATCC 23344. These findings suggest that CtpA regulates in vitro growth, cell morphology and intracellular survival of B. mallei, and a ctpA mutant protects CD1 mice against glanders.

  2. Domain-Specific and Domain-General Learning Factors Are Expressed in Genetically Heterogeneous CD-1 Mice

    ERIC Educational Resources Information Center

    Kolata, Stefan; Light, Kenneth; Matzel, Louis D.

    2008-01-01

    It has been established that both domain-specific (e.g. spatial) as well as domain-general (general intelligence) factors influence human cognition. However, the separation of these processes has rarely been attempted in studies using laboratory animals. Previously, we have found that the performances of outbred mice across a wide range of…

  3. Strawberry phytochemicals inhibit azoxymethane/dextran sodium sulfate-induced colorectal carcinogenesis in Crj: CD-1 mice.

    PubMed

    Shi, Ni; Clinton, Steven K; Liu, Zhihua; Wang, Yongquan; Riedl, Kenneth M; Schwartz, Steven J; Zhang, Xiaoli; Pan, Zui; Chen, Tong

    2015-03-10

    Human and experimental colon carcinogenesis are enhanced by a pro-inflammatory microenvironment. Pharmacologically driven chemopreventive agents and dietary variables are hypothesized to have future roles in the prevention of colon cancer by targeting these processes. The current study was designed to determine the ability of dietary lyophilized strawberries to inhibit inflammation-promoted colon carcinogenesis in a preclinical animal model. Mice were given a single i.p. injection of azoxymethane (10 mg kg-1 body weight). One week after injection, mice were administered 2% (w/v) dextran sodium sulfate in drinking water for seven days and then an experimental diet containing chemically characterized lyophilized strawberries for the duration of the bioassay. Mice fed control diet, or experimental diet containing 2.5%, 5.0% or 10.0% strawberries displayed tumor incidence of 100%, 64%, 75% and 44%, respectively (p < 0.05). The mechanistic studies demonstrate that strawberries reduced expression of proinflammatory mediators, suppressed nitrosative stress and decreased phosphorylation of phosphatidylinositol 3-kinase, Akt, extracellular signal-regulated kinase and nuclear factor kappa B. In conclusion, strawberries target proinflammatory mediators and oncogenic signaling for the preventive efficacies against colon carcinogenesis in mice. This works supports future development of fully characterized and precisely controlled functional foods for testing in human clinical trials for this disease.

  4. Effects of dietary zinc manipulation on growth performance, zinc status and immune response during Giardia lamblia infection: a study in CD-1 mice.

    PubMed

    Iñigo-Figueroa, Gemma; Méndez-Estrada, Rosa O; Quihui-Cota, Luis; Velásquez-Contreras, Carlos A; Garibay-Escobar, Adriana; Canett-Romero, Rafael; Astiazarán-García, Humberto

    2013-09-02

    Associations between Giardia lamblia infection and low serum concentrations of zinc have been reported in young children. Interestingly, relatively few studies have examined the effects of different dietary zinc levels on the parasite-infected host. The aims of this study were to compare the growth performance and zinc status in response to varying levels of dietary zinc and to measure the antibody-mediated response of mice during G. lamblia infection. Male CD-1 mice were fed using 1 of 4 experimental diets: adequate-zinc (ZnA), low-zinc (ZnL), high-zinc (ZnH) and supplemented-zinc (ZnS) diet containing 30, 10, 223 and 1383 mg Zn/kg respectively. After a 10 days feeding period, mice were inoculated orally with 5 × 106 G. lamblia trophozoites and were maintained on the assigned diet during the course of infection (30 days). Giardia-free mice fed ZnL diets were able to attain normal growth and antibody-mediated response. Giardia-infected mice fed ZnL and ZnA diets presented a significant growth retardation compared to non-infected controls. Zinc supplementation avoided this weight loss during G. lamblia infection and up-regulated the host's humoral immune response by improving the production of specific antibodies. Clinical outcomes of zinc supplementation during giardiasis included significant weight gain, higher anti-G. lamblia IgG antibodies and improved serum zinc levels despite the ongoing infection. A maximum growth rate and antibody-mediated response were attained in mice fed ZnH diet. No further increases in body weight, zinc status and humoral immune capacity were noted by feeding higher zinc levels (ZnS) than the ZnH diet. These findings probably reflect biological effect of zinc that could be of public health importance in endemic areas of infection.

  5. Effects of Dietary Zinc Manipulation on Growth Performance, Zinc Status and Immune Response during Giardia lamblia Infection: A Study in CD-1 Mice

    PubMed Central

    Iñigo-Figueroa, Gemma; Méndez-Estrada, Rosa O.; Quihui-Cota, Luis; Velásquez-Contreras, Carlos A.; Garibay-Escobar, Adriana; Canett-Romero, Rafael; Astiazarán-García, Humberto

    2013-01-01

    Associations between Giardia lamblia infection and low serum concentrations of zinc have been reported in young children. Interestingly, relatively few studies have examined the effects of different dietary zinc levels on the parasite-infected host. The aims of this study were to compare the growth performance and zinc status in response to varying levels of dietary zinc and to measure the antibody-mediated response of mice during G. lamblia infection. Male CD-1 mice were fed using 1 of 4 experimental diets: adequate-zinc (ZnA), low-zinc (ZnL), high-zinc (ZnH) and supplemented-zinc (ZnS) diet containing 30, 10, 223 and 1383 mg Zn/kg respectively. After a 10 days feeding period, mice were inoculated orally with 5 × 106 G. lamblia trophozoites and were maintained on the assigned diet during the course of infection (30 days). Giardia-free mice fed ZnL diets were able to attain normal growth and antibody-mediated response. Giardia-infected mice fed ZnL and ZnA diets presented a significant growth retardation compared to non-infected controls. Zinc supplementation avoided this weight loss during G. lamblia infection and up-regulated the host’s humoral immune response by improving the production of specific antibodies. Clinical outcomes of zinc supplementation during giardiasis included significant weight gain, higher anti-G. lamblia IgG antibodies and improved serum zinc levels despite the ongoing infection. A maximum growth rate and antibody-mediated response were attained in mice fed ZnH diet. No further increases in body weight, zinc status and humoral immune capacity were noted by feeding higher zinc levels (ZnS) than the ZnH diet. These findings probably reflect biological effect of zinc that could be of public health importance in endemic areas of infection. PMID:24002196

  6. Systemic Injection of CD34+-Enriched Human Cord Blood Cells Modulates Poststroke Neural and Glial Response in a Sex-Dependent Manner in CD1 Mice

    PubMed Central

    Kadam, Shilpa D.; Chen, HuiGen; Markowitz, Geoffrey J.; Raja, Saba; George, Shanu; Shotwell, Elisabeth; Loechelt, Brett; Johnston, Michael V.; Kamani, Naynesh; Fatemi, Ali

    2015-01-01

    Stroke in the developing brain is an important cause of neurological morbidity. We determined the impact of human cord blood-derived CD34+-enriched mononuclear cells (CBSC) intraperitoneally injected 48 h after an ischemic stroke at postnatal day 12 by evaluating poststroke neurogenic niche proliferation, glial response, and recovery in CD1 mice. Percent brain atrophy was quantified from Nissl-stained sections. Density of BrdU, Iba-1, and GFAP staining were quantified in the dentate gyrus and the subventricular zone (SVZ). Immunohistochemistry for human nuclear antibody, human mitochondrial antibody, and human CD34+ cells was done on injured and uninjured brains from CBSC- and vehicle-treated mice. Developmental neurobehavioral milestones were evaluated pre- and post-treatment. No significant differences in stroke severity were noted between CBSC and vehicle-treated injured animals. With a 1×105 CBSC dose, there was a significant increase in subgranular zone (SGZ) proliferation in the CBSC-versus vehicle-treated stroke-injured male mice. SVZ glial fibrillary acidic protein (GFAP) expression was increased contralaterally in injured females treated with CBSC but suppressed in injured males. Significant negative correlations between severity of the stroke-injury and spleen weights, and between spleen weights and SGZ proliferation, and a positive correlation between GFAP expression and severity of brain injury were noted in the vehicle-treated injured mice but not in the CBSC-treated mice. GFAP expression and SVZ proliferation were positively correlated. In conclusion, neurogenic niche proliferation and glial brain responses to CBSC after neonatal stroke may involve interactions with the spleen and are sex dependent. PMID:25121827

  7. Effect of ethanolic extract of Carpolobia lutea G. Don (polygalaceae) root on learning and memory in CD1 mice.

    PubMed

    Ajiwhen, I O; Bisong, S A

    2013-12-20

    Carpolobia lutea, commonly called cattle stick or poor man's candle, is used by traditional herbalists in eastern Nigeria to treat 'madness'. It has a reported analgesic and anti-nociceptive effect. The effect of its ethanolic root extract on learning and memory was investigated. Thirty mice were divided into three groups of ten each. One group of mice served as the control and was given normal saline (p.o.) while the other two groups were given acute low dose (1500mg/kg, p.o.) and high dose (2500mg/kg, p.o.) (LD50 3338.83mg/kg). The effect of the extract on cognitive memory was investigated using the Novel Object recognition task (NORT) while the effect on visuospatial learning and memory was studied using the Morris Water maze (MWM). The results obtained in the NORT show that the index of habituation was significantly lower following acute treatment with a low dose of C. lutea extract compared to control. However, the index of habituation did not differ following treatment with a high dose of C. lutea compared to control but it was higher compared to the low dose. Following treatment with a low dose of the extract, the index of discrimination was significantly higher compared to control. The index of discrimination in the high dose treatment group did not differ from control, but it was lower compared to the low dose treatment. This indicated that there was improved cognitive memory only in the low dose treatment group. In the MWM there was no significant difference in swim latency during Acquisition and Reversal training. There also was no significant difference in quadrant duration during probe trial. The swim latency during the visible platform test showed that all mice used had good visual acuity. Therefore, the ethanolic extract of C. lutea root enhanced cognitive memory. However it did not affect visuospatial learning and memory.

  8. Comparison of 2-Ethyl-Cyanoacrylate and 2-Butyl-Cyanoacrylate for Use on the Calvaria of CD1 Mice.

    PubMed

    Sohn, Joanne J; Gruber, Theresa M; Zahorsky-Reeves, Joanne L; Lawson, Greg W

    2016-03-01

    Short-chain cyanoacrylates (SCCA), such as ethyl-2-cyanoacrylate (KrazyGlue, Aron Alpha, Columbus, OH) are commonly used as commercial fast-acting glues. Although once used in clinical medicine as skin adhesives, these products caused tissue toxicity and thus their use in live tissue was discontinued. SCCA were replaced by longer-chain versions (LCCA), such as butyl-cyanoacrylate (Vetbond, 3M, St Paul, Minnesota), which were found to be less toxic than the short-chain formulations. Some researchers prefer to use SCCA due to the belief that they create a stronger bond than do the longer-chain counterparts. In survival surgeries, we compared the bone thickness, bone necrosis, fibrosis, inflammation, and bone regeneration in the calvaria of control (naïve), surgery-only, SCCA-treated, and LCCA-treated mice (n = 20 per group). At 1 and 14 d after surgery, all mice except those treated with SCCA showed statistically similar bone measurements to those of the naive control group. The SCCA group had significantly less bone regeneration than did all other groups. These results suggest that the application of SCCA causes bone damage resulting in the loss of bone regeneration. This finding may assist investigators in choosing a tissue glue for their studies and may support the IACUC in advocating the use of pharmaceutical-grade tissue glues.

  9. Comparison of 2-Ethyl-Cyanoacrylate and 2-Butyl-Cyanoacrylate for Use on the Calvaria of CD1 Mice

    PubMed Central

    Sohn, Joanne J; Gruber, Theresa M; Zahorsky-Reeves, Joanne L; Lawson, Greg W

    2016-01-01

    Short-chain cyanoacrylates (SCCA), such as ethyl-2-cyanoacrylate (KrazyGlue, Aron Alpha, Columbus, OH) are commonly used as commercial fast-acting glues. Although once used in clinical medicine as skin adhesives, these products caused tissue toxicity and thus their use in live tissue was discontinued. SCCA were replaced by longer-chain versions (LCCA), such as butyl-cyanoacrylate (Vetbond, 3M, St Paul, Minnesota), which were found to be less toxic than the short-chain formulations. Some researchers prefer to use SCCA due to the belief that they create a stronger bond than do the longer-chain counterparts. In survival surgeries, we compared the bone thickness, bone necrosis, fibrosis, inflammation, and bone regeneration in the calvaria of control (naïve), surgery-only, SCCA-treated, and LCCA-treated mice (n = 20 per group). At 1 and 14 d after surgery, all mice except those treated with SCCA showed statistically similar bone measurements to those of the naive control group. The SCCA group had significantly less bone regeneration than did all other groups. These results suggest that the application of SCCA causes bone damage resulting in the loss of bone regeneration. This finding may assist investigators in choosing a tissue glue for their studies and may support the IACUC in advocating the use of pharmaceutical-grade tissue glues. PMID:27025812

  10. Anthocyanin- and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kappaB pathways and inhibits skin tumorigenesis in CD-1 mice.

    PubMed

    Afaq, Farrukh; Saleem, Mohammad; Krueger, Christian G; Reed, Jess D; Mukhtar, Hasan

    2005-01-20

    Chemoprevention has come of age as an effective cancer control modality; however, the search for novel agent(s) for the armamentarium of cancer chemoprevention continues. We argue that agents capable of intervening at more than one critical pathway in the carcinogenesis process will have greater advantage over other single-target agents. Pomegranate fruit extract (PFE) derived from the tree Punica granatum possesses strong antioxidant and antiinflammatory properties. Pomegranate fruit was extracted with acetone and analyzed based on matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and found to contain anthocyanins, ellagitannins and hydrolyzable tannins. We evaluated whether PFE possesses antitumor-promoting effects. We first determined the effect of topical application of PFE to CD-1 mice against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced conventional markers and other novel markers of skin tumor promotion. We found that topical application of PFE (2 mg/mouse) 30 min prior to TPA (3.2 nmole/mouse) application on mouse skin afforded significant inhibition, in a time-dependent manner, against TPA-mediated increase in skin edema and hyperplasia, epidermal ornithine decarboxylase (ODC) activity and protein expression of ODC and cyclooxygenase-2. We also found that topical application of PFE resulted in inhibition of TPA-induced phosphorylation of ERK1/2, p38 and JNK1/2, as well as activation of NF-kappaB and IKKalpha and phosphorylation and degradation of IkappaBalpha. We next assessed the effect of skin application of PFE on TPA-induced skin tumor promotion in 7,12-dimethylbenz(a)anthracene-initiated CD-1 mouse. The animals pretreated with PFE showed substantially reduced tumor incidence and lower tumor body burden when assessed as total number of tumors per group, percent of mice with tumors and number of tumors per animal as compared to animals that did not receive PFE. In TPA-treated group, 100% of the mice developed tumors at

  11. Repeated social defeat causes increased anxiety-like behavior and alters splenocyte function in C57BL/6 and CD-1 mice.

    PubMed

    Kinsey, Steven G; Bailey, Michael T; Sheridan, John F; Padgett, David A; Avitsur, Ronit

    2007-05-01

    The experimental model, social disruption (SDR), is a model of social stress in which mice are repeatedly attacked and defeated in their home cage by an aggressive conspecific. In terms of the impact of this stressor on the immune response, SDR has been reported to cause hyperinflammation and glucocorticoid insensitivity. To this point however, the behavioral consequences of SDR have not been thoroughly characterized. Because social defeat has been reported to cause anxiety- and depressive-like behaviors, the current study was designed to assess whether SDR also causes anxiety- and depressive-like behaviors. Using the light/dark preference test and the open field test as tools to measure behaviors characteristic of anxiety, the data showed that C57BL/6 and CD-1 male mice subjected to SDR displayed increased anxiety-like behavior. The increase in anxiety-like behaviors persisted for at least 1 week after the cessation of the stressor. In contrast, depressive-like behaviors were not elicited by SDR as assessed by the forced swim test or the tail suspension test. These data indicate that social disruption stress causes an increase in anxiety-like behaviors, but not depressive-like behaviors.

  12. Repeated Social Defeat Causes Increased Anxiety-Like Behavior and Alters Splenocyte Function in C57BL/6 and CD-1 Mice

    PubMed Central

    Kinsey, Steven G.; Bailey, Michael T.; Sheridan, John F.; Padgett, David A.; Avitsur, Ronit

    2007-01-01

    The experimental model, social disruption (SDR), is a model of social stress in which mice are repeatedly attacked and defeated in their home cage by an aggressive conspecific. In terms of the impact of this stressor on the immune response, SDR has been reported to cause hyperinflammation and glucocorticoid insensitivity. To this point however, the behavioral consequences of SDR have not been thoroughly characterized. Because social defeat has been reported to cause anxiety- and depressive-like behaviors, the current study was designed to assess whether SDR also causes anxiety- and depressive-like behaviors. Using the light/dark preference test and the open field test as tools to measure behaviors characteristic of anxiety, the data showed that C57BL/6 and CD-1 male mice subjected to SDR displayed increased anxiety-like behavior. The increase in anxiety-like behaviors persisted for at least one week after the cessation of the stressor. In contrast, depressive-like behaviors were not elicited by SDR as assessed by the forced swim test or the tail suspension test. These data indicate that social disruption stress causes an increase in anxiety-like behaviors, but not depressive-like behaviors. PMID:17178210

  13. Differential effect of restraint procedure on incidence of restraint-stress-induced rib fusion in CD-1 mice.

    PubMed

    Rasco, J F; Hood, R D

    1994-04-01

    In an investigation of the effects of specific maternal stressors on development of the conceptus, pregnant mice were exposed to restraint stress on gestation day 9 (plug = day 1). Mated females were either unrestrained (C), unrestrained and food/water deprived (FWD), or restrained with surgical tape in a supine position for 12 h by one of two methods: I. 1-inch wide tape reaching from each shoulder across the body to the opposite thigh, or II. 1-inch wide tape placed over one shoulder, across the thorax, and over the opposite shoulder and similar tape placed over each thigh and across the intervening pelvic area. For both methods, an additional tape was placed across the tail and a 2-inch wide tape secured the upper abdominal area. There were 32 to 62 litters in each treatment group, and all fetuses were examined on day 18 for gross and skeletal defects. With regard to rib fusion, the percentage of affected fetuses and litters was increased (P < or = 0.05) by Method I (3.5% and 27%, respectively) vs. Method II. (0.5% and 4%), C (0.1% and 1%), or FWD (0%). Incidences of supernumerary ribs, however, did not differ between the restrained groups but were higher in both such groups than in the FWD and C groups. These results suggest that different methods of restraint may result in differences in incidence of rib fusion. Such data suggest that development of the offspring of stressed dams may be significantly influenced by what might appear to be minor differences in the stress techniques used.

  14. Adult neurogenesis in serotonin transporter deficient mice.

    PubMed

    Schmitt, A; Benninghoff, J; Moessner, R; Rizzi, M; Paizanis, E; Doenitz, C; Gross, S; Hermann, M; Gritti, A; Lanfumey, L; Fritzen, S; Reif, A; Hamon, M; Murphy, D L; Vescovi, A; Lesch, K-P

    2007-09-01

    Serotonin (5-HT) is a regulator of morphogenetic activities during early brain development and neurogenesis, including cell proliferation, migration, differentiation, and synaptogenesis. The 5-HT transporter (5-HTT, SLC6A4) mediates high-affinity reuptake of 5-HT into presynaptic terminals and thereby fine-tunes serotonergic neurotransmission. Inactivation of the 5-HTT gene in mice reduces 5-HT clearance resulting in persistently increased concentrations of synaptic 5-HT. In the present study, we investigated the effects of elevated 5-HT levels on adult neurogenesis in the hippocampus of 5-HTT deficient mice, including stem cell proliferation, survival, and differentiation. Using an in vivo approach, we showed an increase in proliferative capacity of hippocampal adult neural stem cells in aged 5-HTT knockout mice (approximately 14.5 months) compared to wildtype controls. In contrast, in vivo and additional in vitro analyses of younger adult 5-HTT knockout mice (approximately 7 weeks and approximately 3.0 months) did not reveal significant changes in proliferation of neural stem cells or survival of newborn cells. We showed that the cellular fate of newly generated cells in 5-HTT knockout mice is not different with respect to the total number and percentage of neurons or glial cells from wildtype controls. Our findings indicate that elevated synaptic 5-HT concentration throughout early development and later life of 5-HTT deficient mice does not induce adult neurogenesis in adult mice, but that elevated 5-HT levels in aged mice influence stem cell proliferation.

  15. The Potential of Cr3 [Triaqua-μ3 -Oxo-Hexa-μ-Propionatotrichromium(III) Chloride] to Reduce Birth Defects in the Offspring of Diabetic CD-1 Mice.

    PubMed

    Keith, Johnathan D; Vincent, Christina; Goetsch, Michael; Lemley, Amie; Kraus, Riley; Broussard, Austin; Kildow, Ashley; Faught, Josh; Vincent, John B; Rasco, Jane F

    2015-04-01

    Diabetes mellitus is a growing concern worldwide and leads to multiple complications during pregnancy. Pharmacologic doses of chromium (Cr) have been linked with improving insulin sensitivity and other positive benefits in the treatment of diabetes in animal models. By using streptozotocin induced hyperglycemia in female CD-1 mice, reproductive outcomes of diabetic and chromium-dosed diabetic females were examined. After dosing 10 mg/kg Cr in the form of triaqua-μ3 -oxo-hexa-μ-propionatotrichromium(III) chloride or Cr3 during gestation days 8-16 (GD8-GD16), all females were sacrificed on gestation day 17 (GD17) and examined for maternal weight gain. The fetuses were examined for gross malformations and for skeletal malformations. The offspring of Cr3-dosed females tended to have a reduction in the incidence of supernumerary ribs. While hyperglycemia still had negative impacts on the health of dams and their offspring, administration of Cr led to an apparent trend in the reduction in the number of malformations and incidence of supernumerary ribs compared to those of untreated diabetic mothers.

  16. Contribution of acetaminophen-cysteine to acetaminophen nephrotoxicity in CD-1 mice: I. Enhancement of acetaminophen nephrotoxicity by acetaminophen-cysteine

    SciTech Connect

    Stern, Stephan T.; Bruno, Mary K.; Hennig, Gayle E.; Horton, Robert A.; Roberts, Jeanette C.; Cohen, Steven D. . E-mail: scohen@mcp.edu

    2005-01-15

    Acetaminophen (APAP) nephrotoxicity has been observed both in humans and research animals. Recent studies suggest a contributory role for glutathione (GSH)-derived conjugates of APAP in the development of nephrotoxicity. Inhibitors of either {gamma}-glutamyl transpeptidase ({gamma}-GT) or the probenecid-sensitive organic anion transporter ameliorate APAP-induced nephrotoxicity but not hepatotoxicity in mice and inhibition of {gamma}-GT similarly protected rats from APAP nephrotoxicity. Protection against APAP nephrotoxicity by disruption of these GSH conjugate transport and metabolism pathways suggests that GSH conjugates are involved. APAP-induced renal injury may involve the acetaminophen-glutathione (APAP-GSH) conjugate or a metabolite derived from APAP-GSH. Acetaminophen-cysteine (APAP-CYS) is a likely candidate for involvement in APAP nephrotoxicity because it is both a product of the {gamma}-GT pathway and a probable substrate for the organic anion transporter. The present experiments demonstrated that APAP-CYS treatment alone depleted renal but not hepatic glutathione (GSH) in a dose-responsive manner. This depletion of renal GSH may predispose the kidney to APAP nephrotoxicity by diminishing GSH-mediated detoxification mechanisms. Indeed, pretreatment of male CD-1 mice with APAP-CYS before challenge with a threshold toxic dose of APAP resulted in significant enhancement of APAP-induced nephrotoxicity. This was evidenced by histopathology and plasma blood urea nitrogen (BUN) levels at 24 h after APAP challenge. APAP alone was minimally nephrotoxic and APAP-CYS alone produced no detectable injury. By contrast, APAP-CYS pretreatment did not alter the liver injury induced by APAP challenge. These data are consistent with there being a selective, contributory role for APAP-GSH-derived metabolites in APAP-induced renal injury that may involve renal-selective GSH depletion.

  17. Differential effects of infralimbic vs. ventromedial orbital PFC lidocaine infusions in CD-1 mice on defensive responding in the mouse defense test battery and rat exposure test.

    PubMed

    Wall, P M; Blanchard, R J; Yang, M; Blanchard, D C

    2004-09-10

    The ventromedial prefrontal cortex (vmPFC) is extremely sensitive to a variety of stressful situations and threatening events, and has been suggested to be an associative cortical brain system processing the integration of anxiety-related cognitive, affective and motivated behavior in rodents, primates and humans. In addition, recent evidence suggests that (a) anxiety-related affective processing appears to be lateralized to the right hemisphere vmPFC; and (b) there appears to be functional heterogeneity within the rodent vmPFC. The present study evaluated the possibility that distinct sub-areas of the right hemisphere ventral PFC might differentially influence anxiety-like defensive responding in two different predator stress situations following transient inactivation of the ventromedial orbital (vMO) or infralimbic (IL) vmPFC in CD-1 mice. In week 1, IL vmPFC lidocaine infusions reduced anxiety-like defensive responding in mice (enhanced approach and contact) confronted with a hand-held anesthetized rat stimulus in the mouse defense test battery (vMO inactivation exerted minimal effects). In week 2, vMO lidocaine infusions enhanced anxiety-like defensive responding (enhanced avoidance and protected risk assessment) toward a barricaded live rat in the rat exposure test (IL inactivation exerted minimal effects). Although it is unclear whether week 1 mouse defense test battery testing influenced week 2 rat exposure test results, these preliminary data suggest functional differences within the mouse right hemisphere ventral PFC related to cautious evaluation of predator threat. Given the dense unilateral reciprocal connectivity between the IL and vMO subregions of the PFC, both associative ventromedial cortical areas may exert complimentary yet dissociable roles in the processing of threat stimuli. This suggests that while the IL vmPFC may mediate cautious evaluation of threat situations (risk assessment), the vMO PFC may inhibit prepotent avoidance responses to

  18. The effect of TiO{sub 2} and Ag nanoparticles on reproduction and development of Drosophila melanogaster and CD-1 mice

    SciTech Connect

    Philbrook, Nicola A.; Winn, Louise M.; Afrooz, A.R.M. Nabiul; Saleh, Navid B.; Walker, Virginia K.

    2011-12-15

    In the last two decades, nanoparticles (NPs) have found applications in a wide variety of consumer goods. Titanium dioxide (TiO{sub 2}) and silver (Ag) NPs are both found in cosmetics and foods, but their increasing use is of concern due to their ability to be taken up by biological systems. While there are some reports of TiO{sub 2} and Ag NPs affecting complex organisms, their effects on reproduction and development have been largely understudied. Here, the effects of orally administered TiO{sub 2} or Ag NPs on reproduction and development in two different model organisms were investigated. TiO{sub 2} NPs reduced the developmental success of CD-1 mice after a single oral dose of 100 or 1000 mg/kg to dams, resulting in a statistically significant increase in fetal deformities and mortality. Similarly, TiO{sub 2} NP addition to food led to a significant progeny loss in the fruit fly, Drosophila, as shown by a decline in female fecundity. Ag NP administration resulted in an increase in the mortality of fetal mice. Similarly in Drosophila, Ag NP feeding led to a significant decrease in developmental success, but unlike TiO{sub 2} NP treatment, there was no decline in fecundity. The distinct response associated with each type of NP likely reflects differences in NP administration as well as the biology of the particular model. Taken together, however, this study warns that these common NPs could be detrimental to the reproductive and developmental health of both invertebrates and vertebrates.

  19. Analysis of PFOA in Dosed CD-1 Mice Part 2: Disposition of PFOA in Tissues and fluids from pregnant and lactating mice and their pups

    EPA Science Inventory

    Previous studies in mice with multiple gestational exposures to perfluorooctanoic acid (PFOA) demonstrate numerous dose dependent growth and developmental effects which appeared to worsen if offspring exposed in utero nursed from PFOA-exposed dams. To evaluate the disposition of ...

  20. GESTATIONAL EXPOSURE TO ETHANE DIMETHANESULFONATE PERMANENTLY ALTERS REPRODUCTIVE COMPETENCE IN THE CD-1 MOUSE

    EPA Science Inventory

    While the adult mouse Leydig cell (LC) has been considered refractory to cytotoxic destruction by ethane dimethanesulfonate (EDS), the potential consequences of exposure during reproductive development in this species are unknown. Herein pregnant CD-1 mice were treated with 160 m...

  1. Analysis of PFOA in Dosed CD1 Mice Part 1: Methods Development for the Analysis of Tissues and Fluids from Pregnant and Lactating Mice and Their Pups

    EPA Science Inventory

    The number of studies involving the analysis of perfluorooctanoic acid (PFOA) has 33 increased recently because PFOA is routinely detected in human blood samples from around the world. Recent studies with mice have shown that dosing pregnant dams with PFOA during gestation gives ...

  2. Detection of TEM-induced reciprocal translocations in F/sub 1/ sons of CD-1 male mice: comparison of sequential fertility evaluation and cytogenetic analysis

    SciTech Connect

    Morris, S.M.; Kodell, R.L.; Domon, O.E.; Bishop, J.B.

    1988-01-01

    To determine the positive and negative classification error rates associated with the HTA in our laboratory, F/sub 1/ sons of TEM-exposed CD-1 male mice were evaluated by the sequential fertility method with subsequent cytogenetic analysis. Males who sired three litters of size 10 or less when mated to primiparous females from either the B6C3F/sub 1/ or the BCF/sub 1/ strain were classified as partial steriles. When meiotic chromosomes analyses revealed the presence of at least two cells containing multivalent figures, males were classified as translocation heterozygotes. When the fertility evaluation and the cytogenetic analysis were compared, normal fertility was observed on 5 of 83 (6.02%) translocation-bearing F/sub 1/ males mated to B6C3F/sub 1/ tester females and on 3 of 83 (3.61%) F/sub 1/ males mated to BCF/sub 1/ tester females. Thus, the false-negative error rates were 6.02% and 3.61% with these two tester strains. Multivalent figures were not observed in the meiotic chromosomes of 410 F/sub 1/ males. The false-positive error rates with these two tester strains were 2.93% for the B6C3F/sub 1/ strain and 1.71% for the BCF/sub 1/ strain. The results indicate that nonzero error rates, both false-positive and false-negative, are associated with the sequential mating method HTA. In addition, the magnitude of these error rates was influenced not only by the tester female strain but also by the genotype of the F/sub 1/ male.

  3. K-ras cancer gene mutations in lung tumors from female Swiss (CD-1) mice exposed transplacentally to 3'-azido-3'-deoxythymidine.

    PubMed

    Koujitani, Takatoshi; Ton, Tai-Vu T; Lahousse, Stephanie A; Hong, Hue-Hua L; Wakamatsu, Nobuko; Sills, Robert C

    2008-12-01

    A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD-1) mice to 0, 50, 100, 200, or 300 mg 3'-azido-3'-deoxythymidine (AZT)/kg body weight (BW) daily for the duration of gestation (18-19 days) [National Toxicology Program,2006]. The incidence of alveolar/bronchiolar adenomas and carcinomas in the 200 and 300 mg/kg groups was significantly higher (P = 0.027 and 0.007, respectively) in male offspring, but not in females (P = 0.338 and 0.315, respectively). The purpose of the present study was to evaluate K-ras mutation status in lung tumors from the female offspring in AZT exposed groups and to determine whether at the molecular level there were signature K-ras mutations in lung tumors that were different from spontaneous tumors. K-ras mutation was detected by cycle sequencing of polymerase chain reaction (PCR)-amplified DNA, isolated from formalin-fixed, paraffin-embedded lung tumors. K-ras mutations were detected in 17 of 28 (61%) lung tumors from the female offspring in AZT exposed groups. No K-ras mutations were detected in the 8 tumors examined from the female control group. The predominant mutations were Codon 12 G-->T transversions in the 50, 100, and 300 mg/kg groups, and Codon 12 G-->C transversions in the 200 and 300 mg/kg groups. K-ras Codon 12 G-->T transversions (TGT mutations) may be induced by oxidative DNA damage and 8-oxoguanine (8-oxoG), while K-ras Codon 12 G-->C transversions (CGT mutations) may be due to further oxidative lesions of guanine and 8-oxoG.

  4. Outcome of xenografted fetal porcine pancreatic tissue is superior in inbred scid (C.B-17/Icr-scid/scid) compared to outbred nude (CD-1-nu/nu) mice.

    PubMed

    Tuch, B E; Casamento, F M

    1999-01-01

    Nude mice are used as recipients of foreign tissue because of their inability to reject these grafts. Our experience has been that there is variable rejection of fetal porcine insulin-producing tissue transplanted into CD-1 (athymic) outbred nude mice. To examine the suitability of this line of nude mouse as a recipient of the tissue, fetal porcine pancreas was grafted either into these outbred animals or into an inbred mutant strain of mice, the more immunocompromised severe combined immunodeficient (scid) mouse. Eight weeks after transplantation grafts were recovered from recipients and assayed for insulin content. Mean insulin levels were not significantly different between the two groups of mice, but a wider range of values was obtained from grafts recovered from nude (CD-1-nu/nu) mice. Reversal of diabetes in hyperglycemic recipients was achieved in 4 of 8 nude mice and 8 of 8 scid (C.B-17/lcr-scid/scid) mice. The time taken to achieve this was longer in the nudes than the scid mice, 121 +/- 12 vs. 44 +/- 2 days, the grafts increasing in size at a slower rate in the nude mice. Time taken for the weight of the grafts to double in size was 94 +/- 17 vs. 32 +/- 1 days, respectively. Histologically the grafts in the scid mice contained mostly epithelial cell clusters, a majority of which were insulin containing. In the nude mice that achieved normoglycemia, a similar pattern was observed and, as well, there was a localized lymphoid infiltrate. In those nude mice that remained diabetic fibrous tissue predominated together with a lymphoid infiltrate. In summary, fetal porcine pancreatic tissue grows and develops more efficiently when xenografted into scid rather than outbred nude mice.

  5. Bisphenol A Alters Autonomic Tone and Extracellular Matrix Structure and Induces Sex-Specific Effects on Cardiovascular Function in Male and Female CD-1 Mice

    PubMed Central

    Gear, Robin B.; Kendig, Eric L.

    2015-01-01

    The aim of this study was to determine whether bisphenol A (BPA) has adverse effects on cardiovascular functions in CD-1 mice and define sex-specific modes of BPA action in the heart. Dams and analyzed progeny were maintained on a defined diet containing BPA (0.03, 0.3, 3, 30, or 300 ppm) that resulted in BPA exposures from 4–5 to approximately 5000 μg/kg · d or a diet containing 17α-ethinyl estradiol (EE; ∼0.02, 0.2, and 0.15 μg/kg · d) as an oral bioavailable estrogen control. Assessment of electrocardiogram parameters using noninvasive methods found that ventricular functions in both male and female mice were not altered by either BPA or EE. However, exposure-related changes in the rates of ventricular contraction, suggestive of a shift in sympathovagal balance of heart rate control toward increased parasympathetic activity, were detected in males. Decreased systolic blood pressure was observed in males exposed to BPA above 5 μg/kg · d and in females from the highest BPA exposure group. Morphometric histological measures revealed sexually dimorphic changes in the composition of the cardiac collagen extracellular matrix, increases in fibrosis, and evidence of modest exposure-related remodeling. Experiments using the α-selective adrenergic agonist phenylephrine found that BPA enhanced reflex bradycardia in females, but not males, revealed that BPA and EE exposure sex specifically altered the sympathetic regulation of the baroreflex circuits. Increased sensitivity to the cardiotoxic effects of the β-adrenergic agonist isoproterenol was observed in BPA- and EE-exposed females. This effect was not observed in males, in which BPA or EE exposures were protective of isoproterenol-induced ischemic damage and hypertrophy. The results of RNA sequence analysis identified significant sex-specific changes in gene expression in response to BPA that were consistent with the observed exposure-related phenotypic changes in the collagenous and noncollagenous

  6. Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury

    PubMed Central

    Lu, Yan; Zhang, Cheng; Chen, Yuan-Hua; Wang, Hua; Zhang, Zhi-Hui; Chen, Xi; Xu, De-Xiang

    2017-01-01

    Acetaminophen (APAP) overdose induces acute liver injury. The aim of the present study was to analyze the difference of susceptibility between immature and adult mice to APAP-induced acute liver injury. Weanling immature and adult mice were injected with APAP (300 mg/kg). As expected, immature mice were more susceptible than adult mice to APAP-induced acute liver injury. APAP-evoked hepatic c-Jun N-terminal kinase phosphorylation was stronger in immature mice than in adult mice. Hepatic receptor-interacting protein (RIP)1 was obviously activated at APAP-exposed immature and adult mice. Interestingly, hepatic RIP3 activation was more obvious in APAP-treated immature mice than adult mice. Although there was no difference on hepatic GSH metabolic enzymes between immature and adult mice, immature mice were more susceptible than adult mice to APAP-induced hepatic GSH depletion. Of interest, immature mice expressed a much higher level of hepatic Cyp2e1 and Cyp3a11 mRNAs than adult mice. Correspondingly, immature mice expressed a higher level of hepatic CYP2E1, the key drug metabolic enzyme that metabolized APAP into the reactive metabolite NAPQI. These results suggest that a higher level of hepatic drug metabolic enzymes in immature mice than adult mice might contribute to the difference of susceptibility to APAP-induced acute liver injury. PMID:28205631

  7. Variations in Phytoestrogen Content between Different Mill Dates of the Same Diet Produces Significant Differences in the Time of Vaginal Opening in CD-1 Mice and F344 Rats but Not in CD Sprague-Dawley Rats

    PubMed Central

    Thigpen, Julius E.; Setchell, Kenneth D.R.; Padilla-Banks, Elizabeth; Haseman, Joseph K.; Saunders, Hannah E.; Caviness, Gordon F.; Kissling, Grace E.; Grant, Mary G.; Forsythe, Diane B.

    2007-01-01

    Background The optimum test diet and rodent species/strain for evaluating endocrine-disrupting compounds (EDCs) are critical. Objectives We conducted studies to evaluate rodent species sensitivity and the effects of diets varying in phytoestrogen content on the time of vaginal opening (VO) in CD-1 mice, Fischer 344 (F344) rats, and CD Sprague-Dawley (S-D) rats. Methods Mice were weaned on postnatal day (PND) 15 and rats on PND19 and randomly assigned to control or test diets. Body weights, food consumption, and time of VO were recorded. Results The time of VO was significantly advanced in F344 rats fed diets containing daidzein and genistein, whereas these same diets did not advance VO in S-D rats. When animals were fed the AIN-76A diet spiked with genistein, time of VO was significantly advanced at all doses in CD-1 mice, at the two highest doses in F344 rats, and at the highest dose in S-D rats. The time of VO in F344 rats was more highly correlated with the phytoestrogen content than with the total metabolizable energy (ME) of 12 diets. Conclusions The S-D rat is less sensitive to dietary phytoestrogens compared with the F344 rat or the CD-1 mouse, suggesting that the S-D rat is not the ideal model for evaluating estrogenic activity of EDCs. The profound effects of dietary phytoestrogens on the time of VO, an estrogen-sensitive marker, indicate that a standardized open-formula phytoestrogen-free diet containing a low ME level should be used to optimize the sensitivity of estrogenic bioassays. PMID:18087589

  8. Phenotypic Dichotomy Following Developmental Exposure to Perfluorooctanic Acid (PFOA) Exposure in CD-1 Mice: Low Doses Induce Elevated Serum, Leptin, Insulin, and Overweight in Mid-Life.

    EPA Science Inventory

    The synthetic surfactant, perfluorooctanoic acid (PFOA) is a proven developmental toxicant in mice, causing prenatal pregnancy loss, increased neonatal mortality, delayed eye opening, and abnormal mammary gland growth in animals exposed during fetal life. PFOA is found in the ser...

  9. Hypoxia induces heart regeneration in adult mice.

    PubMed

    Nakada, Yuji; Canseco, Diana C; Thet, SuWannee; Abdisalaam, Salim; Asaithamby, Aroumougame; Santos, Celio X; Shah, Ajay M; Zhang, Hua; Faber, James E; Kinter, Michael T; Szweda, Luke I; Xing, Chao; Hu, Zeping; Deberardinis, Ralph J; Schiattarella, Gabriele; Hill, Joseph A; Oz, Orhan; Lu, Zhigang; Zhang, Cheng Cheng; Kimura, Wataru; Sadek, Hesham A

    2017-01-12

    The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal. In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage. Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that, in mice, gradual exposure to severe systemic hypoxaemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Notably, we find that exposure to hypoxaemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Genetic fate-mapping analysis confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.

  10. CYP3A-mediated apoptosis of dauricine in cultured human bronchial epithelial cells and in lungs of CD-1 mice

    SciTech Connect

    Jin, Hua; Shen, Shuijie; Chen, Xiaoyan; Zhong, Dafang; Zheng, Jiang

    2012-06-15

    Dauricine is the major bioactive component isolated from the root of Menispermum dauricum DC and has shown promising pharmacologic activities with a great potential for clinical use. Recently, we found that intraperitoneal exposure of dauricine produced selective pulmonary injury in mice. A quinone methide metabolite of dauricine was identified and is suggested to be associated with the pulmonary toxicity of dauricine. The present study evaluated the apoptotic effect of dauricine in cultured cells and mice, determined the change in cellular glutathione (GSH) contents after exposure to dauricine, investigated the role of GSH depletion in dauricine-induced cytotoxicity and apoptosis, and examined the role of CYP3A in dauricine-induced GSH depletion and apoptosis. Dauricine was found to induce apoptosis in NL-20 cells. Additionally, intraperitoneal administration of dauricine caused GSH depletion and apoptosis in lungs of mice. Treatment with ketoconazole, an inhibitor of CYP3A, reversed cellular GSH depletion in lungs of mice given dauricine and showed protective effect on dauricine-induced apoptosis in lungs of mice. This indicates that metabolic activation is involved in dauricine-induced GSH-depletion, cytotoxicity and apoptosis. The glutathione depletor L-buthionine sulfoximine showed potentiating effect on cytotoxicity and apoptosis induced by dauricine. We propose that dauricine is metabolized to a quinone methide intermediate which depletes cellular GSH, and the depletion of GSH may trigger and/or intensify the cytotoxicity and apoptosis induced by dauricine. -- Highlights: ► Dauricine induced apoptosis in lungs in mice and in cultured human pulmonary cells. ► Dauricine depleted cellular GSH in lungs of mice and in the human pulmonary cells. ► CYP3A subfamily mediated GSH depletion and apoptosis induced by dauricine. ► L-Buthionine sulfoximine potentiated dauricine-induced GSH depletion and apoptosis.

  11. Drug-induced regeneration in adult mice

    PubMed Central

    Zhang, Yong; Strehin, Iossif; Bedelbaeva, Khamilia; Gourevitch, Dmitri; Clark, Lise; Leferovich, John; Messersmith, Phillip B.; Heber-Katz, Ellen

    2015-01-01

    Whereas amphibians regenerate lost appendages spontaneously, mammals generally form scars over the injury site through the process of wound repair. The MRL mouse strain is an exception among mammals because it shows a spontaneous regenerative healing trait and so can be used to investigate proregenerative interventions in mammals. We report that hypoxia-inducible factor 1α (HIF-1α) is a central molecule in the process of regeneration in adult MRL mice. The degradation of HIF-1α protein, which occurs under normoxic conditions, is mediated by prolyl hydroxylases (PHDs). We used the drug 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), a PHD inhibitor, to stabilize constitutive expression of HIF-1α protein. A locally injectable hydrogel containing 1,4-DPCA was designed to achieve controlled delivery of the drug over 4 to 10 days. Subcutaneous injection of the 1,4-DPCA/hydrogel into Swiss Webster mice that do not show a regenerative phenotype increased stable expression of HIF-1α protein over 5 days, providing a functional measure of drug release in vivo. Multiple peripheral subcutaneous injections of the 1,4-DPCA/hydrogel over a 10-day period led to regenerative wound healing in Swiss Webster mice after ear hole punch injury. Increased expression of the HIF-1α protein may provide a starting point for future studies on regeneration in mammals. PMID:26041709

  12. CYP3A-mediated apoptosis of dauricine in cultured human bronchial epithelial cells and in lungs of CD-1 mice.

    PubMed

    Jin, Hua; Shen, Shuijie; Chen, Xiaoyan; Zhong, Dafang; Zheng, Jiang

    2012-06-15

    Dauricine is the major bioactive component isolated from the root of Menispermum dauricum DC and has shown promising pharmacologic activities with a great potential for clinical use. Recently, we found that intraperitoneal exposure of dauricine produced selective pulmonary injury in mice. A quinone methide metabolite of dauricine was identified and is suggested to be associated with the pulmonary toxicity of dauricine. The present study evaluated the apoptotic effect of dauricine in cultured cells and mice, determined the change in cellular glutathione (GSH) contents after exposure to dauricine, investigated the role of GSH depletion in dauricine-induced cytotoxicity and apoptosis, and examined the role of CYP3A in dauricine-induced GSH depletion and apoptosis. Dauricine was found to induce apoptosis in NL-20 cells. Additionally, intraperitoneal administration of dauricine caused GSH depletion and apoptosis in lungs of mice. Treatment with ketoconazole, an inhibitor of CYP3A, reversed cellular GSH depletion in lungs of mice given dauricine and showed protective effect on dauricine-induced apoptosis in lungs of mice. This indicates that metabolic activation is involved in dauricine-induced GSH-depletion, cytotoxicity and apoptosis. The glutathione depletor L-buthionine sulfoximine showed potentiating effect on cytotoxicity and apoptosis induced by dauricine. We propose that dauricine is metabolized to a quinone methide intermediate which depletes cellular GSH, and the depletion of GSH may trigger and/or intensify the cytotoxicity and apoptosis induced by dauricine.

  13. Chronic Exposure to Arsenic in Drinking Water Causes Alterations in Locomotor Activity and Decreases Striatal mRNA for the D2 Dopamine Receptor in CD1 Male Mice.

    PubMed

    Moreno Ávila, Claudia Leticia; Limón-Pacheco, Jorge H; Giordano, Magda; Rodríguez, Verónica M

    2016-01-01

    Arsenic exposure has been associated with sensory, motor, memory, and learning alterations in humans and alterations in locomotor activity, behavioral tasks, and neurotransmitters systems in rodents. In this study, CD1 mice were exposed to 0.5 or 5.0 mg As/L of drinking water for 6 months. Locomotor activity, aggression, interspecific behavior and physical appearance, monoamines levels, and expression of the messenger for dopamine receptors D1 and D2 were assessed. Arsenic exposure produced hypoactivity at six months and other behaviors such as rearing and on-wall rearing and barbering showed both increases and decreases. No alterations on aggressive behavior or monoamines levels in striatum or frontal cortex were observed. A significant decrease in the expression of mRNA for D2 receptors was found in striatum of mice exposed to 5.0 mg As/L. This study provides evidence for the use of dopamine receptor D2 as potential target of arsenic toxicity in the dopaminergic system.

  14. Chronic Exposure to Arsenic in Drinking Water Causes Alterations in Locomotor Activity and Decreases Striatal mRNA for the D2 Dopamine Receptor in CD1 Male Mice

    PubMed Central

    Moreno Ávila, Claudia Leticia

    2016-01-01

    Arsenic exposure has been associated with sensory, motor, memory, and learning alterations in humans and alterations in locomotor activity, behavioral tasks, and neurotransmitters systems in rodents. In this study, CD1 mice were exposed to 0.5 or 5.0 mg As/L of drinking water for 6 months. Locomotor activity, aggression, interspecific behavior and physical appearance, monoamines levels, and expression of the messenger for dopamine receptors D1 and D2 were assessed. Arsenic exposure produced hypoactivity at six months and other behaviors such as rearing and on-wall rearing and barbering showed both increases and decreases. No alterations on aggressive behavior or monoamines levels in striatum or frontal cortex were observed. A significant decrease in the expression of mRNA for D2 receptors was found in striatum of mice exposed to 5.0 mg As/L. This study provides evidence for the use of dopamine receptor D2 as potential target of arsenic toxicity in the dopaminergic system. PMID:27375740

  15. Antigenotoxic and Apoptotic Activity of Green Tea Polyphenol Extracts on Hexavalent Chromium-Induced DNA Damage in Peripheral Blood of CD-1 Mice: Analysis with Differential Acridine Orange/Ethidium Bromide Staining

    PubMed Central

    García-Rodríguez, María del Carmen; Carvente-Juárez, Megumi Monserrat; Altamirano-Lozano, Mario Agustín

    2013-01-01

    This study was conducted to investigate the modulating effects of green tea polyphenols on genotoxic damage and apoptotic activity induced by hexavalent chromium [Cr (VI)] in CD-1 mice. Animals were divided into the following groups: (i) injected with vehicle; (ii) treated with green tea polyphenols (30 mg/kg) via gavage; (iii) injected with CrO3 (20 mg/kg) intraperitoneally; (iv) treated with green tea polyphenols in addition to CrO3. Genotoxic damage was evaluated by examining micronucleated polychromatic erythrocytes (MN-PCEs) obtained from peripheral blood at 0, 24, 48, and 72 h after treatment. Induction of apoptosis and cell viability were assessed by differential acridine orange/ethidium bromide (AO/EB) staining. Treatment of green tea polyphenols led to no significant changes in the MN-PCEs. However, CrO3 treatment significantly increased MN-PCEs at 24 and 48 h after injection. Green tea polyphenols treatment prior to CrO3 injection led to a decrease in MN-PCEs compared to the group treated with CrO3 only. The average of apoptotic cells was increased at 48 h after treatment compared to control mice, suggesting that apoptosis could contribute to eliminate the DNA damaged cells induced by Cr (VI). Our findings support the proposed protective effects of green tea polyphenols against the genotoxic damage induced by Cr (VI). PMID:24363823

  16. NTP Toxicology and Carcinogenesis Studies of o-Phenylphenol (CAS No. 90-43-7) Alone and with 7,12-Dimethylbenz(a)anthracene (CAS No. 57-97-6) in Swiss CD-1 Mice (Dermal Studies).

    PubMed

    1986-03-01

    o-Phenylphenol is used primarily as a germicide and fungicide for citrus fruits and vegetables and was selected for carcinogenesis studies because of the potential for human exposure. Four-week studies were conducted in which groups of 10 male and 10 female Swiss Webster mice were given dermal applications to the dorsal interscapular region of 0, 6, 11, 21, 36, or 56 mg of o-phenylphenol in 0.1 ml of acetone. Doses were administered 3 days per week for 4 weeks, and animals were monitored for clinical changes. Reductions in body weights of acetone vehicle control were observed, but no compound-related changes in weight or survival occurred in male or female mice administered o-phenylphenol. o-Phenylphenol caused dose-related ulcerative lesions at the site of application. The severity of these lesions was judged not to be life threatening. Carcinogenesis studies were conducted to determine whether o-phenylphenol was a complete carcinogen for skin or a promoter in a two-stage initiation/promotion skin paint model. Groups of 50 Swiss CD-1 mice of each sex were used for up to 102 weeks. Five dose groups were used: an acetone vehicle control group; a positive control group initiated with 7,12-dimethylbenz(a)- anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA); an initiator control group that received DMBA plus acetone; a group that received repeated applications of o-phenylphenol. The following doses were applied dermally to a clipped area on the dorsal interscapular region 3 days per week: o-phenylphenol - 55.5 mg/0.1 ml acetone; or TPA - 0.005 mg/0.1 ml acetone. DMBA was administered as a single dose at a concentration of 0.05 mg/0.1 ml acetone to the dorsal interscapular region. In the 2-year studies, mean body weights of the o-phenylphenol, DMBA/o-phenylphenol, and DMBA/TPA groups were not markedly different from those of mice that received DMBA/acetone. Similarly, there were no significant group differences in survival except for a

  17. Up-regulation of exploratory tendencies does not enhance general learning abilities in juvenile or young-adult outbred mice.

    PubMed

    Light, Kenneth R; Kolata, Stefan; Hale, Gregory; Grossman, Henya; Matzel, Louis D

    2008-09-01

    "General cognitive ability" describes a trait that transcends specific learning domains and impacts a wide range of cognitive skills. Individual animals (including humans) exhibit wide variations in their expression of this trait. We have previously determined that the propensity for exploration is highly correlated with the general cognitive abilities of individual outbred mice. Here, we asked if inducing an increase in exploratory behaviors would causally promote an increase in animals' general learning abilities. In three experiments, juvenile and young-adult male CD-1 outbred mice were exposed to 12 novel environments starting at post-natal days 39 (juvenile) and 61 (young adult), after which they underwent a series of cognitive and exploratory tests as adults (beginning at post-natal day 79). Exposure to novel environments promoted increases in exploration (across multiple measures) on two different tasks, including an elevated plus maze. However, a subsequent test of general learning abilities (aggregate performance across five distinct learning tasks) determined that exposure to novel environments as juveniles or young-adults had no effect on general learning abilities in adulthood. Therefore, while exposure to novel environments promotes long-lasting increases in mice's exploratory tendencies, these increases in exploration do not appear to causally impact general learning abilities.

  18. Heart regeneration in adult MRL mice

    NASA Astrophysics Data System (ADS)

    Leferovich, John M.; Bedelbaeva, Khamilia; Samulewicz, Stefan; Zhang, Xiang-Ming; Zwas, Donna; Lankford, Edward B.; Heber-Katz, Ellen

    2001-08-01

    The reaction of cardiac tissue to acute injury involves interacting cascades of cellular and molecular responses that encompass inflammation, hormonal signaling, extracellular matrix remodeling, and compensatory adaptation of myocytes. Myocardial regeneration is observed in amphibians, whereas scar formation characterizes cardiac ventricular wound healing in a variety of mammalian injury models. We have previously shown that the MRL mouse strain has an extraordinary capacity to heal surgical wounds, a complex trait that maps to at least seven genetic loci. Here, we extend these studies to cardiac wounds and demonstrate that a severe transmural, cryogenically induced infarction of the right ventricle heals extensively within 60 days, with the restoration of normal myocardium and function. Scarring is markedly reduced in MRL mice compared with C57BL/6 mice, consistent with both the reduced hydroxyproline levels seen after injury and an elevated cardiomyocyte mitotic index of 10-20% for the MRL compared with 1-3% for the C57BL/6. The myocardial response to injury observed in these mice resembles the regenerative process seen in amphibians.

  19. Bone density, strength, and formation in adult cathepsin K (-/-) mice.

    PubMed

    Pennypacker, B; Shea, M; Liu, Q; Masarachia, P; Saftig, P; Rodan, S; Rodan, G; Kimmel, D

    2009-02-01

    Cathepsin K (CatK) is a cysteine protease expressed predominantly in osteoclasts, that plays a prominent role in degrading Type I collagen. Growing CatK null mice have osteopetrosis associated with a reduced ability to degrade bone matrix. Bone strength and histomorphometric endpoints in young adult CatK null mice aged more than 10 weeks have not been studied. The purpose of this paper is to describe bone mass, strength, resorption, and formation in young adult CatK null mice. In male and female wild-type (WT), heterozygous, and homozygous CatK null mice (total N=50) aged 19 weeks, in-life double fluorochrome labeling was performed. Right femurs and lumbar vertebral bodies 1-3 (LV) were evaluated by dual-energy X-ray absorptiometry (DXA) for bone mineral content (BMC) and bone mineral density (BMD). The trabecular region of the femur and the cortical region of the tibia were evaluated by histomorphometry. The left femur and sixth lumbar vertebral body were tested biomechanically. CatK (-/-) mice show higher BMD at the central and distal femur. Central femur ultimate load was positively influenced by genotype, and was positively correlated with both cortical area and BMC. Lumbar vertebral body ultimate load was also positively correlated to BMC. Genotype did not influence the relationship of ultimate load to BMC in either the central femur or vertebral body. CatK (-/-) mice had less lamellar cortical bone than WT mice. Higher bone volume, trabecular thickness, and trabecular number were observed at the distal femur in CatK (-/-) mice. Smaller marrow cavities were also present at the central femur of CatK (-/-) mice. CatK (-/-) mice exhibited greater trabecular mineralizing surface, associated with normal volume-based formation of trabecular bone. Adult CatK (-/-) mice have higher bone mass in both cortical and cancellous regions than WT mice. Though no direct measures of bone resorption rate were made, the higher cortical bone quantity is associated with a smaller

  20. CD1− and CD1+ porcine blood dendritic cells are enriched for the orthologues of the two major mammalian conventional subsets

    PubMed Central

    Edwards, Jane C.; Everett, Helen E.; Pedrera, Miriam; Mokhtar, Helen; Marchi, Emanuele; Soldevila, Ferran; Kaveh, Daryan A.; Hogarth, Philip J.; Johns, Helen L.; Nunez-Garcia, Javier; Steinbach, Falko; Crooke, Helen R.; Graham, Simon P.

    2017-01-01

    Conventional dendritic cells (cDC) are professional antigen-presenting cells that induce immune activation or tolerance. Two functionally specialised populations, termed cDC1 and cDC2, have been described in humans, mice, ruminants and recently in pigs. Pigs are an important biomedical model species and a key source of animal protein; therefore further understanding of their immune system will help underpin the development of disease prevention strategies. To characterise cDC populations in porcine blood, DC were enriched from PBMC by CD14 depletion and CD172a enrichment then stained with lineage mAbs (Lin; CD3, CD8α, CD14 and CD21) and mAbs specific for CD172a, CD1 and CD4. Two distinct porcine cDC subpopulations were FACSorted CD1− cDC (Lin−CD172+ CD1−CD4−) and CD1+ cDC (Lin−CD172a+ CD1+ CD4−), and characterised by phenotypic and functional analyses. CD1+ cDC were distinct from CD1− cDC, expressing higher levels of CD172a, MHC class II and CD11b. Following TLR stimulation, CD1+ cDC produced IL-8 and IL-10 while CD1− cDC secreted IFN-α, IL-12 and TNF-α. CD1− cDC were superior in stimulating allogeneic T cell responses and in cross-presenting viral antigens to CD8 T cells. Comparison of transcriptional profiles further suggested that the CD1− and CD1+ populations were enriched for the orthologues of cDC1 and cDC2 subsets respectively. PMID:28106145

  1. Anti-aging effect of Blakeslea trispora powder on adult mice.

    PubMed

    Hu, Weilian; Dai, Dehui; Li, Wei

    2013-08-01

    Blakeslea trispora powder that contains 1.9 % lycopene was tested for its anti-aging effect on adult mice. 48 adult mice were administered with the powder at 0, 267, 534, 1,068 mg lycopene kg(-1) body daily for 30 days. The body weight, hematology, clinical chemical and antioxidant activities in major organs of adult mice were measured. The powder had no effect on the body weight, hematology, clinical chemical parameters of adult mice but improved the antioxidant activities in major organs of adult mice. Increased activities of superoxide dismutase, catalase and glutathione peroxidase and a decreased amount of malondialdehyde in liver, brain, kidney and skin of adult mice when a high-dose of the B. trispora powder was administered, suggests that it has the ability to enhance the antioxidation system and improve the anti-aging abilities of adult mice.

  2. Endogenous cerebellar neurogenesis in adult mice with progressive ataxia

    PubMed Central

    Kumar, Manoj; Csaba, Zsolt; Peineau, Stéphane; Srivastava, Rupali; Rasika, Sowmyalakshmi; Mani, Shyamala; Gressens, Pierre; El Ghouzzi, Vincent

    2014-01-01

    Objective Transplanting exogenous neuronal progenitors to replace damaged neurons in the adult brain following injury or neurodegenerative disorders and achieve functional amelioration is a realistic goal. However, studies so far have rarely taken into consideration the preexisting inflammation triggered by the disease process that could hamper the effectiveness of transplanted cells. Here, we examined the fate and long-term consequences of human cerebellar granule neuron precursors (GNP) transplanted into the cerebellum of Harlequin mice, an adult model of progressive cerebellar degeneration with early-onset microgliosis. Methods Human embryonic stem cell-derived progenitors expressing Atoh1, a transcription factor key to GNP specification, were generated in vitro and stereotaxically transplanted into the cerebellum of preataxic Harlequin mice. The histological and functional impact of these transplants was followed using immunolabeling and Rotarod analysis. Results Although transplanted GNPs did not survive beyond a few weeks, they triggered the proliferation of endogenous nestin-positive precursors in the leptomeninges that crossed the molecular layer and differentiated into mature neurons. These phenomena were accompanied by the preservation of the granule and Purkinje cell layers and delayed ataxic changes. In vitro neurosphere generation confirmed the enhanced neurogenic potential of the cerebellar leptomeninges of Harlequin mice transplanted with exogenous GNPs. Interpretation The cerebellar leptomeninges of adult mice contain an endogenous neurogenic niche that can be stimulated to yield mature neurons from an as-yet unidentified population of progenitors. The transplantation of human GNPs not only stimulates this neurogenesis, but, despite the potentially hostile environment, leads to neuroprotection and functional amelioration. PMID:25574472

  3. Effects of synchronous and asynchronous embryo transfer on postnatal development, adult health, and behavior in mice.

    PubMed

    López-Cardona, Angela P; Fernández-González, Raúl; Pérez-Crespo, Miriam; Alén, Francisco; de Fonseca, Fernando Rodriguez; Orio, Laura; Gutierrez-Adan, Alfonso

    2015-10-01

    Asynchronous embryo transfer (ET) is a common assisted reproduction technique used in several species, but its biological effects on postnatal and early development remain unknown. The aim of this study was to determine whether asynchronous ET produces long-term effects in mice. Postnatal development, animal weight, systolic blood pressure (SBP), relative organ weight (liver, spleen, kidneys, heart, lungs, brain, and testicles), and behavior (assessed in open-field and elevated plus maze tests) were assessed in CD1 mice produced by different ET procedures: 1) the transfer of Day 3.5 (D3.5) blastocysts to the uterus (BL-UT); 2) the transfer of D3.5 blastocysts to the oviduct (BL-OV); or 3) the transfer of D0.5 zygotes to the oviduct (Z-OV). In vivo conceived animals served as controls (CT). The transfer of blastocysts to the uterus or zygotes to the oviduct was defined as synchronous, and transfer of blastocysts to the oviduct was defined as asynchronous. Both synchronous and asynchronous ET resulted in increased weight at birth that normalized thereafter with the exception of asynchronous ET females. In this group, female BL-OV, a clear lower body weight was recorded along postnatal life when compared with controls (P < 0.05). No effects on animal weight were produced during postnatal development in the synchronous ET groups (BL-UT, Z-OV, and CT). Both synchronous and asynchronous ET had impacts on adult (Wk 30) organ weight. SBP was modified in animals derived from blastocyst but not zygote ET. Effects on behavior (anxiety in the plus maze) were only detected in the BL-UT group (P < 0.05). Our findings indicate that zygotes are less sensitive than blastocysts to ET and that both synchronous and asynchronous blastocyst ET may have long-term consequences on health, with possible impacts on weight, arterial pressure, relative organ weight, and behavior.

  4. CD1A — EDRN Public Portal

    Cancer.gov

    CD1A is a transmembrane glycoprotein that is structurally related to the major histocompatibility complex (MHC) proteins and forms heterodimers with beta-2-microglobulin. CD1A functions as an antigen-presenting protein that binds self and non-self lipid and glycolipid antigens and presents them to T-cell receptors on natural killer T-cells.

  5. Growth Hormone Inhibits Hepatic De Novo Lipogenesis in Adult Mice

    PubMed Central

    Cordoba-Chacon, Jose; Majumdar, Neena; List, Edward O.; Diaz-Ruiz, Alberto; Frank, Stuart J.; Manzano, Anna; Bartrons, Ramon; Puchowicz, Michelle; Kopchick, John J.

    2015-01-01

    Patients with nonalcoholic fatty liver disease (NAFLD) are reported to have low growth hormone (GH) production and/or hepatic GH resistance. GH replacement can resolve the fatty liver condition in diet-induced obese rodents and in GH-deficient patients. However, it remains to be determined whether this inhibitory action of GH is due to direct regulation of hepatic lipid metabolism. Therefore, an adult-onset, hepatocyte-specific, GH receptor (GHR) knockdown (aLivGHRkd) mouse was developed to model hepatic GH resistance in humans that may occur after sexual maturation. Just 7 days after aLivGHRkd, hepatic de novo lipogenesis (DNL) was increased in male and female chow-fed mice, compared with GHR-intact littermate controls. However, hepatosteatosis developed only in male and ovariectomized female aLivGHRkd mice. The increase in DNL observed in aLivGHRkd mice was not associated with hyperactivation of the pathway by which insulin is classically considered to regulate DNL. However, glucokinase mRNA and protein levels as well as fructose-2,6-bisphosphate levels were increased in aLivGHRkd mice, suggesting that enhanced glycolysis drives DNL in the GH-resistant liver. These results demonstrate that hepatic GH actions normally serve to inhibit DNL, where loss of this inhibitory signal may explain, in part, the inappropriate increase in hepatic DNL observed in NAFLD patients. PMID:26015548

  6. Ghrelin signaling in heart remodeling of adult obese mice.

    PubMed

    Lacerda-Miranda, Glauciane; Soares, Vivian M; Vieira, Anatalia K G; Lessa, Juliana G; Rodrigues-Cunha, Alessandra C S; Cortez, Erika; Garcia-Souza, Erica P; Moura, Anibal S

    2012-05-01

    Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), has been suggested to be associated to obesity, insulin secretion, cardiovascular growth and homeostasis. GHS-R has been found in most of the tissues, and among the hormone action it is included the regulation of heart energy metabolism. Therefore, hypernutrition during early life leads to obesity, induces cardiac hypertrophy, compromises myocardial function, inducing heart failure in adulthood. We examined ghrelin signaling process in cardiac remodeling in these obese adult mice. The cardiomyocytes (cmy) of left ventricle were analyzed by light microscopy and stereology, content and phosphorilation of cardiac proteins: ghrelin receptor (growth hormone secretagogue receptor 1a, GHSR-1a), protein kinase B (AKT and pAKT), phosphatidil inositol 3 kinase (PI3K), AMP-activated protein kinase (AMPK and pAMPK) and actin were achieved by Western blotting. GHSR-1a gene expression was analyzed by Real Time-PCR. We observed hyperglycemia and higher liver and visceral fat weight in obese when compared to control group. Obese mice presented a marked increase in heart weight/tibia length, indicating an enlarged heart size or a remodeling process. Obese mice had increased GHSR-1a content and expression in the heart associated to PI3K content and increased AKT content and phosphorylation. In contrast, AMPK content and phosphorylation in heart was not different between experimental groups. Ghrelin plasma levels in obese group were decreased when compared to control group. Our data suggest that remodeled myocardial in adult obese mice overnourished in early life are associated with higher phosphorylation of GHSR-1a, PI3K and AKT but not with AMPK.

  7. Bone status of adult female butyrylcholinesterase gene-deficient mice.

    PubMed

    Haupt, Malte; Kauschke, Vivien; Sender, Jonas; Kampschulte, Marian; Kovtun, Anna; Dürselen, Lutz; Heiss, Christian; Lips, Katrin Susanne

    2015-11-01

    Butyrylcholinesterase (BChE) degrades acetylcholine in addition to acetylcholinesterase (AChE) which is involved in embryonic development of limbs. Since BChE is expressed by osteoblast-like cells we asked whether it is functional in adult bone remodeling. We addressed this issue by analyzing BChE gene-deficient mice (BChE-KO). Bones were extracted from 16-week old female BChE-KO and corresponding wild type mice (WT). Femoral bones were used for biomechanical testing and μCT evaluation of cancellous and cortical bone. Also vertebrae Th12 and L1 were investigated with μCT while L3 was used for tartrate-resistant acidic phosphatase (TRAP) histomorphometry and Th10 for gene expression analysis by means of real-time RT-PCR. BChE-KO did not reveal significant differences in biomechanical bone strength and bone mineral density determined by μCT. Microarchitecture of cancellous and cortical bone showed an increase in μCT parameters like trabecular thickness, trabecular separation, and relative cortical bone area of femoral BChE-KO bone compared to WT. In vertebrae no changes of microstructure and mRNA expression were detected. However, osteoclast histomorphometry with TRAP stained sections demonstrated a significant increase in relative osteoclast number. In conclusion, in adult murine bone the role of BChE is limited to bone specific changes in microarchitecture and to an increase in relative number of bone resorbing osteoclasts whereas the main collagen resorbing enzyme Cathepsin-K (CtsK) was stably expressed. Besides, AChE might be able to compensate the lack of BChE. Thus, further analyses using bone tissue specific AChE BChE cre-lox double knockout mice would be helpful.

  8. CD1 antigen presentation: how it works.

    PubMed

    Barral, Duarte C; Brenner, Michael B

    2007-12-01

    The classic concept of self-non-self discrimination by the immune system focused on the recognition of fragments from proteins presented by classical MHC molecules. However, the discovery of MHC-class-I-like CD1 antigen-presentation molecules now explains how the immune system also recognizes the abundant and diverse universe of lipid-containing antigens. The CD1 molecules bind and present amphipathic lipid antigens for recognition by T-cell receptors. Here, we outline the recent advances in our understanding of how the processes of CD1 assembly, trafficking, lipid-antigen binding and T-cell activation are achieved and the new insights into how lipid antigens differentially elicit CD1-restricted innate and adaptive T-cell responses.

  9. Gestational Exposure to Bisphenol A Affects the Function and Proteome Profile of F1 Spermatozoa in Adult Mice

    PubMed Central

    Rahman, Md Saidur; Kwon, Woo-Sung; Karmakar, Polash Chandra; Yoon, Sung-Jae; Ryu, Buom-Yong; Pang, Myung-Geol

    2016-01-01

    Background: Maternal exposure to the endocrine disruptor bisphenol A (BPA) has been linked to offspring reproductive abnormalities. However, exactly how BPA affects offspring fertility remains poorly understood. Objectives: The aim of the present study was to evaluate the effects of gestational BPA exposure on sperm function, fertility, and proteome profile of F1 spermatozoa in adult mice. Methods: Pregnant CD-1 mice (F0) were gavaged with BPA at three different doses (50 μg/kg bw/day, 5 mg/kg bw/day, and 50 mg/kg bw/day) on embryonic days 7 to 14. We investigated the function, fertility, and related processes of F1 spermatozoa at postnatal day 120. We also evaluated protein profiles of F1 spermatozoa to monitor their functional affiliation to disease. Results: BPA inhibited sperm count, motility parameters, and intracellular ATP levels in a dose-dependent manner. These effects appeared to be caused by reduced numbers of stage VIII seminiferous epithelial cells in testis and decreased protein kinase A (PKA) activity and tyrosine phosphorylation in spermatozoa. We also found that BPA compromised average litter size. Proteins differentially expressed in spermatozoa from BPA treatment groups are known to play a critical role in ATP generation, oxidative stress response, fertility, and in the pathogenesis of several diseases. Conclusions: Our study provides mechanistic support for the hypothesis that gestational exposure to BPA alters sperm function and fertility via down-regulation of tyrosine phosphorylation through a PKA-dependent mechanism. In addition, we anticipate that the BPA-induced changes in the sperm proteome might be partly responsible for the observed effects in spermatozoa. Citation: Rahman MS, Kwon WS, Karmakar PC, Yoon SJ, Ryu BY, Pang MG. 2017. Gestational exposure to bisphenol-A affects the function and proteome profile of F1 spermatozoa in adult mice. Environ Health Perspect 125:238–245; http://dx.doi.org/10.1289/EHP378 PMID:27384531

  10. Comparative contribution of CD1 on the development of CD4+ and CD8+ T cell compartments.

    PubMed

    Wang, B; Chun, T; Wang, C R

    2000-01-15

    CD1 molecules are MHC class I-like glycoproteins whose expression is essential for the development of a unique subset of T cells, the NK T cells. To evaluate to what extent CD1 contributes to the development of CD4+ and CD8+ T cells, we generated CD1oIIo and CD1oTAPo mice and compared the generation of T cells in these double-mutant mice and IIo or TAPo mice. FACS analysis showed that the number of CD4+ T cells in CD1oIIo mice was reduced significantly compared with the corresponding population in IIo mice. Both CD4+ NK1.1+ and the CD4+ NK1.1- population were reduced in CD1oIIo mice, suggesting that CD1 can select not only CD4+ NK1.1+ T cells but also some NK1.1- CD4+ T cells. Functional analysis showed that the residual CD4+ cells in CD1oIIo can secrete large amounts of IFN-gamma and a significant amount of IL-4 during primary stimulation with anti-CD3, suggesting that this population may be enriched for NK T cells restricted by other class I molecules. In contrast to the CD4+ population, no significant differences in the CD8+ T cell compartment can be detected between TAPo and CD1oTAPo mice in all lymphoid tissues tested, including intestinal intraepithelial lymphocytes. Our data suggest that, unlike other MHC class I molecules, CD1 does not contribute in a major way to the development of CD8+ T cells.

  11. Pubertal immune challenge blocks the ability of estradiol to enhance performance on cognitive tasks in adult female mice.

    PubMed

    Ismail, Nafissa; Blaustein, Jeffrey D

    2013-07-01

    Puberty is a period characterized by brain reorganization that contributes to the development of neural and behavioral responses to gonadal steroids. Previously, we have shown that a single injection of the bacterial endotoxin, lipopolysaccharide (LPS; 1.5mg/kg IP), during the pubertal period (around 6weeks old) in mice decreases sexual receptivity in response to estradiol and progesterone in adulthood. These findings suggest that pubertal immune challenge has an enduring effect of decreasing the behavioral responsiveness to gonadal steroid hormones. Since estradiol improves cognitive function in certain tasks in mice, we investigated the effect of pubertal immune challenge on the ability of estradiol to enhance cognitive function. We hypothesized that estradiol would be less effective at enhancing performance on particular cognitive tasks in female mice treated with LPS during puberty. Six-week old (pubertal) and 10-week old (adult) female CD1 mice were injected with either saline or LPS. Five weeks later, they were ovariectomized and implanted subcutaneously with either an estradiol- or oil-filled Silastic(©) capsule followed 1week later with testing for cognitive function. The duration of juvenile investigation during social discrimination and recognition tests was used as a measure of social memory, and the duration of object investigation during object recognition and placement tests was used as a measure of object memory. Chronic estradiol treatment enhanced social and object memory in saline-treated females and in females treated with LPS in adulthood. In contrast, in females treated with LPS at 6weeks old, estradiol failed to improve social and object memories. These results support the hypothesis that exposure to an immune challenge during puberty reduces at least some of the cognitive effects of estradiol. Moreover, these results support the idea that pubertal immune challenge compromises a wide variety of behavioral influences of ovarian hormones.

  12. The effects of nesting material on energy homeostasis in BALB/cAnNCrl, C57BL/6NCrl, and Crl:CD1(ICR) laboratory mice housed at 20°C

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objective: A discrepancy exists between the preferred ambient temperature range for mice (26 to 32°C) and the current recommendations (20 to 26°C) that can result in mild hypothermia. As a consequence, animal welfare may be reduced and physiological state can be altered, which can impact research ...

  13. Effects of early-onset voluntary exercise on adult physical activity and associated phenotypes in mice.

    PubMed

    Acosta, Wendy; Meek, Thomas H; Schutz, Heidi; Dlugosz, Elizabeth M; Vu, Kim T; Garland, Theodore

    2015-10-01

    The purpose of this study was to evaluate the effects of early-life exercise on adult physical activity (wheel running, home-cage activity), body mass, food consumption, and circulating leptin levels in males from four replicate lines of mice selectively bred for high voluntary wheel running (High Runner or HR) and their four non-selected control (C) lines. Half of the mice were given wheel access shortly after weaning for three consecutive weeks. Wheel access was then removed for 52 days, followed by two weeks of adult wheel access for all mice. A blood sample taken prior to adult wheel testing was analyzed for circulating leptin concentration. Early-life wheel access significantly increased adult voluntary exercise on wheels during the first week of the second period of wheel access, for both HR and C mice, and HR ran more than C mice. During this same time period, activity in the home cages was not affected by early-age wheel access, and did not differ statistically between HR and C mice. Throughout the study, all mice with early wheel access had lower body masses than their sedentary counterparts, and HR mice had lower body masses than C mice. With wheel access, HR mice also ate significantly more than C mice. Early-life wheel access increased plasma leptin levels (adjusted statistically for fat-pad mass as a covariate) in C mice, but decreased them in HR mice. At sacrifice, early-life exercise had no statistically significant effects on visceral fat pad, heart (ventricle), liver or spleen masses (all adjusted statistically for variation in body mass). Results support the hypothesis that early-age exercise in mice can have at least transitory positive effects on adult levels of voluntary exercise, in addition to reducing body mass, and may be relevant for the public policy debates concerning the importance of physical education for children.

  14. The Effects of a Single Developmentally Entrained Pulse of Testosterone in Female Neonatal Mice on Reproductive and Metabolic Functions in Adult Life.

    PubMed

    Jang, Hyeran; Bhasin, Shalender; Guarneri, Tyler; Serra, Carlo; Schneider, Mary; Lee, Mi-Jeong; Guo, Wen; Fried, Susan K; Pencina, Karol; Jasuja, Ravi

    2015-10-01

    Early postnatal exposures to sex steroids have been well recognized to modulate predisposition to diseases of adulthood. There is a complex interplay between timing, duration and dose of endocrine exposures through environmental or dietary sources that may alter the sensitivity of target tissues to the exogenous stimuli. In this study, we determined the metabolic and reproductive programming effects of a single developmentally entrained pulse of testosterone (T) given to female mice in early postnatal period. CD-1 female mice pups were injected with either 5 μg of T enanthate (TE) or vehicle (control [CON] group) within 24 hours after birth and followed to adult age. A total of 66% of T-treated mice exhibited irregular cycling, anovulatory phenotype, and significantly higher ovarian weights than vehicle-treated mice. Longitudinal nuclear magnetic resonance measurements revealed that TE group had greater body weight, whole-body lean, and fat mass than the CON group. Adipose tissue cellularity analysis in TE group revealed a trend toward higher size and number than their littermate CONs. The brown adipose tissue of TE mice exhibited white fat infiltration with down-regulation of several markers, including uncoupling protein 1 (UCP-1), cell death-inducing DNA fragmentation factor, α-subunit-like effector A, bone morphogenetic protein 7 as well as brown adipose tissue differentiation-related transcription regulators. T-injected mice were also more insulin resistant than CON mice. These reproductive and metabolic reprogramming effects were not observed in animals exposed to TE at 3 and 6 weeks of age. Collectively, these data suggest that sustained reproductive and metabolic alterations may result in female mice from a transient exposure to T during a narrow postnatal developmental window.

  15. Maternal Consumption of Hesperidin and Naringin Flavanones Exerts Transient Effects to Tibia Bone Structure in Female CD-1 Offspring

    PubMed Central

    Sacco, Sandra M.; Saint, Caitlin; LeBlanc, Paul J.; Ward, Wendy E.

    2017-01-01

    Hesperidin (HSP) and naringin (NAR), flavanones rich in citrus fruits, support skeletal integrity in adult and aging rodent models. This study determined whether maternal consumption of HSP and NAR favorably programs bone development, resulting in higher bone mineral density (BMD) and greater structure and biomechanical strength (i.e., peak load) in female offspring. Female CD-1 mice were fed a control diet or a HSP + NAR diet five weeks before pregnancy and throughout pregnancy and lactation. At weaning, female offspring were fed a control diet until six months of age. The structure and BMD of the proximal tibia were measured longitudinally using in vivo micro-computed tomography at 2, 4, and 6 months of age. The trabecular bone structure at two and four months and the trabecular BMD at four months were compromised at the proximal tibia in mice exposed to HSP and NAR compared to the control diet (p < 0.001). At six months of age, these differences in trabecular structure and BMD at the proximal tibia had disappeared. At 6 months of age, the tibia midpoint peak load, BMD, structure, and the peak load of lumbar vertebrae and femurs were similar (p > 0.05) between the HSP + NAR and control groups. In conclusion, maternal consumption of HSP and NAR does not enhance bone development in female CD-1 offspring. PMID:28282882

  16. Spontaneous novelty seeking and amphetamine-induced conditioning and sensitization in adult mice: evidence of dissociation as a function of age at weaning.

    PubMed

    Adriani, Walter; Laviola, Giovanni

    2002-08-01

    Individual differences in coping with novelty and in the response to psychoactive drugs have been related to early life events, such as the age of weaning. Outbred CD-1 mice underwent a precocious (postnatal day (pnd) 15, Wean-15 group), regular (pnd 21, Wean-21 group), or delayed (pnd 27, Wean-27 group) weaning, and were tested as adults (pnd > 60). In Experiment 1, animals underwent a treatment history with d-amphetamine (AMPH 0, 1, or 5 mg/kg once/day for three days) in a familiar environment. On testing day, mice were challenged with SAL or a standard 1 mg/kg AMPH dose (to evaluate acute drug effects and sensitization), and placed in the familiar environment. As expected, regular Wean-21 animals showed an AMPH-induced hyperactivity and a profile of conditioned locomotion, whereas the same dosage failed to induce any change in Wean-15 and Wean-27 groups. Levels of spontaneous novelty seeking were particularly elevated for Wean-27 mice, when compared with the other weaning groups. In Experiment 2, pairing of AMPH administration (0, 1, 2, 3.3, or 5 mg/kg once/day for three days) with a distinct environment produced a classical conditioned place preference. The magnitude of the preference profile was significantly more marked for Wean-15 mice, when compared with the other two weaning groups. Both experiments also provided evidence that the development of sensitization was particularly evident in Wean-27 mice. In summary, delayed weaning was associated in adult mice with both elevated levels of novelty seeking and increased sensitization to drug effects. Conversely, animals weaned precociously were much more responsive to AMPH-induced incentive conditioning. These results appear relevant to the issue of early experiences as possible risk factors for a number of psychiatric disorders in humans, including the abuse of drugs.

  17. Self administration of oxycodone by adolescent and adult mice affects striatal neurotransmitter receptor gene expression.

    PubMed

    Mayer-Blackwell, B; Schlussman, S D; Butelman, E R; Ho, A; Ott, J; Kreek, M J; Zhang, Y

    2014-01-31

    Illicit use of prescription opioid analgesics (e.g., oxycodone) in adolescence is a pressing public health issue. Our goal was to determine whether oxycodone self administration differentially affects striatal neurotransmitter receptor gene expression in the dorsal striatum of adolescent compared to adult C57BL/6J mice. Groups of adolescent mice (4 weeks old, n=12) and of adult mice (11 weeks old, n=11) underwent surgery during which a catheter was implanted into their jugular veins. After recovering from surgery, mice self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or served as yoked saline controls. Mice were sacrificed within 1h after the last self-administration session and the dorsal striatum was isolated for mRNA analysis. Gene expression was analyzed with real time PCR using a commercially available neurotransmitter receptor PCR array containing 84 genes. We found that adolescent mice self administered less oxycodone than adult mice over the 14 days. Monoamine oxidase A (Maoa) and neuropeptide Y receptor 5 mRNA levels were lower in adolescent mice than in adult mice without oxycodone exposure. Oxycodone self administration increased Maoa mRNA levels compared to controls in both age groups. There was a positive correlation of the amount of oxycodone self administered in the last session or across 14 sessions with Maoa mRNA levels. Gastrin-releasing peptide receptor mRNA showed a significant Drug × Age interaction, with point-wise significance. More genes in the dorsal striatum of adolescents (19) changed in response to oxycodone self administration compared to controls than in adult (4) mice. Overall, this study demonstrates that repeated oxycodone self administration alters neurotransmitter receptors gene expression in the dorsal striatum of adolescent and adult mice.

  18. Characterization of juvenile and young adult mice following induction of hydrocephalus with kaolin.

    PubMed

    Lopes, Luiza da Silva; Slobodian, Ili; Del Bigio, Marc R

    2009-09-01

    Hydrocephalus is a common neurological problem in humans, usually caused by an impairment of cerebrospinal fluid (CSF) flow or absorption. A reliable induced model of chronic hydrocephalus in mice would be useful to test hypotheses using genetic mutants. Our goal was to characterize behavioral and histological changes in juvenile and young adult mice with kaolin (aluminum silicate)-induced hydrocephalus. Seven-day old and 7-8 week old mice received injection of kaolin into the cisterna magna. Behavior was assessed repeatedly. Seven or 14 days following kaolin, magnetic resonance (MR) imaging was used to assess ventricle size. In hydrocephalic mice, body weight was significantly lower than in age-matched saline-injected sham controls and the gait and posture score were impaired. Juvenile mice developed severe ventriculomegaly and had reduced corpus callosum thickness with gross white matter destruction by 14 days. Reactive astroglial change in white matter and cortex and reduced cellular proliferation in the subependymal zone were also apparent. Young adult mice developed only moderate ventricular enlargement without overt white matter destruction, although there was corpus callosum atrophy and mild astroglial reaction in white matter. Glial fibrillary acidic protein content was significantly higher in juvenile and young adult hydrocephalic mice at 7 and 14 days, but myelin basic protein content was not significantly altered. In conclusion, hydrocephalus induced by percutaneous injection of kaolin in juvenile and young adult mice is feasible. The associated periventricular alterations are essentially the same as those reported in rats of comparable ages.

  19. Selenium status alters the immune response and expulsion of adult Heligmosomodies bakeri in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Heligmosomoides bakeri is a nematode with parasitic development exclusively in the small intestine of infected mice that induces a potent STAT6-dependent Th2 immune response. We previously demonstrated that host protective expulsion of adult H. bakeri was delayed in selenium (Se) deficient mice. ...

  20. Simvastatin and artesunate impact the structural organization of adult Schistosoma mansoni in hypercholesterolemic mice.

    PubMed

    Alencar, Alba Cristina Miranda de Barros; Santos, Thais da Silva; Neves, Renata Heisler; Lopes Torres, Eduardo José; Nogueira-Neto, José Firmino; Machado-Silva, José Roberto

    2016-08-01

    Experimental data have shown that simvastatin and artesunate possess activity against Schistosoma mansoni worms in mice fed standard chow. However, little is known regarding the roles of these drugs in mice fed high-fat chow. We have extended past studies by measuring the effects of these drugs on the structural organization of adult schistosomes in hypercholesterolemic mice. For this purpose, mice were gavaged with either simvastatin or artesunate at nine weeks post-infection and were euthanized by cervical dislocation at two weeks post-treatment. Adult worms were then collected and examined by conventional light microscopy, morphometry and confocal laser scanning microscopy. Plasma total cholesterol and worm reduction rates were significantly increased in mice fed high-fat chow compared with their respective control groups. Simvastatin and artesunate caused changes in the tegument, tubercles, and reproductive system (testicular lobes, vitelline glands and ovarian cells), particularly when administered to mice fed high-fat chow. In particular, the tegument and tubercles were significantly thinner in artesunate-treated worms in mice fed high-fat chow compared with mice fed standard chow. This study thus demonstrated that simvastatin and artesunate have several novel effects on the structural organization of adult worms. Together, these results show, for the first time, that simvastatin and artesunate display antischistosomal activity in hypercholesterolemic mice.

  1. Apple pectin affects the efficacy of epigallocatechin gallate on oral sucrose tolerance test in adult mice.

    PubMed

    Tamura, M; Hori, S

    2011-11-01

    Epigallocatechin gallate (EGCg), a dietary polyphenol and a major tea catechin, is a known sucrase inhibitor. Since dietary pectin is known to modulate some of the functions of the gastrointestinal tract, we investigated whether it could specifically affect the efficacy of EGCg on an oral sucrose tolerance test in mice. Male Crj:CD-1 (ICR) mice (seven weeks old) were randomly divided into two groups and fed a 5 % apple pectin (PE) or 5 % cellulose (CE) diet (control diet) for 28 days. After the experimental diet period, all mice were fasted overnight. A volume of 0.2 mL EGCg (20 mg/mL) was orally administered to all the mice by stainless steel feeding needle via injection syringe and a sucrose tolerance test was performed. The blood glucose levels were measured in blood collected from the tail vein using the OneTouch® Ultra® blood glucose monitoring system. Blood glucose levels at 30 minutes and 60 minutes after sucrose loading in the PE group were significantly higher than initial blood glucose levels. However, blood glucose levels at 30 minutes, 60 minutes, and 120 minutes after sucrose loading in the CE group were not significantly higher than initial blood glucose levels. After laparotomy, plasma lipids were also measured. Plasma triglyceride concentrations were significantly greater in the PE group than in the CE (control) group. This demonstrates that dietary pectin can affect the efficacy of EGCg on the oral sucrose tolerance test in mice.

  2. CD1c+ blood dendritic cells have Langerhans cell potential.

    PubMed

    Milne, Paul; Bigley, Venetia; Gunawan, Merry; Haniffa, Muzlifah; Collin, Matthew

    2015-01-15

    Langerhans cells (LCs) are self-renewing in the steady state but repopulated by myeloid precursors after injury. Human monocytes give rise to langerin-positive cells in vitro, suggesting a potential precursor role. However, differentiation experiments with human lineage-negative cells and CD34(+) progenitors suggest that there is an alternative monocyte-independent pathway of LC differentiation. Recent data in mice also show long-term repopulation of the LC compartment with alternative myeloid precursors. Here we show that, although monocytes are able to express langerin, when cultured with soluble ligands granulocyte macrophage colony-stimulating factor (GM-CSF), transforming growth factor β (TGFβ), and bone morphogenetic protein 7 (BMP7), CD1c(+) dendritic cells (DCs) become much more LC-like with high langerin, Birbeck granules, EpCAM, and E-cadherin expression under the same conditions. These data highlight a new potential precursor function of CD1c(+) DCs and demonstrate an alternative pathway of LC differentiation that may have relevance in vivo.

  3. Monocular Deprivation in Adult Mice Alters Visual Acuity and Single-Unit Activity

    ERIC Educational Resources Information Center

    Evans, Scott; Lickey, Marvin E.; Pham, Tony A.; Fischer, Quentin S.; Graves, Aundrea

    2007-01-01

    It has been discovered recently that monocular deprivation in young adult mice induces ocular dominance plasticity (ODP). This contradicts the traditional belief that ODP is restricted to a juvenile critical period. However, questions remain. ODP of young adults has been observed only using methods that are indirectly related to vision, and the…

  4. Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance.

    PubMed

    Sun, Yuxiang; Butte, Nancy F; Garcia, Jose M; Smith, Roy G

    2008-02-01

    Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R), are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and negative (caloric restriction) energy balance. In contrast to results from young N2 mutant mice, changes in body weight and energy expenditure are not clearly distinguishable across genotypes. Although respiratory quotient was lower in mice fed a high-fat diet, no differences were evident between littermate wild-type and null genotypes. With normal chow, a modest decrease trend in respiratory quotient was detected in ghrelin(-/-) mice but not in Ghsr(-/-) mice. Under caloric restriction, the weight loss of ghrelin(-/-) and Ghsr(-/-) mice was identical to wild-type littermates, but blood glucose levels were significantly lower. We conclude that adult congenic ghrelin(-/-) and Ghsr(-/-) mice are not resistant to diet-induced obesity but under conditions of negative energy balance show impairment in maintaining glucose homeostasis. These results support our hypothesis that the primary metabolic function of ghrelin in adult mice is to modulate glucose sensing and insulin sensitivity, rather than directly regulate energy intake and energy expenditure.

  5. Analysis of the reptile CD1 genes: evolutionary implications.

    PubMed

    Yang, Zhi; Wang, Chunyan; Wang, Tao; Bai, Jianhui; Zhao, Yu; Liu, Xuhan; Ma, Qingwei; Wu, Xiaobing; Guo, Ying; Zhao, Yaofeng; Ren, Liming

    2015-06-01

    CD1, as the third family of antigen-presenting molecules, is previously only found in mammals and chickens, which suggests that the chicken and mammalian CD1 shared a common ancestral gene emerging at least 310 million years ago. Here, we describe CD1 genes in the green anole lizard and Crocodylia, demonstrating that CD1 is ubiquitous in mammals, birds, and reptiles. Although the reptilian CD1 protein structures are predicted to be similar to human CD1d and chicken CD1.1, CD1 isotypes are not found to be orthologous between mammals, birds, and reptiles according to phylogenetic analyses, suggesting an independent diversification of CD1 isotypes during the speciation of mammals, birds, and reptiles. In the green anole lizard, although the single CD1 locus and MHC I gene are located on the same chromosome, there is an approximately 10-Mb-long sequence in between, and interestingly, several genes flanking the CD1 locus belong to the MHC paralogous region on human chromosome 19. The CD1 genes in Crocodylia are located in two loci, respectively linked to the MHC region and MHC paralogous region (corresponding to the MHC paralogous region on chromosome 19). These results provide new insights for studying the origin and evolution of CD1.

  6. Different regulation of adult hippocampal neurogenesis in Western house mice (Mus musculus domesticus) and C57BL/6 mice.

    PubMed

    Klaus, Fabienne; Hauser, Thomas; Lindholm, Anna K; Cameron, Heather A; Slomianka, Lutz; Lipp, Hans-Peter; Amrein, Irmgard

    2012-02-14

    Adult hippocampal neurogenesis (AHN) of laboratory rodents is enhanced by physical exercise in a running wheel. However, little is known about modulation of AHN in wild-living rodent species. The finding that AHN cannot be modulated by voluntary exercise in wild wood mice suggests that AHN may be regulated differently under natural conditions than in laboratory adapted animals. In order to minimize genetic influences, we aimed to investigate the genetically closest wild-living relatives of laboratory mice. Here, C57BL/6 mice and F1 offspring of wild house mice (Mus musculus domesticus) were tested in two different running paradigms: voluntary running and running-for-food--a condition in which mice had to run for their daily allowance of food. In house mice, we found a non-significant trend towards increased numbers of proliferating cells and doublecortin-positive immature neurons in both voluntary runners and runners-for-food. Voluntary running in C57BL/6 mice resulted in a 30% increase in cell proliferation and a pronounced 70% increase in doublecortin-positive cells. C57BL/6 runners-for-food ran as much as voluntary runners, but they showed no enhancement of cell proliferation, a small increase in the number of doublecortin-positive cells and more pyknotic cells compared to controls. Taken together, these findings suggest that motivational aspects of running are critical determinants of the increased cell proliferation in C57BL/6 mice. In contrast, running has smaller and context-independent effects in house mice. The findings imply a difference in the regulation of AHN in C57BL/6 mice and their wild-derived conspecifics.

  7. Normalizing the environment recapitulates adult human immune traits in laboratory mice.

    PubMed

    Beura, Lalit K; Hamilton, Sara E; Bi, Kevin; Schenkel, Jason M; Odumade, Oludare A; Casey, Kerry A; Thompson, Emily A; Fraser, Kathryn A; Rosato, Pamela C; Filali-Mouhim, Ali; Sekaly, Rafick P; Jenkins, Marc K; Vezys, Vaiva; Haining, W Nicholas; Jameson, Stephen C; Masopust, David

    2016-04-28

    Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.

  8. Adolescent mice are more vulnerable than adults to single injection-induced behavioral sensitization to amphetamine.

    PubMed

    Kameda, Sonia R; Fukushiro, Daniela F; Trombin, Thaís F; Procópio-Souza, Roberta; Patti, Camilla L; Hollais, André W; Calzavara, Mariana B; Abílio, Vanessa C; Ribeiro, Rosana A; Tufik, Sergio; D'Almeida, Vânia; Frussa-Filho, Roberto

    2011-04-01

    Drug-induced behavioral sensitization in rodents has enhanced our understanding of why drugs acquire increasing motivational and incentive value. Compared to adults, human adolescents have accelerated dependence courses with shorter times from first exposure to dependence. We compared adolescent and adult mice in their ability to develop behavioral sensitization to amphetamine following a single injection. Adult (90-day-old) and adolescent (45-day-old) male Swiss mice received an acute intraperitoneal injection of saline or amphetamine (1.0, 2.0 or 4.0 mg/kg). Seven days later, half of the mice from the saline group received a second injection of saline. The remaining animals were challenged with 2.0 mg/kg amphetamine. Following all of the injections, mice were placed in activity chambers and locomotion was quantified for 45 min. The magnitude of both the acute and sensitized locomotor stimulatory effect of amphetamine was higher in the adolescent mice. Previous experience with the test environment inhibited the acute amphetamine stimulation in both adolescent and adult mice, but facilitated the detection of elevated spontaneous locomotion in adolescent animals. These results support the notion that the adolescent period is associated with an increased risk for development of drug abuse. Additionally, they indicate a complex interaction between the environmental novelty, adolescence and amphetamine.

  9. The CD1 size problem: lipid antigens, ligands, and scaffolds

    PubMed Central

    Ly, Dalam

    2014-01-01

    Whereas research on CD1d has emphasized a few glycosyl ceramides, the broader family of four human CD1 antigen-presenting molecules binds hundreds of distinct self-lipids. Individual lipid types bind within CD1 grooves in different ways, such that they partially fill the groove, match the groove volume, or protrude substantially from the groove. These differing modes of binding can now be connected to differing immunological functions, as individual lipids can act as stimulatory antigens, inhibitory ligands, or space-filling scaffolds. Because each type of CD1 protein folds to produce antigen-binding grooves with differing sizes and shapes, CD1a, CD1b, CD1c, CD1d, and CD1e have distinct mechanisms of capturing self-lipids and exchanging them for foreign lipids. The size discrepancy between endogeneous lipids and groove volume is most pronounced for CD1b. Recent studies show that the large CD1b cavity can simultaneously bind two self-lipids, the antigen, and its scaffold lipid, which can be exchanged for one large bacterial lipid. In this review, we will highlight recent studies showing how cells regulate lipid antigen loading and the roles CD1 groove structures have in control of the presentation of chemically diverse lipids to T cells. PMID:24658584

  10. 2-Methoxyethanol metabolism in pregnant CD-1 mice and embryos.

    PubMed

    Mebus, C A; Clarke, D O; Stedman, D B; Welsch, F

    1992-01-01

    Upon oxidation to 2-methoxyacetic acid (2-MAA), 2-methoxyethanol (2-ME) causes malformations in all animal species that have been examined. Commonly, 2-MAA is thought to be the proximate toxicant. However, our previous studies with [1,2-14C]2-ME and the present data obtained with [1-14C]2-MAA, [2-14C]2-ME and [methoxy-14C]2-ME revealed that metabolism beyond 2-MAA occurs. Regardless of the 14C position, dams exhaled approximately 5% of the radioactivity administered as a single teratogenic oral dose (3.3 mmol/kg on Gestation Day [gd] 11) as 14CO2. With all isotopic variants urine contained 70-80% of the dose within 24 hr after administration and 13-18% in the next 24 hr. Three labeled products were resolved using HPLC: an unidentified Peak A (12-18% of dose), 2-MAA (approximately 50%), and the glycine conjugate of 2-MAA (approximately 25%). Short-term (4 hr) whole embryo culture on gd 11 with 3 mM 2-MAA and a tracer dose of [1-14C]2-MAA, [2-14C]2-MAA, or [methoxy-14C]2-MAA showed that 14CO2 evolved from the former two substrates, while there was none detectable from the latter. The data indicate that dams metabolized [methoxy-14]2-MAA to 14CO2, while embryos apparently did not. The production of labeled CO2 from [2-14C]2-ME suggests that 2-methoxyacetyl approximately CoA (the precursor for amino acid conjugation with glycine) entered into the tricarboxylic acid (TCA) cycle. This interpretation is supported by the inhibition of 14CO2 evolution elicited by fluoroacetate (0.1 or 1.0 mM) and sodium acetate (5 mM). It is not yet clear whether entry of 2-methoxyacetyl approximately CoA as a "false substrate" in the TCA cycle is of significance for the embryotoxic effects of 2-ME/2MAA.

  11. Developmental Toxicity of Perfluoroalkyl Acid Mixtures in CD-1 Mice

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and perfluorononanoic acid (PFNA) belong to a family of fluoro-organic compounds known as perfluoroalkyl acids (PFAAs). PFAAs have been widely used in industrial and commercial applications, and have been found to be...

  12. Transient Suppression of Dbx1 PreBötzinger Interneurons Disrupts Breathing in Adult Mice

    PubMed Central

    Vann, Nikolas C.; Pham, Francis D.; Hayes, John A.; Kottick, Andrew; Del Negro, Christopher A.

    2016-01-01

    Interneurons derived from Dbx1-expressing precursors located in the brainstem preBötzinger complex (preBötC) putatively form the core oscillator for inspiratory breathing movements. We tested this Dbx1 core hypothesis by expressing archaerhodopsin in Dbx1-derived interneurons and then transiently hyperpolarizing these neurons while measuring respiratory rhythm in vitro or breathing in vagus-intact adult mice. Transient illumination of the preBötC interrupted inspiratory rhythm in both slice preparations and sedated mice. In awake mice, light application reduced breathing frequency and prolonged the inspiratory duration. Support for the Dbx1 core hypothesis previously came from embryonic and perinatal mouse experiments, but these data suggest that Dbx1-derived preBötC interneurons are rhythmogenic in adult mice too. The neural origins of breathing behavior can be attributed to a localized and genetically well-defined interneuron population. PMID:27611210

  13. Transient Suppression of Dbx1 PreBötzinger Interneurons Disrupts Breathing in Adult Mice.

    PubMed

    Vann, Nikolas C; Pham, Francis D; Hayes, John A; Kottick, Andrew; Del Negro, Christopher A

    2016-01-01

    Interneurons derived from Dbx1-expressing precursors located in the brainstem preBötzinger complex (preBötC) putatively form the core oscillator for inspiratory breathing movements. We tested this Dbx1 core hypothesis by expressing archaerhodopsin in Dbx1-derived interneurons and then transiently hyperpolarizing these neurons while measuring respiratory rhythm in vitro or breathing in vagus-intact adult mice. Transient illumination of the preBötC interrupted inspiratory rhythm in both slice preparations and sedated mice. In awake mice, light application reduced breathing frequency and prolonged the inspiratory duration. Support for the Dbx1 core hypothesis previously came from embryonic and perinatal mouse experiments, but these data suggest that Dbx1-derived preBötC interneurons are rhythmogenic in adult mice too. The neural origins of breathing behavior can be attributed to a localized and genetically well-defined interneuron population.

  14. Neuroinflammation Induced by Surgery Does Not Impair the Reference Memory of Young Adult Mice

    PubMed Central

    Zhao, Yanhua; Huang, Lili; Xu, Huan; Wu, Guangxi; Zhu, Mengyi; Tian, Jie; Wang, Hao; Yu, Weifeng

    2016-01-01

    Postoperative cognitive dysfunction (POCD) increases morbidity and mortality after surgery. But the underlying mechanism is not clear yet. While age is now accepted as the top one risk factor for POCD, results from studies investigating postoperative cognitive functions in adults have been controversial, and data about the very young adult individuals are lacking. The present study investigated the spatial reference memory, IL-1β, IL-6, and microglia activation changes in the hippocampus in 2-month-old mice after anesthesia and surgery. We found that hippocampal IL-1β and IL-6 increased at 6 hours after surgery. Microglia were profoundly activated in the hippocampus 6 to 24 hours after surgery. However, no significant behavior changes were found in these mice. These results indicate that although anesthesia and surgery led to neuroinflammation, the latter was insufficient to impair the spatial reference memory of young adult mice. PMID:27956760

  15. Neuroendocrine function in adult female transgenic mice expressing the human growth hormone gene.

    PubMed

    Chandrashekar, V; Bartke, A; Wagner, T E

    1992-04-01

    Adult female transgenic mice expressing the human GH (hGH) gene with mouse metallothionein-I promoter are sterile. To evaluate the hypothalamic-pituitary function in these animals, adult female transgenic mice and nontransgenic normal littermates were ovariectomized. On days 7 and 8 after ovariectomy, mice were injected with either oil or primed with 0.5 micrograms estradiol benzoate (EB) in oil, 24 h later treated with 10 micrograms EB/100 g body wt and a day later bled for measurements of FSH, LH, and PRL levels. Plasma gonadotropin and PRL levels were also measured in ovary-intact transgenic and normal siblings at estrus. Additional ovariectomized EB-treated transgenic mice and normal siblings were injected with either saline or GnRH in saline (1 ng/g body wt) and were bled 15 min later for determination of circulating hormone levels. At estrus, in transgenic mice, circulating FSH and PRL levels were significantly lower (FSH:P less than 0.001; PRL:P less than 0.025), but plasma LH concentrations were higher (P less than 0.001) than those in nontransgenic mice. As expected, ovariectomy significantly increased (P less than 0.001) circulating FSH and LH levels in both groups of mice relative to ovary-intact animals, but the increase in plasma LH levels was attenuated in transgenic mice. The suppressive effect of estrogen on circulating FSH and LH levels were similar in transgenic and nontransgenic mice. Treatment with GnRH significantly increased plasma FSH and LH levels in both transgenic and normal mice. However, the plasma FSH and LH responses to GnRH administration were significantly reduced (P less than 0.001) in transgenic mice. The results of these studies indicate that adult female transgenic mice expressing the hGH gene are hypoprolactinemic. Yet due to PRL-like activity of hGH, the gonadotropin secretion is altered. Thus, endogenously secreted hGH modulates the hypothalamic-pituitary function of adult female transgenic mice bearing the hGH gene.

  16. The autophagy machinery restrains iNKT cell activation through CD1D1 internalization.

    PubMed

    Keller, Christian W; Loi, Monica; Ewert, Svenja; Quast, Isaak; Theiler, Romina; Gannagé, Monique; Münz, Christian; De Libero, Gennaro; Freigang, Stefan; Lünemann, Jan D

    2017-03-15

    Invariant natural killer T (iNKT) cells are innate T cells with powerful immune regulatory functions that recognize glycolipid antigens presented by the CD1D protein. While iNKT-cell-activating glycolipids are currently being explored for their efficacy to improve immunotherapy against infectious diseases and cancer, little is known about the mechanisms that control CD1D antigen presentation and iNKT cell activation in vivo. CD1D molecules survey endocytic pathways to bind lipid antigens in MHC class II containing compartments (MIICs) before recycling to the plasma membrane. Autophagosomes intersect with MIICs and autophagy-related proteins are known to support antigen loading for increased CD4(+) T cell immunity. Here, we report that mice with dendritic cell (DC)-specific deletion of the essential autophagy gene Atg5 showed better CD1D1-restricted glycolipid presentation in vivo. These effects led to enhanced iNKT cell cytokine production upon antigen recognition and lower bacterial loads during Sphingomonas paucimobilis infection. Enhanced iNKT cell activation was independent of receptor-mediated glycolipid uptake or costimulatory signals. Instead, loss of Atg5 in DCs impaired clathrin-dependent internalization of CD1D1 molecules via the adaptor protein complex 2 (AP2) and, thus, increased surface expression of stimulatory CD1D1-glycolipid complexes. These findings indicate that the autophagic machinery assists in the recruitment of AP2 to CD1D1 molecules resulting in attenuated iNKT cell activation, in contrast to the supporting role of macroautophagy in CD4(+) T cell stimulation.

  17. A humanized version of Foxp2 does not affect ultrasonic vocalization in adult mice.

    PubMed

    Hammerschmidt, K; Schreiweis, C; Minge, C; Pääbo, S; Fischer, J; Enard, W

    2015-11-01

    The transcription factor FOXP2 has been linked to severe speech and language impairments in humans. An analysis of the evolution of the FOXP2 gene has identified two amino acid substitutions that became fixed after the split of the human and chimpanzee lineages. Studying the functional consequences of these two substitutions in the endogenous Foxp2 gene of mice showed alterations in dopamine levels, striatal synaptic plasticity, neuronal morphology and cortico-striatal-dependent learning. In addition, ultrasonic vocalizations (USVs) of pups had a significantly lower average pitch than control littermates. To which degree adult USVs would be affected in mice carrying the 'humanized' Foxp2 variant remained unclear. In this study, we analyzed USVs of 68 adult male mice uttered during repeated courtship encounters with different females. Mice carrying the Foxp2(hum/hum) allele did not differ significantly in the number of call elements, their element structure or in their element composition from control littermates. We conclude that neither the structure nor the usage of USVs in adult mice is affected by the two amino acid substitutions that occurred in FOXP2 during human evolution. The reported effect for pup vocalization thus appears to be transient. These results are in line with accumulating evidence that mouse USVs are hardly influenced by vocal learning. Hence, the function and evolution of genes that are necessary, but not sufficient for vocal learning in humans, must be either studied at a different phenotypic level in mice or in other organisms.

  18. Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine.

    PubMed

    Jedynak, Paulina; Kos, Tomasz; Sandi, Carmen; Kaczmarek, Leszek; Filipkowski, Robert K

    2014-09-01

    The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression.

  19. Recapitulating adult human immune traits in laboratory mice by normalizing environment

    PubMed Central

    Beura, Lalit K.; Hamilton, Sara E.; Bi, Kevin; Schenkel, Jason M.; Odumade, Oludare A.; Casey, Kerry A.; Thompson, Emily A.; Fraser, Kathryn A.; Rosato, Pamela C.; Filali-Mouhim, Ali; Sekaly, Rafick P.; Jenkins, Marc K.; Vezys, Vaiva; Haining, W. Nicholas; Jameson, Stephen C.; Masopust, David

    2016-01-01

    Our current understanding of immunology was largely defined in laboratory mice because of experimental advantages including inbred homogeneity, tools for genetic manipulation, the ability to perform kinetic tissue analyses starting with the onset of disease, and tractable models. Comparably reductionist experiments are neither technically nor ethically possible in humans. Despite revealing many fundamental principals of immunology, there is growing concern that mice fail to capture relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside1–8. Laboratory mice live in abnormally hygienic “specific pathogen free” (SPF) barrier facilities. Here we show that the standard practice of laboratory mouse husbandry has profound effects on the immune system and that environmental changes result in better recapitulation of features of adult humans. Laboratory mice lack effector-differentiated and mucosally distributed memory T cells, which more closely resembles neonatal than adult humans. These cell populations were present in free-living barn populations of feral mice, pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting a role for environment. Consequences of altering mouse housing profoundly impacted the cellular composition of the innate and adaptive immune system and resulted in global changes in blood cell gene expression patterns that more closely aligned with immune signatures of adult humans rather than neonates, altered the mouse’s resistance to infection, and impacted T cell differentiation to a de novo viral infection. These data highlight the impact of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modeling immunological events in free-living organisms, including humans. PMID

  20. Ligation of TLR7 on CD19(+) CD1d(hi) B cells suppresses allergic lung inflammation via regulatory T cells.

    PubMed

    Khan, Adnan R; Amu, Sylvie; Saunders, Sean P; Hams, Emily; Blackshields, Gordon; Leonard, Martin O; Weaver, Casey T; Sparwasser, Tim; Sheils, Orla; Fallon, Padraic G

    2015-06-01

    B cells have been described as having the capacity to regulate cellular immune responses and suppress inflammatory processes. One such regulatory B-cell population is defined as IL-10-producing CD19(+) CD1d(hi) cells. Previous work has identified an expansion of these cells in mice infected with the helminth, Schistosoma mansoni. Here, microarray analysis of CD19(+) CD1d(hi) B cells from mice infected with S. mansoni demonstrated significantly increased Tlr7 expression, while CD19(+) CD1d(hi) B cells from uninfected mice also demonstrated elevated Tlr7 expression. Using IL-10 reporter, Il10(-/-) and Tlr7(-/-) mice, we formally demonstrate that TLR7 ligation of CD19(+) CD1d(hi) B cells increases their capacity to produce IL-10. In a mouse model of allergic lung inflammation, the adoptive transfer of TLR7-elicited CD19(+) CD1d(hi) B cells reduced airway inflammation and associated airway hyperresponsiveness. Using DEREG mice to deplete FoxP3(+) T regulatory cells in allergen-sensitized mice, we show that that TLR7-elicited CD19(+) CD1d(hi) B cells suppress airway hyperresponsiveness via a T regulatory cell dependent mechanism. These studies identify that TLR7 stimulation leads to the expansion of IL-10-producing CD19(+) CD1d(hi) B cells, which can suppress allergic lung inflammation via T regulatory cells.

  1. Evidence for a mature B cell subpopulation in Peyer's patches of young adult xid mice

    PubMed Central

    1983-01-01

    Peyer's patch (PP) and mesenteric lymph node (MLN) cell cultures from young adult X-linked immunodeficient (xid) CBA/N and (CBA/N X DBA/2) F1 male mice support primary anti-sheep erythrocyte (SRBC) plaque-forming cell (PFC) responses, which suggests that gut-associated lymphoreticular tissue (GALT) contains a normal B lymphocyte subpopulation. Further support for this was provided by the observation that PP cells from xid mice gave responses to both TI-1 and TI-2 antigens that were similar to the responses of PP cell cultures from normal mice. Spleen cell cultures from xid mice were unresponsive to SRBC and TI-2 antigens. Proof that GALT of xid mice contain mature B lymphocytes was provided by the demonstration of PP B cells that bear a low density of surface immunoglobulin M. When these cells were separated by flow cytometry and immunized with trinitrophenyl (TNP)- Ficoll in vitro, good anti-TNP PFC responses were observed. These results suggest that GALT of young adult xid mice contain mature B cells and may represent the origin for the mature B cell responses seen in aged xid mice. PMID:6600493

  2. Early postnatal motor experience shapes the motor properties of C57BL/6J adult mice.

    PubMed

    Serradj, Nadjet; Picquet, Florence; Jamon, Marc

    2013-11-01

    This study aimed to evaluate the long-term consequences of early motor training on the muscle phenotype and motor output of middle-aged C57BL/6J mice. Neonatal mice were subjected to a variety of motor training procedures, for 3 weeks during the period of acquisition of locomotion. These procedures are widely used for motor training in adults; they include enriched environment, forced treadmill, chronic centrifugation, and hindlimb suspension. At 9 months, the mice reared in the enriched environment showed a slower type of fibre in slow muscles and a faster type in fast muscles, improved performance in motor tests, and a modified gait and body posture while walking. The proportion of fibres in the postural muscles of centrifuged mice did not change, but these mice showed improved resistance to fatigue. The suspended mice showed increased persistence of immature hybrid fibres in the tibialis, with a slower shift in the load-bearing soleus, without any behavioural changes. The forced treadmill was very stressful for the mice, but had limited effects on motor output, although a slower profile was observed in the tibialis. These results support the hypothesis that motor experience during a critical period of motor development shapes muscle phenotype and motor output. The different impacts of the various training procedures suggest that motor performance in adults can be optimized by appropriate training during a defined period of motor development.

  3. Early exposure to ethanol but not red wine at the same alcohol concentration induces behavioral and brain neurotrophin alterations in young and adult mice.

    PubMed

    Fiore, Marco; Laviola, Giovanni; Aloe, Luigi; di Fausto, Veronica; Mancinelli, Rosanna; Ceccanti, Mauro

    2009-01-01

    Ethanol exposure during pregnancy is one of the major causes of mental retardation in western countries by inducing fetal-alcohol-like-syndromes. Red wine is known to contain ethanol but also compounds with putative antioxidant properties. It has also been shown that nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are severely affected by ethanol during prenatal and postnatal life. The aim of the current study was to investigate in male CD1 mice brain alterations in NGF and BDNF due to chronic early exposure to ethanol solution (11 vol%) or to red wine at the same alcohol concentration starting from 60 days before pregnancy up to pups weaning. Data revealed no differences between groups of dams in pregnancy duration, neither in pups delivery, pups mortality and sex ratio. Data also showed that adult animals exposed to only ethanol had disrupted levels of both NGF and BDNF in the hippocampus and other brain areas. This profile was associated with impaired ChAT immunopositivity in the septum and Nuclei Basalis and with altered cognition and emotional behavior. Quite interestingly mice exposed to red wine had no change in the behavior or in ChAT immunopositivity but a decrease in hippocampal BDNF and a mild NGF decrease in the cortex. Also NGF-induced neuritic outgrowth in PC-12 cells was still present when exposed to red wine but not when exposed to ethanol solution only. Data suggest differences in ethanol-induced neurotoxicity between red wine and ethanol solution only.

  4. Altered neuronal architecture and plasticity in the visual cortex of adult MMP-3-deficient mice.

    PubMed

    Aerts, Jeroen; Nys, Julie; Moons, Lieve; Hu, Tjing-Tjing; Arckens, Lutgarde

    2015-09-01

    Matrix metalloproteinases (MMPs) are Zn(2+)-dependent endopeptidases considered to be essential for normal brain development and neuroplasticity by modulating extracellular matrix proteins, receptors, adhesion molecules, growth factors and cytoskeletal proteins. Specifically, MMP-3 has recently been implicated in synaptic plasticity, hippocampus-dependent learning and neuronal development and migration in the cerebellum. However, the function(s) of this enzyme in the neocortex is understudied. Therefore, we explored the phenotypical characteristics of the neuronal architecture and the capacity for experience-dependent cortical plasticity in the visual cortex of adult MMP-3-deficient (MMP-3(-/-)) mice. Golgi-Cox stainings revealed a significant reduction in apical dendritic length and an increased number of apical obliques for layer V pyramidal neurons in the visual cortex of adult MMP-3(-/-) mice compared to wild-type (WT) animals. In addition, a significant upregulation of both phosphorylated and non-phosphorylated neurofilament protein (NF)-high, phosphorylated NF-medium, NF-low and α-internexin was detected in the visual cortex of MMP-3(-/-) mice. To assess the effect of MMP-3 deficiency on cortical plasticity, we monocularly enucleated adult MMP-3(-/-) mice and analyzed the reactivation of the contralateral visual cortex 7 weeks post-enucleation. In contrast to previous results in C57Bl/6J adult mice, activity remained confined to the binocular zone and did not expand into the monocular regions indicative for an aberrant open-eye potentiation. Permanent hypoactivity in the monocular cortex lateral and medial to V1 also indicated a lack of cross-modal plasticity. These observations demonstrate that genetic inactivation of MMP-3 has profound effects on the structural integrity and plasticity response of the visual cortex of adult mice.

  5. Food restriction increases long-term memory persistence in adult or aged mice.

    PubMed

    Talhati, F; Patti, C L; Zanin, K A; Lopes-Silva, L B; Ceccon, L M B; Hollais, A W; Bizerra, C S; Santos, R; Tufik, S; Frussa-Filho, R

    2014-04-03

    Food restriction (FR) seems to be the unique experimental manipulation that leads to a remarkable increase in lifespan in rodents. Evidences have suggested that FR can enhance memory in distinct animal models mainly during aging. However, only few studies systemically evaluated the effects FR on memory formation in both adult (3-month-old) and aged (18-24-month-old) mice. Thus, the aim of the present study was to investigate the effects of acute (12h) or repeated (12h/day for 2days) FR protocols on learning and memory of adult and aged mice evaluated in the plus-maze discriminative avoidance task (PM-DAT), an animal model that concurrently (but independently) evaluates learning and memory, anxiety and locomotion. We also investigated the possible role of FR-induced stress by the corticosterone concentration in adult mice. Male mice were kept at home cage with food ad libitum (CTRL-control condition) or subjected to FR during the dark phase of the cycle for 12h/day or 12h/2days. The FR protocols were applied before training, immediately after it or before testing. Our results demonstrated that only FR for 2days enhanced memory persistence when applied before training in adults and before testing in aged mice. Conversely, FR for 2days impaired consolidation and exerted no effects on retrieval irrespective of age. These effects do not seem to be related to corticosterone concentration. Collectively, these results indicate that FR for 2days can promote promnestic effects not only in aged mice but also in adults.

  6. EFFECT OF HYPOXIA ON THE RATE OF OXYGEN CONSUMPTION OF NEWBORN, YOUNG, AND ADULT MICE AT VARIOUS ENVIRONMENTAL TEMPERATURES,

    DTIC Science & Technology

    Critical Po2 that is, Po2 below the point at which oxygen consumption is reduced - was measured in newborn, 5-day-old, and adult mice. At...thermoneutral environmental temperatures, the critical Po2 of newborn was 85 mm. Hg; that of 5-day-old mice was 100 mm. Hg; and that of adults was 70 mm. Hg

  7. Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice

    PubMed Central

    La Merrill, Michele A.; Sethi, Sunjay; Benard, Ludovic; Moshier, Erin; Haraldsson, Borje; Buettner, Christoph

    2016-01-01

    Background: Dichlorodiphenyltrichloroethane (DDT) was used extensively to control malaria, typhus, body lice, and bubonic plague worldwide, until countries began restricting its use in the 1970s. However, the use of DDT to control vector-borne diseases continues in developing countries. Prenatal DDT exposure is associated with elevated blood pressure in humans. Objective: We hypothesized that perinatal DDT exposure causes hypertension in adult mice. Methods: DDT was administered to C57BL/6J dams from gestational day 11.5 to postnatal day 5. Blood pressure (BP) and myocardial wall thickness were measured in male and female adult offspring. Adult mice were treated with an angiotensin converting enzyme (ACE) inhibitor, captopril, to evaluate sensitivity to amelioration of DDT-associated hypertension by ACE inhibition. We further assessed the influence of DDT exposure on the expression of mRNAs that regulate BP through renal ion transport. Results: Adult mice perinatally exposed to DDT exhibited chronically increased systolic BP, increased myocardial wall thickness, and elevated expression of mRNAs of several renal ion transporters. Captopril completely reversed hypertension in mice perinatally exposed to DDT. Conclusions: These data demonstrate that perinatal exposure to DDT causes hypertension and cardiac hypertrophy in adult offspring. A key mechanism underpinning this hypertension is an overactivated renin angiotensin system because ACE inhibition reverses the hypertension induced by perinatal DDT exposure. Citation: La Merrill M, Sethi S, Benard L, Moshier E, Haraldsson B, Buettner C. 2016. Perinatal DDT exposure induces hypertension and cardiac hypertrophy in adult mice. Environ Health Perspect 124:1722–1727; http://dx.doi.org/10.1289/EHP164 PMID:27325568

  8. Striatal magnetic resonance spectroscopy abnormalities in young adult SAPAP3 knockout mice

    PubMed Central

    Mintzopoulos, Dionyssios; Gillis, Timothy E.; Robertson, Holly R.; Dalia, Triana; Feng, Guoping; Rauch, Scott L.; Kaufman, Marc J.

    2015-01-01

    Background Obsessive compulsive disorder (OCD) is a debilitating condition with lifetime prevalence of 1–3%. OCD typically arises in youth but delays in diagnosis impede optimal treatment and developmental studies of the disorder. Research using genetically modified rodents may provide models of etiology that enable earlier detection and intervention. The SAPAP3 knockout (KO) transgenic mouse was developed as an animal model of OCD and related disorders (OCRD). KO mice exhibit compulsive self-grooming behavior analogous to behaviors found in people with OCRD. Striatal hyperactivity has been reported in these mice and in humans with OCD. Methods Striatal and medial frontal cortex 9.4 Tesla proton spectra were acquired from young adult SAPAP3 KO and wild-type control mice to determine whether KO mice have metabolic and neurochemical abnormalities. Results Young adult KO mice had lower striatal lactate (P=0.006) and glutathione (P=0.039) levels. Among all mice, striatal lactate and glutathione levels were associated (R=0.73, P=0.007). We found no group differences in medial frontal cortex metabolites. At the age range studied, only 1 of 8 KO mice had skin lesions indicative of severe compulsive grooming. Conclusion Young adult SAPAP3 KO mice have striatal but not medial frontal cortex MRS abnormalities that may reflect striatal hypermetabolism accompanied by oxidative stress. These abnormalities typically preceded the onset of severe compulsive grooming. Our findings are consistent with striatal hypermetabolism in OCD. Together, these results suggest that striatal MRS measures of lactate or glutathione might be useful biomarkers for early detection of risk for developing compulsive behavior disorders. PMID:26858992

  9. Nonhematopoietic Nrf2 dominantly impedes adult progression of sickle cell anemia in mice

    PubMed Central

    Ghosh, Samit; Ihunnah, Chibueze A.; Hazra, Rimi; Walker, Aisha L.; Hansen, Jason M.; Archer, David R.; Owusu-Ansah, Amma T.; Ofori-Acquah, Solomon F.

    2016-01-01

    The prevention of organ damage and early death in young adults is a major clinical concern in sickle cell disease (SCD). However, mechanisms that control adult progression of SCD during the transition from adolescence are poorly defined with no cognate prophylaxis. Here, we demonstrate in a longitudinal cohort of homozygous SCD (SS) mice a link between intravascular hemolysis, vascular inflammation, lung injury, and early death. Prophylactic Nrf2 activation in young SS mice stabilized intravascular hemolysis, reversed vascular inflammation, and attenuated lung edema in adulthood. Enhanced Nrf2 activation in endothelial cells in vitro concurred with the dramatic effect on vascular inflammation in the mice. BM chimeric SS mice lacking Nrf2 expression in nonhematopoietic tissues were created to dissect the role of nonerythroid Nrf2 in SCD progression. The SS chimeras developed severe intravascular hemolysis despite having erythroid Nrf2. In addition, they developed premature vascular inflammation and pulmonary edema and died younger than donor littermates with intact nonhematopoietic Nrf2. Our results reveal a dominant protective role for nonhematopoietic Nrf2 against tissue damage in both erythroid and nonerythroid tissues in SCD. Furthermore, we show that prophylactic augmentation of Nrf2-coordinated cytoprotection effectively impedes onset of the severe adult phenotype of SCD in mice. PMID:27158670

  10. Identification of two novel human CD1E alleles.

    PubMed

    Mirones, I; Oteo, M; Parra-Cuadrado, J F; Martínez-Naves, E

    2000-08-01

    CD1 is a family of proteins structurally related to major histocompatibility complex (MHC) molecules and specialized in presenting lipids or glycolipids to T cells. In humans, there are five CD1 genes (CD1A to CD1E). It has been shown that, in contrast with classical MHC genes, CD1 loci display a very limited polymorphism. In the present work we describe two novel CD1E alleles found in two healthy Caucasian individuals. One allele differs from the wild-type by a point mutation resulting in a replacement of arginine at position 154 by a tryptophan. In the second allele we found a substitution of the leucine 184 by a proline.

  11. THE EFFECTS OF HYPERTHERMIA ON SPERMATOGENESIS, APOPTOSIS, GENE EXPRESSION AND FERTILITY IN ADULT MALE MICE

    EPA Science Inventory

    The effects of hyperthermia on spermatogenesis, apoptosis, gene expression and fertility in adult male mice
    John C. Rockett1, Faye L. Mapp1, J. Brian Garges1, J. Christopher Luft1, Chisato Mori2 and David J. Dix1.
    1Reproductive Toxicology Division, National Health and Envir...

  12. Deletion of Lkb1 in adult mice results in body weight reduction and lethality.

    PubMed

    Shan, Tizhong; Xiong, Yan; Kuang, Shihuan

    2016-11-08

    Liver kinase B1 (Lkb1) plays crucial roles in development, metabolism and survival. As constitutive knockout of Lkb1 in mice leads to embryonic lethality, whether Lkb1 is required for the growth and survival of adult mice is unclear. Here we address this question using a tamoxifen-inducible Lkb1 knockout (KO) mouse model: Rosa26-Cre(ER): Lkb1(flox/flox) (abbreviated as Rosa-Lkb1). The Rosa-Lkb1 mice exhibited body weight reduction and died within 6 weeks after tamoxifen induction. The body weight reduction was due to reduced weight of various tissues but the brown and white adipose tissues underwent much more pronounced weight reduction relative to the overall body weight reduction. Accordingly, the Rosa-Lkb1 mice had increased blood glucose levels and were intolerant to glucose challenge. Expression levels of adipogenic and lipogenic genes in adipose tissues were also dramatically reduced by Lkb1 deletion. Additionally, Lkb1 deletion reduced lipid deposition and increased expression of mitochondrial (Pgc1a, Cox5b and Cox7a) and hepatic gluconeogenesis related genes (Pepck) in liver. Finally, the Rosa-Lkb1 mice had much reduced oxygen consumption, carbon dioxide production, and energy expenditure. These results demonstrate that Lkb1 plays an important role in maintaining body weight, liver and adipose tissue function, blood glucose homeostasis and survival in adult mice.

  13. Voluntary Wheel Running Does not Affect Lipopolysaccharide-Induced Depressive-Like Behavior in Young Adult and Aged Mice

    PubMed Central

    Martin, Stephen A.; Dantzer, Robert; Kelley, Keith W.; Woods, Jeffrey A.

    2014-01-01

    Peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes prolonged depressive-like behavior in aged mice that is dependent on indoleamine 2,3 dioxygenase (IDO) activation. Regular moderate intensity exercise training has been shown to exert neuroprotective effects that might reduce depressive-like behavior in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced depressive-like behavior and brain IDO gene expression in 4-month-old and 22-month-old C57BL/6J mice. Mice were housed with a running wheel (Voluntary Wheel Running, VWR) or no wheel (Standard) for 30 days (young adult mice) or 70 days (aged mice), after which they were intraperitoneally injected with LPS (young adult mice: 0.83 mg/kg; aged mice: 0.33 mg/kg). Young adult VWR mice ran on average 6.9 km/day, while aged VWR mice ran on average 3.4 km/day. Both young adult and aged VWR mice increased their forced exercise tolerance compared to their respective Standard control groups. VWR had no effect on LPS-induced anorexia, weight-loss, increased immobility in the tail suspension test, and decreased sucrose preference in either young adult or aged mice. Four (young adult mice) and twenty-four (aged mice) hours after injection of LPS transcripts for TNF-α, IL-1β, IL-6, and IDO were upregulated in the whole brain independently of VWR. These results indicate that prolonged physical exercise has no effect on the neuroinflammatory response to LPS and its behavioral consequences. PMID:24281669

  14. Pathological impact of SMN2 mis-splicing in adult SMA mice.

    PubMed

    Sahashi, Kentaro; Ling, Karen K Y; Hua, Yimin; Wilkinson, John Erby; Nomakuchi, Tomoki; Rigo, Frank; Hung, Gene; Xu, David; Jiang, Ya-Ping; Lin, Richard Z; Ko, Chien-Ping; Bennett, C Frank; Krainer, Adrian R

    2013-10-01

    Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. The related SMN2 gene expresses suboptimal levels of functional SMN protein, due to a splicing defect. Many SMA patients reach adulthood, and there is also adult-onset (type IV) SMA. There is currently no animal model for adult-onset SMA, and the tissue-specific pathogenesis of post-developmental SMN deficiency remains elusive. Here, we use an antisense oligonucleotide (ASO) to exacerbate SMN2 mis-splicing. Intracerebroventricular ASO injection in adult SMN2-transgenic mice phenocopies key aspects of adult-onset SMA, including delayed-onset motor dysfunction and relevant histopathological features. SMN2 mis-splicing increases during late-stage disease, likely accelerating disease progression. Systemic ASO injection in adult mice causes peripheral SMN2 mis-splicing and affects prognosis, eliciting marked liver and heart pathologies, with decreased IGF1 levels. ASO dose-response and time-course studies suggest that only moderate SMN levels are required in the adult central nervous system, and treatment with a splicing-correcting ASO shows a broad therapeutic time window. We describe distinctive pathological features of adult-onset and early-onset SMA.

  15. Growth restriction, leptin, and the programming of adult behavior in mice.

    PubMed

    Meyer, Lauritz R; Zhu, Vivian; Miller, Alise; Roghair, Robert D

    2014-12-15

    Prematurity and neonatal growth restriction (GR) are risk factors for autism and attention deficit hyperactivity disorder (ADHD). Leptin production is suppressed during periods of undernutrition, and we have shown that isolated neonatal leptin deficiency leads to adult hyperactivity while neonatal leptin supplementation normalizes the brain morphology of GR mice. We hypothesized that neonatal leptin would prevent the development of GR-associated behavioral abnormalities. From postnatal day 4-14, C57BL/6 mice were randomized to daily injections of saline or leptin (80ng/g), and GR was identified by a weanling weight below the tenth percentile. The behavioral phenotypes of GR and control mice were assessed beginning at 4 months. Within the tripartite chamber, GR mice had significantly impaired social interaction. Baseline escape times from the Barnes maze were faster for GR mice (65+/-6s vs 87+/-7s for controls, p<0.05), but GR mice exhibited regression in their escape times on days 2 and 3 (56% regressed vs 22% of control saline mice, p<0.05). Compared to controls, GR mice entered the open arms of the elevated plus maze more often and stayed there longer (72+/-10s vs 36+/-5s, p<0.01). Neonatal leptin supplementation normalized the behavior of GR mice across all behavioral assays. In conclusion, GR alters the social interactions, learning and activity of mice, and supplementation with the neurotrophic hormone leptin mitigates these effects. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with postnatal growth restriction, and postnatal leptin therapy may be protective.

  16. Very slow turnover of beta-cells in aged adult mice.

    PubMed

    Teta, Monica; Long, Simon Y; Wartschow, Lynn M; Rankin, Matthew M; Kushner, Jake A

    2005-09-01

    Although many signaling pathways have been shown to promote beta-cell growth, surprisingly little is known about the normal life cycle of preexisting beta-cells or the signaling pathways required for beta-cell survival. Adult beta-cells have been speculated to have a finite life span, with ongoing adult beta-cell replication throughout life to replace lost cells. However, little solid evidence supports this idea. To more accurately measure adult beta-cell turnover, we performed continuous long-term labeling of proliferating cells with the DNA precursor analog 5-bromo-2-deoxyuridine (BrdU) in 1-year-old mice. We show that beta-cells of aged adult mice have extremely low rates of replication, with minimal evidence of turnover. Although some pancreatic components acquired BrdU label in a linear fashion, only 1 in approximately 1,400 adult beta-cells were found to undergo replication per day. We conclude that adult beta-cells are very long lived.

  17. Premature aging of the hippocampal neurogenic niche in adult Bmal1‐ deficient mice

    PubMed Central

    Ali, Amira A. H.; Schwarz‐Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

    2015-01-01

    Hippocampal neurogenesis undergoes dramatic age‐related changes. Mice with targeted deletion of the clock gene Bmal1 (Bmal1‐/‐) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1‐/‐ mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1‐/‐ mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70kDa and expression of the cell cycle inhibitor p21 Waf1/CIP1 were increased in adult Bmal1‐/‐ mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age‐dependent decline in adult neurogenesis presumably as a consequence of oxidative stress. PMID:26142744

  18. Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice.

    PubMed

    Ali, Amira A H; Schwarz-Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

    2015-06-01

    Hippocampal neurogenesis undergoes dramatic age-related changes. Mice with targeted deletion of the clock geneBmal1 (Bmal1(-/-)) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1(-/-) mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1(-/-) mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70 kDa and expression of the cell cycle inhibitor p21(Waf1/CIP1) were increased in adult Bmal1(-/-) mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age-dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.

  19. GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knock-in Mice

    PubMed Central

    Li, Gang; Bien-Ly, Nga; Andrews-Zwilling, Yaisa; Xu, Qin; Bernardo, Aubrey; Ring, Karen; Halabisky, Brian; Deng, Changhui; Mahley, Robert W.; Huang, Yadong

    2010-01-01

    SUMMARY Apolipoprotein (apo) E has important and diverse functions in neurobiology, and apoE4 is the major known genetic risk factor for Alzheimer’s disease. Here we report that adult neural stem/progenitor cells (NSCs) express apoE. In apoE knockout mice, neurogenesis in the hippocampus was ~60% lower than in wildtype mice, and most newborn cells developed into astrocytes rather than into neurons as in wildtype mice. This impairment was not observed in human apoE3 knock-in mice. In apoE4 knock-in mice, however, the maturation and dendritic development of newborn hippocampal neurons was significantly impaired as a result of apoE4 and its fragment-caused GABAergic interneuron dysfunction. This impairment was fully rescued by treatment with a GABAA receptor potentiator. These findings demonstrate the importance of apoE in adult hippocampal neurogenesis and show that apoE4 inhibits hippocampal neurogenesis by impairing neuronal maturation mediated by GABA signaling. PMID:19951691

  20. The effect of brief neonatal cryoanesthesia on physical development and adult cognitive function in mice

    PubMed Central

    Janus, Christopher; Golde, Todd

    2013-01-01

    Deep hypothermia (cryoanesthesia) is often used as general anesthesia during surgery in neonatal rodents. Neonatal cryoanesthesia has been used recently to generate somatic brain transgenic (SBT) mouse models via intracerebral ventricular injection of rAAV vectors into both non-transgenic mice and numerous transgenic mouse models. Since, the evaluation of cognition is one of the main experimental endpoints in many of these studies, we examined the consequences of brief neonatal cryoanesthesia on the physical development and mnemonic function of adult mice. Two groups of 129FVBF1 pups from reciprocal breeding crosses underwent cryoanesthesia for 6 (Cryo6) or 12 (Cryo12) min, respectively, within the first hours (< 12hr) of postnatal life. A group of pups separated from the nest and kept in ambient temperature of 33 °C for 6 min served as a control. Our results revealed that lowering the temperature of pups to ~8 °C (Cryo6) or ~5 °C (Cryo12) did not affect their body weight at pre-weaning stage and in the adulthood. The evaluation of cognitive function in adult mice revealed strong and comparable to controls spatial reference, and context and tone fear memories of neonatally cryoanesthetized mice. Also, the experimental and control groups had comparable brain weight at the end of the study. Our results demonstrate that neonatal cryoanesthesia, lasting up to 12 min, has no adverse effects on the body weight of mice during development, and on their cognition in the adulthood. PMID:24239696

  1. Functional CD1d and/or NKT cell invariant chain transcript in horse, pig, African elephant and guinea pig, but not in ruminants

    PubMed Central

    Looringh van Beeck, Frank A.; Reinink, Peter; Hermsen, Roel; Zajonc, Dirk M.; Laven, Marielle J.; Fun, Axel; Troskie, Milana; Schoemaker, Nico J.; Morar, Darshana; Lenstra, Johannes A.; Vervelde, Lonneke; Rutten, Victor P.M.G.; van Eden, Willem; Van Rhijn, Ildiko

    2009-01-01

    CD1d-restricted invariant natural killer T cells (NKT cells) have been well characterized in humans and mice, but it is unknown whether they are present in other species. Here we describe the invariant TCR α chain and the full length CD1d transcript of pig and horse. Molecular modeling predicts that porcine (po) invariant TCR α chain/poCD1d/α-GalCer and equine (eq) invariant TCR α chain/eqCD1d/α-GalCer form complexes that are highly homologous to the human complex. Since a prerequisite for the presence of NKT cells is the expression of CD1d protein, we performed searches for CD1D genes and CD1d transcripts in multiple species. Previously, cattle and guinea pig have been suggested to lack CD1D genes. The CD1D genes of European taurine cattle (Bos taurus) are known to be pseudogenes because of disrupting mutations in the start codon and in the donor splice site of the first intron. Here we show that the same mutations are found in six other ruminants: African buffalo, sheep, bushbuck, bongo, N’Dama cattle, and roe deer. In contrast, intact CD1d transcripts were found in guinea pig, African elephant, horse, rabbit, and pig. Despite the discovery of a highly homologous NKT/CD1d system in pig and horse, our data suggest that functional CD1D and CD1d-restricted NKT cells are not universally present in mammals. PMID:19185921

  2. Sertraline exposure leads to small left heart syndrome in adult mice

    PubMed Central

    Haskell, Sarah E.; Hermann, Gregory M.; Reinking, Benjamin E.; Volk, Kenneth A.; Peotta, Veronica A.; Zhu, Vivian; Roghair, Robert D.

    2013-01-01

    Background Sertraline, a selective serotonin reuptake inhibitor (SSRI), is the most commonly prescribed therapy for maternal depression. Epidemiologic studies have linked SSRI exposure with decreased fetal growth, altered autonomic regulation, and cardiac malformations. We hypothesized SSRI exposure decreases left ventricular volumes and increases adult sympathetic nervous system activation, resulting in increased adult heart rates. Methods C57BL/6 mice received saline or sertraline (5 or 15 mg/kg/day i.p.) on postnatal days 1–14. Adult phenotypes were assessed at 5 months. Results Sertraline-exposed mice had smaller left ventricular internal diameters in diastole (control 4.0 ± 0.1 mm, SSRI 3.7 ± 0.1 mm, p < 0.05), decreased stroke volumes (control 46 ± 2.6 μL, SSRI 37 ± 2.3 μL, p < 0.05), higher heart rates (control 530 ± 13 beats per minute (bpm), SSRI 567 ± 6 bpm, p <0.05) and increased urinary excretion of noradrenaline (control 174 ± 29.4 ng/mL, SSRI 276 ± 35.1 ng/mL, p<0.05). These changes were associated with increased cerebral serotonin transporter (5-HTT) expression. Conclusion Neonatal sertraline exposure causes long term changes in cardiac morphology and physiology. We speculate that early life SSRI exposure impairs cardiomyocyte growth and central serotonin signaling, leading to a small left heart syndrome in adult mice. PMID:23232669

  3. The Cox-2 Inhibitor Meloxicam Ameliorates Neuroinflammation and Depressive Behavior in Adult Mice after Splenectomy

    PubMed Central

    Haile, Michael; Boutajangout, Allal; Chung, Kevin; Chan, Jeffrey; Stolper, Tanya; Vincent, Nemahun; Batchan, Marc; D’Urso, John; Lin, Yan; Kline, Richard; Yaghmoor, Faris; Jahfal, Saad; Kamal, Robel; Aljohani, Waleed; Blanck, Thomas; Bekker, Alex; Wisniewski, Thomas

    2016-01-01

    Background Peripheral surgical trauma may incite neuroinflammation that leads to neuronal dysfunction associated with both depression and cognitive deficits. In a previous study, we found that adult mice developed neuroinflammation and short-term working memory dysfunction in a delayed, transient manner after splenectomy that was ameliorated by the cyclooxygenase-2 inhibitor meloxicam. We tested the hypothesis that splenectomy in mice would also cause anhedonia, the diminished response to pleasure or rewarding stimuli that is a hallmark of depression, and that treatment with meloxicam would be ameliorative. Methods After Institutional Animal Care and Use Committee approval, Swiss-Webster mice underwent sucrose preference training before being randomized into groups on day 0, when they had either splenectomy and anesthesia or anesthesia alone. Within each group, half were randomized to receive intraperitoneal saline at 24 hours, while the other half received intraperitoneal meloxicam at 24 hours. Sucrose preference ratios were determined on days 1, 5, 9, and 14. Additional mice were randomized into groups for brain histochemistry. Specimens were stained for glial fibrillary acidic protein (GFAP), a marker of astrocytes, and CD45, a protein tyrosine phosphatase that identifies microglial activation. Results On day 5, mice receiving splenectomy and saline demonstrated diminished sucrose preference, which was not seen in mice receiving splenectomy and meloxicam. Semiquantitative analysis of histological slides taken from splenectomized mice treated with meloxicam revealed reduced microglial-based neuroinflammation and reactive astrocytosis compared to mice receiving saline. Conclusion Splenectomy in mice is associated with neuroinflammation and anhedonia, as evidenced by reactive microgliosis, astrocytosis, and behavioral changes. Postsurgical treatment with meloxicam attenuates both neuroinflammation and anhedonia. These findings suggest that cyclooxygenase-2

  4. Medulloblastoma expresses CD1d and can be targeted for immunotherapy with NKT cells.

    PubMed

    Liu, Daofeng; Song, Liping; Brawley, Vita S; Robison, Nathan; Wei, Jie; Gao, Xiuhua; Tian, Gengwen; Margol, Ashley; Ahmed, Nabil; Asgharzadeh, Shahab; Metelitsa, Leonid S

    2013-10-01

    Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Current therapies are toxic and not always curative that necessitates development of targeted immunotherapy. However, little is known about immunobiology of this tumor. In this study, we show that MB cells in 9 of 20 primary tumors express CD1d, an antigen-presenting molecule for Natural Killer T cells (NKTs). Quantitative RT-PCR analysis of 61 primary tumors revealed an elevated level of CD1d mRNA expression in a molecular subgroup characterized by an overactivation of Sonic Hedgehog (SHH) oncogene compared with Group 4. CD1d-positive MB cells cross-presented glycolipid antigens to activate NKT-cell cytotoxicity. Intracranial injection of NKTs resulted in regression of orthotopic MB xenografts in NOD/SCID mice. Importantly, the numbers and function of peripheral blood type-I NKTs were preserved in MB patients. Therefore, CD1d is expressed on tumor cells in a subset of MB patients and represents a novel target for immunotherapy.

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

    PubMed Central

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

    2005-01-01

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

  6. Pkd1 transgenic mice: adult model of polycystic kidney disease with extrarenal and renal phenotypes

    PubMed Central

    Kurbegovic, Almira; Côté, Olivier; Couillard, Martin; Ward, Christopher J.; Harris, Peter C.; Trudel, Marie

    2010-01-01

    While high levels of Pkd1 expression are detected in tissues of patients with autosomal dominant polycystic kidney disease (ADPKD), it is unclear whether enhanced expression could be a pathogenetic mechanism for this systemic disorder. Three transgenic mouse lines were generated from a Pkd1-BAC modified by introducing a silent tag via homologous recombination to target a sustained wild-type genomic Pkd1 expression within the native tissue and temporal regulation. These mice specifically overexpressed the Pkd1 transgene in extrarenal and renal tissues from ∼2- to 15-fold over Pkd1 endogenous levels in a copy-dependent manner. All transgenic mice reproducibly developed tubular and glomerular cysts leading to renal insufficiency. Interestingly, Pkd1TAG mice also exhibited renal fibrosis and calcium deposits in papilla reminiscent of nephrolithiasis as frequently observed in ADPKD. Similar to human ADPKD, these mice consistently displayed hepatic fibrosis and ∼15% intrahepatic cysts of the bile ducts affecting females preferentially. Moreover, a significant proportion of mice developed cardiac anomalies with severe left-ventricular hypertrophy, marked aortic arch distention and/or valvular stenosis and calcification that had profound functional impact. Of significance, Pkd1TAG mice displayed occasional cerebral lesions with evidence of ruptured and unruptured cerebral aneurysms. This Pkd1TAG mouse model demonstrates that overexpression of wild-type Pkd1 can trigger the typical adult renal and extrarenal phenotypes resembling human ADPKD. PMID:20053665

  7. Schmallenberg virus infection of adult type I interferon receptor knock-out mice.

    PubMed

    Wernike, Kerstin; Breithaupt, Angele; Keller, Markus; Hoffmann, Bernd; Beer, Martin; Eschbaumer, Michael

    2012-01-01

    Schmallenberg virus (SBV), a novel orthobunyavirus, was discovered in Europe in late 2011. It causes mild and transient disease in adult ruminants, but fetal infection can lead to abortion or severe malformations. There is considerable demand for SBV research, but in vivo studies in large animals are complicated by their long gestation periods and the cost of high containment housing. The goal of this study was to investigate whether type I interferon receptor knock-out (IFNAR(-/-)) mice are a suitable small animal model for SBV. Twenty IFNAR(-/-) mice were inoculated with SBV, four were kept as controls. After inoculation, all were observed and weighed daily; two mice per day were sacrificed and blood, brain, lungs, liver, spleen, and intestine were harvested. All but one inoculated mouse lost weight, and two mice died spontaneously at the end of the first week, while another two had to be euthanized. Real-time RT-PCR detected large amounts of SBV RNA in all dead or sick mice; the controls were healthy and PCR-negative. IFNAR(-/-) mice are susceptible to SBV infection and can develop fatal disease, making them a handy and versatile tool for SBV vaccine research.

  8. Social experience modulates ocular dominance plasticity differentially in adult male and female mice.

    PubMed

    Balog, Jenny; Matthies, Ulrike; Naumann, Lisa; Voget, Mareike; Winter, Christine; Lehmann, Konrad

    2014-12-01

    Environmental factors have long been known to regulate brain plasticity. We investigated the potential influence of social experience on ocular dominance plasticity. Fully adult female or male mice were monocularly deprived for four days and kept a) either alone or in pairs of the same sex and b) either in a small cage or a large, featureless arena. While mice kept alone did not show ocular dominance plasticity, no matter whether in a cage or in an arena, paired female mice in both environmental conditions displayed a shift of ocular dominance towards the open eye. Paired male mice, in contrast, showed no plasticity in the cage, but a very strong ocular dominance shift in the arena. This effect was not due to increased locomotion, since the covered distance was similar in single and paired male mice in the arena, and furnishing cages with a running wheel did not enable ocular dominance plasticity in cage-housed mice. Confirming recent results in rats, the plasticity-enhancing effect of the social environment was shown to be mediated by serotonin. Our results demonstrate that social experience has a strong effect on cortical plasticity that is sex-dependent. This has potential consequences both for animal research and for human education and rehabilitation.

  9. Round and Round and Round We Go: Behavior of Adult Female Mice on the ISS

    NASA Technical Reports Server (NTRS)

    Ronca, April E.

    2016-01-01

    The NASA Decadal Survey (2011) emphasized the importance of long duration rodent experiments on the International Space Station (ISS). To accomplish this objective, flight hardware and science capabilities supporting mouse studies in space were developed at Ames Research Center. Here we present a video-based behavioral analysis of ten C57BL6 female adult mice exposed to a total of 37 days in space compared with identically housed Ground Controls. Flight and Control mice exhibited the same range of behaviors, including feeding, drinking, exploratory behavior, grooming, and social interactions. Mice propelled themselves freely and actively throughout the Habitat using their forelimbs to push off or by floating from one cage area to another. Overall activity was greater in Flt as compared to GC mice. Spontaneous, organized circling or race-tracking behavior emerged within the first few days of flight and encompassed the primary dark cycle activity for the remainder of the experiment. I will summarize qualitative observations and quantitative comparisons of mice in microgravity and 1g conditions. Behavioral phenotyping revealed important insights into the overall health and adaptation of mice to the space environment, and identified unique behaviors that can guide future habitat development and research on rodents in space.

  10. Antigen presentation by peritoneal macrophages from young adult and old mice

    SciTech Connect

    Perkins, E.H.; Massucci, J.M.; Glover, P.L.

    1982-01-01

    Macrophages perform vital inductive and regulatory functions in immune processes and host defense mechanisms. However, macrophage function during senescence has not been extensively studied. Although antibody response is dramatically reduced in old animals, antigen presentation has never been directly assessed. Therefore, the antigen-presenting capabilities of purified peritoneal macrophages from young adult and old mice were studied by quantitatively measuring their ability to induce antigen specific proliferation of lymph node T lymphocytes. Increasing numbers (10/sup 2/ to 10/sup 5/) of macrophages from nonimmunized young adult (3 to 6 months) or aged (27 to 36 months) animals were cultured in the presence of antigen with a constant number (2 x 10/sup 5/) of column-separated popliteal lymph node cells from young adult mice. The latter had been immunized with the dinitrophenyl conjugate of bovine ..gamma..-globulin in complete Freund's adjuvant by footpad injection. Macrophages from old animals were equal to macrophages from young adult in stimulating T-lymphocyte proliferation, and the kinetics of incorporation was identical with increasing numbers of macrophages from either young adult or old animals. However, greater numbers of resident or induced peritoneal macrophages were always harvested from old animals. Differences in macrophage activity as assessed by different functional parameters may be reconciled by implicating subpopulations of macrophages that perform separate functions, e.g. Ia-positive antigen presenter and Ia-negative scavenger macrophages.

  11. Establishment of a tamoxifen-inducible Cre-driver mouse strain for widespread and temporal genetic modification in adult mice.

    PubMed

    Ichise, Hirotake; Hori, Akiko; Shiozawa, Seiji; Kondo, Saki; Kanegae, Yumi; Saito, Izumu; Ichise, Taeko; Yoshida, Nobuaki

    2016-07-29

    Temporal genetic modification of mice using the ligand-inducible Cre/loxP system is an important technique that allows the bypass of embryonic lethal phenotypes and access to adult phenotypes. In this study, we generated a tamoxifen-inducible Cre-driver mouse strain for the purpose of widespread and temporal Cre recombination. The new line, named CM32, expresses the GFPneo-fusion gene in a wide variety of tissues before FLP recombination and tamoxifen-inducible Cre after FLP recombination. Using FLP-recombined CM32 mice (CM32Δ mice) and Cre reporter mouse lines, we evaluated the efficiency of Cre recombination with and without tamoxifen administration to adult mice, and found tamoxifen-dependent induction of Cre recombination in a variety of adult tissues. In addition, we demonstrated that conditional activation of an oncogene could be achieved in adults using CM32Δ mice. CM32Δ;T26 mice, which harbored a Cre recombination-driven, SV40 large T antigen-expressing transgene, were viable and fertile. No overt phenotype was found in the mice up to 3 months after birth. Although they displayed pineoblastomas (pinealoblastomas) and/or thymic enlargement due to background Cre recombination by 6 months after birth, they developed epidermal hyperplasia when administered tamoxifen. Collectively, our results suggest that the CM32Δ transgenic mouse line can be applied to the assessment of adult phenotypes in mice with loxP-flanked transgenes.

  12. Adolescent mice, unlike adults, consume more alcohol in the presence of peers than alone.

    PubMed

    Logue, Sheree; Chein, Jason; Gould, Thomas; Holliday, Erica; Steinberg, Laurence

    2014-01-01

    One hallmark of adolescent risk-taking is that it typically occurs when adolescents are with peers. It has been hypothesized that the presence of peers primes a reward-sensitive motivational state that overwhelms adolescents' immature capacity for inhibitory control. We examined this hypothesis using a rodent model. A sample of mice were raised in same-sex triads and were tested for alcohol consumption either as juveniles or as adults, with half in each age group tested alone and half tested with their cagemates. The presence of 'peers' increased alcohol consumption among adolescent mice, but not adults. The peer effect on human adolescent reward-seeking may reflect a hard-wired, evolutionarily conserved process through which the presence of agemates increases individuals' sensitivity to potential rewards in their immediate environment.

  13. Differences in tissue distribution of HBCD alpha and gamma between adult and developing mice.

    PubMed

    Szabo, David T; Diliberto, Janet J; Huwe, Janice K; Birnbaum, Linda S

    2011-09-01

    Hexabromocyclododecane (HBCD) is a mixture of three stereoisomers alpha (α), beta (β), and gamma (γ). γ-HBCD dominates the mixture (∼70%), and despite α-HBCD's minor contribution to global HBCD production and usage (∼10%), it is the dominant congener found in most biotic samples worldwide. Evidence of toxicity and lack of stereoisomer studies drives the importance of understanding HBCD toxicokinetics in potentially susceptible populations. The majority of public health concern has focused on hazardous effects resulting from exposure of infants and young children to HBCD due to reports on adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to HBCD. This study was designed to investigate differences in the disposition of both γ-HBCD and α-HBCD in infantile mice reported to be susceptible to the HBCD commercial mixture. The tissue distribution of α-[(14)C]HBCD- and γ-[(14)C]HBCD-derived radioactivity was monitored in C57BL/6 mice following a single oral dose of either compound (3 mg/kg) after direct gavage at postnatal day 10. Mice were held up to 7 days in shoebox cages after which pups were sacrificed, tissue collected, and internal dosimetry was measured. Developing mice exposed to α-HBCD had an overall higher body burden than γ-HBCD at every time point measured; at 4 days postexposure, they retained 22% of the α-HBCD administered dose, whereas pups exposed to γ-HBCD retained 10%. Total body burden in infantile mice after exposure to γ-HBCD was increased 10-fold as compared with adults. Similarly, after exposure to α-HBCD, infantile mice contained 2.5-fold higher levels than adult. These differences lead to higher concentrations of the HBCD diastereomers at target tissues during critical windows of development. The results indicate that the toxicokinetics of the two HBCD diastereomers differ between developing and adult mice

  14. Neonatal Colon Insult Alters Growth Factor Expression and TRPA1 Responses in Adult Mice

    PubMed Central

    Christianson, Julie A.; Bielefeldt, Klaus; Malin, Sacha A.; Davis, Brian M.

    2010-01-01

    Inflammation or pain during neonatal development can result in long-term structural and functional alterations of nociceptive pathways, ultimately altering pain perception in adulthood. We have developed a mouse model of neonatal colon irritation (NCI) to investigate the plasticity of pain processing within the viscerosensory system. Mouse pups received an intracolonic administration of 2% mustard oil (MO) on postnatal days 8 and 10. Distal colons were processed at subsequent timepoints for myeloperoxidase (MPO) activity and growth factor expression. Adult mice were assessed for visceral hypersensitivity by measuring the visceromotor response during colorectal distension. Dorsal root ganglion (DRG) neurons from adult mice were retrogradely labeled from the distal colon and calcium imaging was used to measure transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) responses to acute application of capsaicin and MO, respectively. Despite the absence of inflammation (as indicated by MPO activity), neonatal exposure to intracolonic MO transiently maintained a higher expression level of growth factor messenger RNA (mRNA). Adult NCI mice displayed significant visceral hypersensitivity, as well as increased sensitivity to mechanical stimulation of the hindpaw, compared to control mice. The percentage of TRPA1-expressing colon afferents was significantly increased in NCI mice, however they displayed no increase in the percentage of TRPV1-immunopositive or capsaicin-sensitive colon DRG neurons. These results suggest that early neonatal colon injury results in a long-lasting visceral hypersensitivity, possibly driven by an early increase in growth factor expression and maintained by permanent changes in TRPA1 function. PMID:20850221

  15. Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

    PubMed

    Mustroph, M L; Merritt, J R; Holloway, A L; Pinardo, H; Miller, D S; Kilby, C N; Bucko, P; Wyer, A; Rhodes, J S

    2015-01-01

    Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice.

  16. Behavioral responses to and brain distribution of morphine in mature adult and aged mice

    SciTech Connect

    Burton, C.K.; Ho, I.K.; Hoskins, B.

    1986-03-01

    Mature adult (3-6 mo old) and aged (2 yr old) male ICR mice were injected with 10 to 100 mg/kg morphine, s.c. The ED50 values for running behavior (as measured using Stoelting activity monitors and having each mouse serve as its own control) representing 5 times control activity was approximately 7.5 mg/kg for aged mice and approximately 17.5 mg/kg for the mature adults. The ED50 values for analgesia 1 hr after morphine administration using the tail-flick method (max. response time = 8 sec) were approx. 70 mg/kg for the aged mice and 15 mg/kg for the mature adults. One hour after injecting /sup 3/H-morphine at doses of 30 and 100 mg/kg, 0.13 and 0.14% of the doses appeared in brains of aged and mature adult mice, respectively. Regional distribution of the morphine was the same for both age groups. Expressed as percent of total brain morphine, it was as follows: cortex, 30%; midbrain, 18%; cerebellum, 17%; medulla, 12%; pons, 9%; striatum, 8% and periaqueductal gray, 6%. Expressed as g morphine/g tissue for the 2 doses, the distribution was; periaqueductal gray, 30 and 80; striatum, 9 and 34; medulla, 6 and 20 pons; 5 and 19; cerebellum, 4 and 13; midbrain 2.5 and 8.5 and cortex, 2 and 8. These results suggest that the differences in response to morphine by the two age groups were due to age-related differences in opioid receptor populations and/or affinities.

  17. Enriched environment increases neurogenesis and improves social memory persistence in socially isolated adult mice.

    PubMed

    Monteiro, Brisa M M; Moreira, Fabrício A; Massensini, André R; Moraes, Márcio F D; Pereira, Grace S

    2014-02-01

    Social memory consists of the information necessary to identify and recognize cospecifics and is essential to many forms of social interaction. Social memory persistence is strongly modulated by the animal's experiences. We have shown in previous studies that social isolation (SI) in adulthood impairs social memory persistence and that an enriched environment (EE) prevents this impairment. However, the mechanisms involved in the effects of SI and EE on social memory persistence remain unknown. We hypothesized that the mechanism by which SI and EE affect social memory persistence is through their modulation of neurogenesis. To investigate this hypothesis, adult mice were submitted to 7 days of one of the following conditions: group-housing in a standard (GH) or enriched environment (GH+EE); social isolation in standard (SI) or enriched environment (SI+EE). We observed an increase in the number of newborn neurons in the dentate gyrus of the hippocampus (DG) and glomerular layer of the olfactory bulb (OB) in both GH+EE and SI+EE mice. However, this increase of newborn neurons in the granule cell layer of the OB was restricted to the GH+EE group. Furthermore, both SI and SI+EE groups showed less neurogenesis in the mitral layer of the OB. Interestingly, the performance of the SI mice in the buried food-finding task was inferior to that of the GH mice. To further analyze whether increased neurogenesis is in fact the mechanism by which the EE improves social memory persistence in SI mice, we administered the mitotic inhibitor AraC or saline directly into the lateral ventricles of the SI+EE mice. We found that the AraC treatment decreased cell proliferation in both the DG and OB, and impaired social memory persistence in the SI+EE mice. Taken together, our results strongly suggest that neurogenesis is what supports social memory persistence in socially isolated mice.

  18. Generation of Venus reporter knock-in mice revealed MAGI-2 expression patterns in adult mice.

    PubMed

    Ihara, Kan-ichiro; Nishimura, Tomoki; Fukuda, Tomokazu; Ookura, Tetsuya; Nishimori, Katsuhiko

    2012-01-01

    The membrane-associated guanylate kinase inverted 2 (MAGI-2) protein, which is known to localize at the tight junction of epithelial cells, contains multiple copies of the PDZ and WW domains in its structure. Although the expression pattern of Magi2 mRNA in representative organs has been previously published, its detailed cellular distribution at the histological level remains unknown. Such detailed information would be useful to clarify the biological function of MAGI-2. Here, we report the generation of Venus reporter knock-in mice for Magi2 in which exon 6 of the gene was substituted by the Venus-encoding sequence. We detected the expression of the Venus reporter protein in kidney podocytes from these knock-in mice. We also detected Venus reporter protein expression in spermatids within the testes and within neurons in various regions of the brain. Detection of the reporter protein from these diverse locations indicated the endogenous expression of MAGI-2 in these tissues. Our data suggested a potential function of MAGI-2 in the glomerular filtration process and sperm cell maturation. These data indicate that the Venus reporter knock-in mouse for Magi2 is a useful model for the further study of Magi2 gene function.

  19. Juvenile mice show greater flexibility in multiple choice reversal learning than adults

    PubMed Central

    Johnson, Carolyn; Wilbrecht, Linda

    2011-01-01

    We hypothesized that decision-making strategies in juvenile animals, rather than being immature, are optimized to navigate the uncertainty and instability likely to be encountered in the environment at the time of the animal’s transition to independence. We tested juvenile and young adult mice on discrimination and reversal of a 4-choice and 2-choice odor-based foraging task. Juvenile mice (P26–27) learned a 4-choice discrimination and reversal faster than adults (P60–70), making fewer perseverative and distraction errors. Juvenile mice had shorter choice latencies and more focused search strategies. In both ages, performance of the task was significantly impaired by a lesion of the dorsomedial frontal cortex. Our data show that the frontal cortex can support highly flexible behavior in juvenile mice at a time coincident with weaning and first independence. The unexpected developmental decline in flexibility of behavior one month later suggests that frontal cortex based executive function may not inevitably become more flexible with age, but rather may be developmentally tuned to optimize exploratory and exploitative behavior for each life stage. PMID:21949556

  20. Pleiotropic effects of extended blockade of CSF1R signaling in adult mice.

    PubMed

    Sauter, Kristin A; Pridans, Clare; Sehgal, Anuj; Tsai, Yi Ting; Bradford, Barry M; Raza, Sobia; Moffat, Lindsey; Gow, Deborah J; Beard, Philippa M; Mabbott, Neil A; Smith, Lee B; Hume, David A

    2014-08-01

    We investigated the role of CSF1R signaling in adult mice using prolonged treatment with anti-CSF1R antibody. Mutation of the CSF1 gene in the op/op mouse produces numerous developmental abnormalities. Mutation of the CSF1R has an even more penetrant phenotype, including perinatal lethality, because of the existence of a second ligand, IL-34. These effects on development provide limited insight into functions of CSF1R signaling in adult homeostasis. The carcass weight and weight of several organs (spleen, kidney, and liver) were reduced in the treated mice, but overall body weight gain was increased. Despite the complete loss of Kupffer cells, there was no effect on liver gene expression. The treatment ablated OCL, increased bone density and trabecular volume, and prevented the decline in bone mass seen in female mice with age. The op/op mouse has a deficiency in pancreatic β cells and in Paneth cells in the gut wall. Only the latter was reproduced by the antibody treatment and was associated with increased goblet cell number but no change in villus architecture. Male op/op mice are infertile as a result of testosterone insufficiency. Anti-CSF1R treatment ablated interstitial macrophages in the testis, but there was no sustained effect on testosterone or LH. The results indicate an ongoing requirement for CSF1R signaling in macrophage and OCL homeostasis but indicate that most effects of CSF1 and CSF1R mutations are due to effects on development.

  1. Short-Term Treatment with Bisphenol-A Leads to Metabolic Abnormalities in Adult Male Mice

    PubMed Central

    Batista, Thiago M.; Alonso-Magdalena, Paloma; Vieira, Elaine; Amaral, Maria Esmeria C.; Cederroth, Christopher R.; Nef, Serge; Quesada, Ivan; Carneiro, Everardo M.; Nadal, Angel

    2012-01-01

    Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDC) used as the base compound in the manufacture of polycarbonate plastics. Although evidence points to consider exposure to BPA as a risk factor for insulin resistance, its actions on whole body metabolism and on insulin-sensitive tissues are still unclear. The aim of the present work was to study the effects of low doses of BPA in insulin-sensitive peripheral tissues and whole body metabolism in adult mice. Adult mice were treated with subcutaneous injection of 100 µg/kg BPA or vehicle for 8 days. Whole body energy homeostasis was assessed with in vivo indirect calorimetry. Insulin signaling assays were conducted by western blot analysis. Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. BPA-treated mice had decreased food intake, lower body temperature and locomotor activity compared to control. In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit was impaired in BPA-treated mice. This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr308 residue. Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. The mitogen-activated protein kinase (MAPK) signaling pathway was also impaired in the skeletal muscle from BPA-treated mice. In the liver, BPA effects were of lesser intensity with decreased insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit. In conclusion, short-term treatment with low doses of BPA slows down whole body energy metabolism and disrupts insulin signaling in peripheral tissues. Thus, our findings support the notion that BPA can be considered a risk factor for the development of type 2 diabetes. PMID:22470480

  2. Psychological stress in adolescent and adult mice increases neuroinflammation and attenuates the response to LPS challenge

    PubMed Central

    2012-01-01

    Background There is ample evidence that psychological stress adversely affects many diseases. Recent evidence has shown that intense stressors can increase inflammation within the brain, a known mediator of many diseases. However, long-term outcomes of chronic psychological stressors that elicit a neuroinflammatory response remain unknown. Methods To address this, we have modified previously described models of rat/mouse predatory stress (PS) to increase the intensity of the interaction. We postulated that these modifications would enhance the predator-prey experience and increase neuroinflammation and behavioral dysfunction in prey animals. In addition, another group of mice were subjected to a modified version of chronic unpredictable stress (CUS), an often-used model of chronic stress that utilizes a combination of stressors that include physical, psychological, chemical, and other. The CUS model has been shown to exacerbate a number of inflammatory-related diseases via an unknown mechanism. Using these two models we sought to determine: 1) whether chronic PS or CUS modulated the inflammatory response as a proposed mechanism by which behavioral deficits might be mediated, and 2) whether chronic exposure to a pure psychological stressor (PS) leads to deficits similar to those produced by a CUS model containing psychological and physical stressors. Finally, to determine whether acute PS has neuroinflammatory consequences, adult mice were examined at various time-points after PS for changes in inflammation. Results Adolescent mice subjected to chronic PS had increased basal expression of inflammation within the midbrain. CUS and chronic PS mice also had an impaired inflammatory response to a subsequent lipopolysaccharide challenge and PS mice displayed increased anxiety- and depressive-like behaviors following chronic stress. Finally, adult mice subjected to acute predatory stress had increased gene expression of inflammatory factors. Conclusion Our results

  3. Repeatability and consistency of individual behaviour in juvenile and adult Eurasian harvest mice

    NASA Astrophysics Data System (ADS)

    Schuster, Andrea C.; Carl, Teresa; Foerster, Katharina

    2017-04-01

    Knowledge on animal personality has provided new insights into evolutionary biology and animal ecology, as behavioural types have been shown to affect fitness. Animal personality is characterized by repeatable and consistent between-individual behavioural differences throughout time and across different situations. Behavioural repeatability within life history stages and consistency between life history stages should be checked for the independence of sex and age, as recent data have shown that males and females in some species may differ in the repeatability of behavioural traits, as well as in their consistency. We measured the repeatability and consistency of three behavioural and one cognitive traits in juvenile and adult Eurasian harvest mice ( Micromys minutus). We found that exploration, activity and boldness were repeatable in juveniles and adults. Spatial recognition measured in a Y Maze was only repeatable in adult mice. Exploration, activity and boldness were consistent before and after maturation, as well as before and after first sexual contact. Data on spatial recognition provided little evidence for consistency. Further, we found some evidence for a litter effect on behaviours by comparing different linear mixed models. We concluded that harvest mice express animal personality traits as behaviours were repeatable across sexes and consistent across life history stages. The tested cognitive trait showed low repeatability and was less consistent across life history stages. Given the rising interest in individual variation in cognitive performance, and in its relationship to animal personality, we suggest that it is important to gather more data on the repeatability and consistency of cognitive traits.

  4. Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles.

    PubMed

    Lei, Lei; Spradling, Allan C

    2013-05-21

    Whether or not mammalian females generate new oocytes during adulthood from germ-line stem cells to sustain the ovarian follicle pool has recently generated controversy. We used a sensitive lineage-labeling system to determine whether stem cells are needed in female adult mice to compensate for follicular losses and to directly identify active germ-line stem cells. Primordial follicles generated during fetal life are highly stable, with a half-life during adulthood of 10 mo, and thus are sufficient to sustain adult oogenesis without a source of renewal. Moreover, in normal mice or following germ-cell depletion with Busulfan, only stable, single oocytes are lineage-labeled, rather than cell clusters indicative of new oocyte formation. Even one germ-line stem cell division per 2 wk would have been detected by our method, based on the kinetics of fetal follicle formation. Thus, adult female mice neither require nor contain active germ-line stem cells or produce new oocytes in vivo.

  5. Membrane potential dye imaging of ventromedial hypothalamus neurons from adult mice to study glucose sensing.

    PubMed

    Vazirani, Reema P; Fioramonti, Xavier; Routh, Vanessa H

    2013-11-27

    Studies of neuronal activity are often performed using neurons from rodents less than 2 months of age due to the technical difficulties associated with increasing connective tissue and decreased neuronal viability that occur with age. Here, we describe a methodology for the dissociation of healthy hypothalamic neurons from adult-aged mice. The ability to study neurons from adult-aged mice allows the use of disease models that manifest at a later age and might be more developmentally accurate for certain studies. Fluorescence imaging of dissociated neurons can be used to study the activity of a population of neurons, as opposed to using electrophysiology to study a single neuron. This is particularly useful when studying a heterogeneous neuronal population in which the desired neuronal type is rare such as for hypothalamic glucose sensing neurons. We utilized membrane potential dye imaging of adult ventromedial hypothalamic neurons to study their responses to changes in extracellular glucose. Glucose sensing neurons are believed to play a role in central regulation of energy balance. The ability to study glucose sensing in adult rodents is particularly useful since the predominance of diseases related to dysfunctional energy balance (e.g. obesity) increase with age.

  6. Duct Cells Contribute to Regeneration of Endocrine and Acinar Cells Following Pancreatic Damage in Adult Mice

    PubMed Central

    CRISCIMANNA, ANGELA; SPEICHER, JULIE A.; HOUSHMAND, GOLBAHAR; SHIOTA, CHIYO; PRASADAN, KRISHNA; Ji, BAOAN; LOGSDON, CRAIG D.; GITTES, GEORGE K.; ESNI, FARZAD

    2015-01-01

    BACKGROUND & AIMS There have been conflicting results on a cell of origin in pancreatic regeneration. These discrepancies predominantly stem from lack of specific markers for the pancreatic precursors/stem cells, as well as differences in the targeted cells and severity of tissue injury in the experimental models so far proposed. We attempted to create a model that used diphtheria toxin receptor (DTR) to ablate specific cell populations, control the extent of injury, and avoid induction of the inflammatory response. METHODS To target specific types of pancreatic cells, we crossed R26DTR or R26dtR/lacZ mice with transgenic mice that express the Cre recombinase in the pancreas, under control of the Pdx1 (global pancreatic) or elastase (acinar-specific) promoters. RESULTS Exposure of PdxCre;R26DTR mice to diphtheria toxin resulted in extensive ablation of acinar and endocrine tissues but not ductal cells. Surviving cells within the ductal compartment contributed to regeneration of endocrine and acinar cells via recapitulation of the embryonic pancreatic developmental program. However, following selective ablation of acinar tissue in ElaCre-ERT2;R26DTR mice, regeneration likely occurred by reprogramming of ductal cells to acinar lineage. CONCLUSIONS In the pancreas of adult mice, epithelial cells within the ductal compartment contribute to regeneration of endocrine and acinar cells. The severity of injury determines the regenerative mechanisms and cell types that contribute to this process. PMID:21763240

  7. Synaptosomal-associated protein 25 mutation induces immaturity of the dentate granule cells of adult mice

    PubMed Central

    2013-01-01

    Background Synaptosomal-associated protein, 25 kDa (SNAP-25) regulates the exocytosis of neurotransmitters. Growing evidence suggests that SNAP-25 is involved in neuropsychiatric disorders, such as schizophrenia, attention-deficit/hyperactivity disorder, and epilepsy. Recently, increases in anxiety-related behaviors and epilepsy have been observed in SNAP-25 knock-in (KI) mice, which have a single amino acid substitution of Ala for Ser187. However, the molecular and cellular mechanisms underlying the abnormalities in this mutant remain unknown. Results In this study, we found that a significant number of dentate gyrus (DG) granule cells was histologically and electrophysiologically similar to immature DG neurons in the dentate gyrus of the adult mutants, a phenomenon termed the “immature DG” (iDG). SNAP-25 KI mice and other mice possessing the iDG phenotype, i.e., alpha-calcium/calmodulin-dependent protein kinase II heterozygous mice, Schnurri-2 knockout mice, and mice treated with the antidepressant fluoxetine, showed similar molecular expression patterns, with over 100 genes similarly altered. A working memory deficit was also identified in mutant mice during a spontaneous forced alternation task using a modified T-maze, a behavioral task known to be dependent on hippocampal function. Chronic treatments with the antiepileptic drug valproate abolished the iDG phenotype and the working memory deficit in mutants. Conclusions These findings suggest that the substitution of Ala for Ser187 in SNAP-25 induces the iDG phenotype, which can also be caused by epilepsy, and led to a severe working memory deficit. In addition, the iDG phenotype in adulthood is likely an endophenotype for at least a part of some common psychiatric disorders. PMID:23497716

  8. Loss of AND-34/BCAR3 expression in mice results in rupture of the adult lens

    PubMed Central

    Near, Richard I.; Smith, Richard S.; Toselli, Paul A.; Freddo, Thomas F.; Bloom, Alexander B.; Vanden Borre, Pierre; Seldin, David C.

    2009-01-01

    Purpose AND-34/BCAR3 (Breast Cancer Anti-Estrogen Resistance 3) associates with the focal adhesion adaptor protein, p130CAS/BCAR1. Expression of AND-34 regulates epithelial cell growth pattern, motility, and growth factor dependence. We sought to establish the effects of the loss of AND-34 expression in a mammalian organism. Methods AND-34−/− mice were generated by homologous recombination. Histopathology, in situ hybridization, and western blotting were performed on murine tissues. Results Western analyses confirmed total loss of expression in AND-34−/− splenic lymphocytes. Mice lacking AND-34 are fertile and have normal longevity. While AND-34 is widely expressed in wild type mice, histologic analysis of multiple organs in AND-34−/− mice is unremarkable and analyses of lymphocyte development show no overt changes. A small percentage of AND-34−/− mice show distinctive small white eye lesions resulting from the migration of ruptured cortical lens tissue into the anterior chamber. Following initial vacuolization and liquefaction of the lens cortex first observed at postnatal day three, posterior lens rupture occurs in all AND-34−/− mice, beginning as early as three weeks and seen in all mice at three months. Western blot analysis and in situ hybridization confirmed the presence of AND-34 RNA and protein in lens epithelial cells, particularly at the lens equator. Prior data link AND-34 expression to the activation of Akt signaling. While Akt Ser 473 phosphorylation was readily detectable in AND-34+/+ lens epithelial cells, it was markedly reduced in the AND-34−/− lens epithelium. Basal levels of p130Cas phosphorylation were higher in AND-34+/+ than in AND-34−/− lens epithelium. Conclusions These results demonstrate the loss of AND-34 dysregulates focal adhesion complex signaling in lens epithelial cells and suggest that AND-34-mediated signaling is required for maintenance of the structural integrity of the adult ocular lens. PMID:19365570

  9. Morphological and behavioral characterization of adult mice deficient for SrGAP3.

    PubMed

    Bertram, Jonathan; Koschützke, Leif; Pfannmöller, Jörg P; Esche, Jennifer; van Diepen, Laura; Kuss, Andreas W; Hartmann, Bianca; Bartsch, Dusan; Lotze, Martin; von Bohlen Und Halbach, Oliver

    2016-10-01

    SrGAP3 belongs to the family of Rho GTPase proteins. These proteins are thought to play essential roles in development and in the plasticity of the nervous system. SrGAP3-deficient mice have recently been created and approximately 10 % of these mice developed a hydrocephalus and died shortly after birth. The others survived into adulthood, but displayed neuroanatomical alteration, including increased ventricular size. We now show that SrGAP3-deficient mice display increased brain weight together with increased hippocampal volume. This increase was accompanied by an increase of the thickness of the stratum oriens of area CA1 as well as of the thickness of the molecular layer of the dentate gyrus (DG). Concerning hippocampal adult neurogenesis, we observed no significant change in the number of proliferating cells. The density of doublecortin-positive cells also did not vary between SrGAP3-deficient mice and controls. By analyzing Golgi-impregnated material, we found that, in SrGAP3-deficient mice, the morphology and number of dendritic spines was not altered in the DG. Likewise, a Sholl-analysis revealed no significant changes concerning dendritic complexity as compared to controls. Despite the distinct morphological alterations in the hippocampus, SrGAP3-deficient mice were relatively inconspicuous in their behavior, not only in the open-field, nest building but also in the Morris water-maze. However, the SrGAP3-deficient mice showed little to no interest in burying marbles; a behavior that is seen in some animal models related to autism, supporting the view that SrGAP3 plays a role in neurodevelopmental disorders.

  10. CD8 T cells protect adult naive mice from JEV-induced morbidity via lytic function

    PubMed Central

    Chawla, Amanpreet Singh; Agrawal, Tanvi; Biswas, Moanaro; Vrati, Sudhanshu; Rath, Satyajit; George, Anna; Medigeshi, Guruprasad R.

    2017-01-01

    Following Japanese encephalitis virus (JEV) infection neutralizing antibodies are shown to provide protection in a significant proportion of cases, but not all, suggesting additional components of immune system might also contribute to elicit protective immune response. Here we have characterized the role of T cells in offering protection in adult mice infected with JEV. Mice lacking α/β–T cells (TCRβ–null) are highly susceptible and die over 10–18 day period as compared to the wild-type (WT) mice which are resistant. This is associated with high viral load, higher mRNA levels of proinflammatory cytokines and breach in the blood-brain-barrier (BBB). Infected WT mice do not show a breach in BBB; however, in contrast to TCRβ-null, they show the presence of T cells in the brain. Using adoptive transfer of cells with specific genetic deficiencies we see that neither the presence of CD4 T cells nor cytokines such as IL-4, IL-10 or interferon-gamma have any significant role in offering protection from primary infection. In contrast, we show that CD8 T cell deficiency is more critical as absence of CD8 T cells alone increases mortality in mice infected with JEV. Further, transfer of T cells from beige mice with defects in granular lytic function into TCRβ-null mice shows poor protection implicating granule-mediated target cell lysis as an essential component for survival. In addition, for the first time we report that γ/δ-T cells also make significant contribution to confer protection from JEV infection. Our data show that effector CD8 T cells play a protective role during primary infection possibly by preventing the breach in BBB and neuronal damage. PMID:28151989

  11. Methanol exposure does not produce oxidatively damaged DNA in lung, liver or kidney of adult mice, rabbits or primates

    SciTech Connect

    McCallum, Gordon P.; Siu, Michelle; Sweeting, J. Nicole; Wells, Peter G.

    2011-01-15

    In vitro and in vivo genotoxicity tests indicate methanol (MeOH) is not mutagenic, but carcinogenic potential has been claimed in one controversial long-term rodent cancer bioassay that has not been replicated. To determine whether MeOH could indirectly damage DNA via reactive oxygen species (ROS)-mediated mechanisms, we treated male CD-1 mice, New Zealand white rabbits and cynomolgus monkeys with MeOH (2.0 g/kg ip) and 6 h later assessed oxidative damage to DNA, measured as 8-oxo-2'-deoxyguanosine (8-oxodG) by HPLC with electrochemical detection. We found no MeOH-dependent increases in 8-oxodG in lung, liver or kidney of any species. Chronic treatment of CD-1 mice with MeOH (2.0 g/kg ip) daily for 15 days also did not increase 8-oxodG levels in these organs. These results were corroborated in DNA repair-deficient oxoguanine glycosylase 1 (Ogg1) knockout (KO) mice, which accumulated 8-oxodG in lung, kidney and liver with age, but exhibited no increase following MeOH, despite a 2-fold increase in renal 8-oxodG in Ogg1 KO mice following treatment with a ROS-initiating positive control, the renal carcinogen potassium bromate (KBrO{sub 3}; 100 mg/kg ip). These observations suggest that MeOH exposure does not promote the accumulation of oxidatively damaged DNA in lung, kidney or liver, and that environmental exposure to MeOH is unlikely to initiate carcinogenesis in these organs by DNA oxidation.

  12. Oestradiol Exposure Early in Life Programs Daily and Circadian Activity Rhythms in Adult Mice.

    PubMed

    Royston, S E; Bunick, D; Mahoney, M M

    2016-01-01

    Hormone signalling during critical periods organises the adult circadian timekeeping system by altering adult hormone sensitivity and shaping fundamental properties of circadian rhythmicity. However, the timing of when developmental oestrogens modify the timekeeping system is poorly understood. To test the hypothesis that alterations in postnatal oestrogenic signalling organise adult daily activity rhythms, we utilised aromatase knockout mice (ArKO), which lack the enzyme required for oestradiol synthesis. ArKO and wild-type (WT) males and females were administered either oestradiol (E) or oil (OIL) daily for the first 5 postnatal days (p1-5E and p1-5OIL , respectively) because this time encompasses the emergence of clock gene rhythmicity and light responsiveness in the suprachiasmatic nucleus, a bilateral hypothalamic structure regarded as the 'master oscillator'. After sexual maturation, gonadectomy and exogenous oestradiol supplementation, locomotor parameters were assessed. We determined that altered oestrogenic signalling in early life exerts organisational control over the expression of daily and circadian activity rhythms in adult mice. Specifically, p1-5E reduced total wheel running activity in male and female ArKO and female WT mice but had no effect on WT male activity levels. In females, wheel running was consolidated by p1-5E to the early versus late evening, a phenomenon characteristic of male mice. The time of peak activity was advanced by p1-5E in WT and ArKO females but not males. P1-5E shortened the length of the active phase (alpha) in WT males but had no effect on ArKO males or females of either genotypes. Finally, p1-5E altered the magnitude of photic-induced shifts, suggesting that developmental oestrogenic signalling impacts adult circadian functions. In the present study, we further define both a critical period of development of the adult timekeeping system and the role that oestrogenic signalling plays in the expression of daily and

  13. Steroidogenic Factor 1 Differentially Regulates Fetal and Adult Leydig Cell Development in Male Mice1

    PubMed Central

    Karpova, Tatiana; Ravichandiran, Kumarasamy; Insisienmay, Lovella; Rice, Daren; Agbor, Valentine; Heckert, Leslie L.

    2015-01-01

    The nuclear receptor steroidogenic factor 1 (SF-1, AD4BP, NR5A1) is a key regulator of the endocrine axes and is essential for adrenal and gonad development. Partial rescue of Nr5a1−/− mice with an SF-1-expressing transgene caused a hypomorphic phenotype that revealed its roles in Leydig cell development. In contrast to controls, all male rescue mice (Nr5a1−/−;tg+/0) showed varying signs of androgen deficiency, including spermatogenic arrest, cryptorchidism, and poor virilization. Expression of various Leydig cell markers measured by immunohistochemistry, Western blot analysis, and RT-PCR indicated fetal and adult Leydig cell development were differentially impaired. Whereas fetal Leydig cell development was delayed in Nr5a1−/−;tg+/0 embryos, it recovered to control levels by birth. In contrast, Sult1e1, Vcam1, and Hsd3b6 transcript levels in adult rescue testes indicated complete blockage in adult Leydig cell development. In addition, between Postnatal Days 8 and 12, peritubular cells expressing PTCH1, SF-1, and CYP11A1 were observed in control testes but not in rescue testes, indicating SF-1 is needed for either survival or differentiation of adult Leydig cell progenitors. Cultured prepubertal rat peritubular cells also expressed SF-1 and PTCH1, but Cyp11a1 was expressed only after treatment with cAMP and retinoic acid. Together, data show SF-1 is needed for proper development of fetal and adult Leydig cells but with distinct primary functions; in fetal Leydig cells, it regulates differentiation, whereas in adult Leydig cells it regulates progenitor cell formation and/or survival. PMID:26269506

  14. Inducible neuronal inactivation of Sim1 in adult mice causes hyperphagic obesity.

    PubMed

    Tolson, Kristen P; Gemelli, Terry; Meyer, Donna; Yazdani, Umar; Kozlitina, Julia; Zinn, Andrew R

    2014-07-01

    Germline haploinsufficiency of human or mouse Sim1 is associated with hyperphagic obesity. Sim1 encodes a transcription factor required for proper formation of the paraventricular (PVN), supraoptic, and anterior periventricular hypothalamic nuclei. Sim1 expression persists in these neurons in adult mice, raising the question of whether it plays a physiologic role in regulation of energy balance. We previously showed that Sim1 heterozygous mice had normal numbers of PVN neurons that were hyporesponsive to melanocortin 4 receptor agonism and showed reduced oxytocin expression. Furthermore, conditional postnatal neuronal inactivation of Sim1 also caused hyperphagic obesity and decreased hypothalamic oxytocin expression. PVN projections to the hindbrain, where oxytocin is thought to act to modulate satiety, were anatomically intact in both Sim1 heterozygous and conditional knockout mice. These experiments provided evidence that Sim1 functions in energy balance apart from its role in hypothalamic development but did not rule out effects of Sim1 deficiency on postnatal hypothalamic maturation. To address this possibility, we used a tamoxifen-inducible, neural-specific Cre transgene to conditionally inactivate Sim1 in adult mice with mature hypothalamic circuitry. Induced Sim1 inactivation caused increased food and water intake and decreased expression of PVN neuropeptides, especially oxytocin and vasopressin, with no change in energy expenditure. Sim1 expression was not required for survival of PVN neurons. The results corroborate previous evidence that Sim1 acts physiologically as well as developmentally to regulate body weight. Inducible knockout mice provide a system for studying Sim1's physiologic function in energy balance and identifying its relevant transcriptional targets in the hypothalamus.

  15. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice.

    PubMed

    Wang, Hong; Warner-Schmidt, Jennifer; Varela, Santiago; Enikolopov, Grigori; Greengard, Paul; Flajolet, Marc

    2015-08-04

    Adult neurogenesis in the hippocampus subgranular zone is associated with the etiology and treatment efficiency of depression. Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of depression. Glutamate, the major excitatory neurotransmitter, plays a critical role in different aspects of neurogenesis. Of the eight metabotropic glutamate receptors (mGluRs), mGluR5 is the most highly expressed in neural stem cells. We previously identified Norbin as a positive regulator of mGluR5 and showed that its expression promotes neurite outgrowth. In this study, we investigated the role of Norbin in adult neurogenesis and depressive-like behaviors using Norbin-deficient mice. We found that Norbin deletion significantly reduced hippocampal neurogenesis; specifically, the loss of Norbin impaired the proliferation and maturation of newborn neurons without affecting cell-fate specification of neural stem cells/neural progenitor cells (NSCs/NPCs). Norbin is highly expressed in the granular neurons in the dentate gyrus of the hippocampus, but it is undetectable in NSCs/NPCs or immature neurons, suggesting that the effect of Norbin on neurogenesis is likely caused by a nonautonomous niche effect. In support of this hypothesis, we found that the expression of a cell-cell contact gene, Desmoplakin, is greatly reduced in Norbin-deletion mice. Moreover, Norbin-KO mice show an increased immobility in the forced-swim test and the tail-suspension test and reduced sucrose preference compared with wild-type controls. Taken together, these results show that Norbin is a regulator of adult hippocampal neurogenesis and that its deletion causes depressive-like behaviors.

  16. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice

    PubMed Central

    Wang, Hong; Warner-Schmidt, Jennifer; Varela, Santiago; Enikolopov, Grigori; Greengard, Paul; Flajolet, Marc

    2015-01-01

    Adult neurogenesis in the hippocampus subgranular zone is associated with the etiology and treatment efficiency of depression. Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of depression. Glutamate, the major excitatory neurotransmitter, plays a critical role in different aspects of neurogenesis. Of the eight metabotropic glutamate receptors (mGluRs), mGluR5 is the most highly expressed in neural stem cells. We previously identified Norbin as a positive regulator of mGluR5 and showed that its expression promotes neurite outgrowth. In this study, we investigated the role of Norbin in adult neurogenesis and depressive-like behaviors using Norbin-deficient mice. We found that Norbin deletion significantly reduced hippocampal neurogenesis; specifically, the loss of Norbin impaired the proliferation and maturation of newborn neurons without affecting cell-fate specification of neural stem cells/neural progenitor cells (NSCs/NPCs). Norbin is highly expressed in the granular neurons in the dentate gyrus of the hippocampus, but it is undetectable in NSCs/NPCs or immature neurons, suggesting that the effect of Norbin on neurogenesis is likely caused by a nonautonomous niche effect. In support of this hypothesis, we found that the expression of a cell–cell contact gene, Desmoplakin, is greatly reduced in Norbin-deletion mice. Moreover, Norbin-KO mice show an increased immobility in the forced-swim test and the tail-suspension test and reduced sucrose preference compared with wild-type controls. Taken together, these results show that Norbin is a regulator of adult hippocampal neurogenesis and that its deletion causes depressive-like behaviors. PMID:26195764

  17. Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice

    PubMed Central

    Ho, New Fei; Han, Siew Ping; Dawe, Gavin S

    2009-01-01

    Background Cholinergic neuronal dysfunction of the basal forebrain is observed in patients with Alzheimer's disease and dementia, and has been linked to decreased neurogenesis in the hippocampus, a region involved in learning and memory. Running is a robust inducer of adult hippocampal neurogenesis. This study aims to address the effect of running on hippocampal neurogenesis in lesioned mice, where septohippocampal cholinergic neurones have been selectively eliminated in the medial septum and diagonal band of Broca of the basal forebrain by infusion of mu-p75-saporin immunotoxin. Results Running increased the number of newborn cells in the dentate gyrus of the hippocampus in cholinergic denervated mice compared to non-lesioned mice 24 hours after injection of bromodeoxyuridine (BrdU). Although similar levels of surviving cells were present in cholinergic depleted animals and their respective controls four weeks after injection of BrdU, the majority of progenitors that proliferate in response to the initial period of running were not able to survive beyond one month without cholinergic input. Despite this, the running-induced increase in the number of surviving neurones was not affected by cholinergic depletion. Conclusion The lesion paradigm used here models aspects of the cholinergic deficits associated with Alzheimer's Disease and aging. We showed that running still increased the number of newborn cells in the adult hippocampal dentate gyrus in this model of neurodegenerative disease. PMID:19500352

  18. Chronic and progressive Parkinson's disease MPTP model in adult and aged mice.

    PubMed

    Muñoz-Manchado, Ana B; Villadiego, Javier; Romo-Madero, Sonia; Suárez-Luna, Nela; Bermejo-Navas, Alfonso; Rodríguez-Gómez, José A; Garrido-Gil, Pablo; Labandeira-García, José L; Echevarría, Miriam; López-Barneo, José; Toledo-Aral, Juan J

    2016-01-01

    Despite the different animal models of Parkinson's disease developed during the last years, they still present limitations modelling the slow and progressive process of neurodegeneration. Here, we undertook a histological, neurochemical and behavioural analysis of a new chronic parkinsonian mouse model generated by the subcutaneous administration of low doses of MPTP (20 mg/kg, 3 times per week) for 3 months, using both young adult and aged mice. The MPTP-induced nigrostriatal neurodegeneration was progressive and was accompanied by a decrease in striatal dopamine levels and motor impairment. We also demonstrated the characteristic neuroinflammatory changes (microglial activation and astrogliosis) associated with the neurodegenerative process. Aged animals showed both a faster time course of neurodegeneration and an altered neuroinflammatory response. The long-term systemic application of low MPTP doses did not induce any increase in mortality in either young adult or aged mice and better resembles the slow evolution of the neurodegenerative process. This treatment could be useful to model different stages of Parkinson's disease, providing a better understanding of the pathophysiology of the disease and facilitating the testing of both protective and restorative treatments. Here, we show a new chronic and progressive parkinsonian mouse model, in young and aged mice. This model produces a stable degeneration of the dopaminergic nigrostriatal pathway, continuous neuroinflammatory reaction and motor deficits. Aged animals showed a faster neurodegeneration and an altered neuroinflammatory response. This treatment could be useful to model different stages of PD and to test both protective and restorative therapeutic approaches.

  19. Of Mice and Men-Warning: Intact Versus Castrated Adult Male Mice as Xenograft Hosts Are Equivalent to Hypogonadal Versus Abiraterone Treated Aging Human Males, Respectively

    PubMed Central

    Sedelaar, J.P. Michiel; Dalrymple, Susan S.; Isaacs, John T.

    2014-01-01

    BACKGROUND Immune deficient male mice bearing human prostate cancer xenografts are used to evaluate therapeutic response to novel androgen ablation approaches and the results compared to surgical castration based upon assumption that testosterone microenvironment in intact and castrated adult male mice mimics eugonadal and castrated aging adult human males. METHODS To test these assumptions, serum total testosterone (TT) and free testosterone (FT) were determined longitudinally in groups (n > 20) of intact versus castrated adult male nude, NOG, and immune competent C57BL/6 mice. RESULTS In adult male mice, TT and FT varies by 30- to 100-fold within the same animal providing a microenvironment that is only equivalent to hypogonadal, not eugonadal, adult human males (TT is 1.7 ± 1.2 ng/ml [5.8 ± 4.1 nM] in nude and 2.5 ± 1.3 ng/ml [8.7 ± 4.4 nM] in NOG mice versus >4.2 ng/ml [14.7 nM] in eugonadal humans). This was confirmed based upon enhanced growth of androgen dependent human prostate cancer xenografts inoculated into mice supplemented with exogenous testosterone to elevate and chronically maintain serum TT at a level (5 ng/ml [18 nM]) equivalent to a 50-year-old eugonadal human male. In castrated mice, TT and FT range from 2 to 20 pg/ml (7–70 pM) and <0.8 pg/ml (<2.6 pM), respectively, which is equivalent to castrate resistant prostate cancer (CRPC) patients treated with abiraterone. This was confirmed based upon the inability of another CYP17A1 inhibitor, ketoconazole, to inhibit the growth of CRPC xenografts in castrated mice. CONCLUSIONS Adult male mice supplemented with testosterone mimic eugonadal human males, while unsupplemented animals mimic standard androgen ablation and castrated animals mimic abiraterone treated patients. These studies confirm what is claimed in Robert Burns’ poem “To a Mouse” that “The best laid schemes of mice and men/often go awry. PMID:23775398

  20. Suppressor T-cell population induced by Junin virus in adult mice.

    PubMed Central

    Campetella, O E; Barrios, H A; Galassi, N V

    1988-01-01

    Intracerebral (i.c.) Junin virus (JV) infection of adult BALB/c mice is characterized by the absence of morbidity and a low mortality (barely 8-10%). In contrast, the suckling mouse model exhibits almost 100% mortality following central nervous system (CNS) alterations consistent with a delayed-type hypersensitivity (DTH)-like immune response. Besides, JV infection of adult (resistant) mice leads to immunosuppression of DTH to unrelated antigens. Here we present evidence demonstrating that such suppression is mediated by JV-induced cells present in spleen from 24 hr to 24 days post-infection, bearing the Thy-1+, Ly-1+2- phenotype and reactive to an unrelated antigen such as sheep red blood cells (SRBC). No evidence of suppressor factors was found. A relatively low number of total splenic cells (5 x 10(6) cells/mouse) was enough to transfer suppression. Therefore, this cell population may be involved in adult mouse survival to JV infection. PMID:2970429

  1. Osthole Upregulates BDNF to Enhance Adult Hippocampal Neurogenesis in APP/PS1 Transgenic Mice.

    PubMed

    Liu, Hong; Xue, Xinhong; Shi, Huijian; Qi, Lifeng; Gong, Dianrong

    2015-01-01

    Adult hippocampal neurogenesis occurs in the dentate gyrus (DG) of the mouse hippocampus, and plays roles in learning and memory progresses. In amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice, a rodent model of Alzheimer's disease (AD), severe impairment of neurogenesis in the dentate subgranular zone (SGZ) of the DG has been reported. Osthole, an active constituent of Cnidium monnieri (L.) CUSSON, has been reported to exert neuroprotective effects and may promote neural stem cell proliferation. However, whether osthole ameliorates spatial memory deficits and improves hippocampal neurogenesis in APP/PS1 mice remains unknown. In this study we found that osthole (30 mg/kg intraperitoneally (i.p.) once daily) treatment dramatically ameliorated the cognitive impairments by Morris Water Maze test and passive avoidance test, and augmented neurogenesis in the DG of hippocampus in APP/PS1 mice. Furthermore, osthole treatment upregulated expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of the BDNF receptor tyrosine receptor kinase B (TrkB) following increased phosphorylation of cyclic AMP response element-binding protein (CREB), indicating that osthole improves neurogenesis via stimulating BDNF/TrkB/CREB signaling in APP/PS1 transgenic mice.

  2. Effect of extract of Hibiscus on the ultrastructure of the testis in adult mice.

    PubMed

    Mahmoud, Yomna Ibrahim

    2012-07-01

    Hibiscus sabdariffa extract is a popular beverage in many tropical and sub-tropical countries. Although, Hibiscus tea is known for its medicinal effects for thousands of years, scientific evidence of its systemic safety is very limited. The current study aimed to assess the potential adverse effects of H. sabdariffa extract on sperm morphology and testicular ultrastructure of albino mice. Thirty adult male albino mice were divided into three equal groups and were given: (a) distilled water, (b) cold Hibiscus aqueous extract, and (c) boiled Hibiscus aqueous extract. Hibiscus extract was administered orally daily for 4 weeks in a dose of 200 mg/kg body weight/mouse. Twenty-four hours after the last treatment, mice were decapitated and the testes and epididymides were excised and processed for transmission electron microscopy to assess ultrastructural and sperm abnormalities. The results clearly demonstrate that aqueous extracts from dried calyx of H. sabdariffa, either cold or boiled, alter normal sperm morphology and testicular ultrastructure and adversely influence the male reproductive fertility in albino mice. The current data suggest that Hibiscus extract should be consumed with caution, and reasonable estimates of the human risk associated with its consumption should be provided.

  3. Characterization of intrinsic properties of cingulate pyramidal neurons in adult mice after nerve injury

    PubMed Central

    2009-01-01

    The anterior cingulate cortex (ACC) is important for cognitive and sensory functions including memory and chronic pain. Glutamatergic excitatory synaptic transmission undergo long-term potentiation in ACC pyramidal cells after peripheral injury. Less information is available for the possible long-term changes in neuronal action potentials or intrinsic properties. In the present study, we characterized cingulate pyramidal cells in the layer II/III of the ACC in adult mice. We then examined possible long-term changes in intrinsic properties of the ACC pyramidal cells after peripheral nerve injury. In the control mice, we found that there are three major types of pyramidal cells according to their action potential firing pattern: (i) regular spiking (RS) cells (24.7%), intrinsic bursting (IB) cells (30.9%), and intermediate (IM) cells (44.4%). In a state of neuropathic pain, the population distribution (RS: 21.3%; IB: 31.2%; IM: 47.5%) and the single action potential properties of these three groups were indistinguishable from those in control mice. However, for repetitive action potentials, IM cells from neuropathic pain animals showed higher initial firing frequency with no change for the properties of RS and IB neurons from neuropathic pain mice. The present results provide the first evidence that, in addition to synaptic potentiation reported previously, peripheral nerve injury produces long-term plastic changes in the action potentials of cingulate pyramidal neurons in a cell type-specific manner. PMID:20015370

  4. Effects of postnatal alcohol exposure on hippocampal gene expression and learning in adult mice.

    PubMed

    Lee, Dong Hoon; Moon, Jihye; Ryu, Jinhyun; Jeong, Joo Yeon; Roh, Gu Seob; Kim, Hyun Joon; Cho, Gyeong Jae; Choi, Wan Sung; Kang, Sang Soo

    2016-04-28

    Fetal alcohol syndrome (FAS) is a condition resulting from excessive drinking by pregnant women. Symptoms of FAS include abnormal facial features, stunted growth, intellectual deficits and attentional dysfunction. Many studies have investigated FAS, but its underlying mechanisms remain unknown. This study evaluated the relationship between alcohol exposure during the synaptogenesis period in postnatal mice and subsequent cognitive function in adult mice. We delivered two injections, separated by 2 h, of ethanol (3 g/kg, ethanol/saline, 20% v/v) to ICR mice on postnatal day 7. After 10 weeks, we conducted a behavioral test, sacrificed the animals, harvested brain tissue and analyzed hippocampal gene expression using a microarray. In ethanol-treated mice, there was a reduction in brain size and decreased neuronal cell number in the cortex, and also cognitive impairment. cDNA microarray results indicated that 1,548 genes showed a > 2-fold decrease in expression relative to control, whereas 974 genes showed a > 2-fold increase in expression relative to control. Many of these genes were related to signal transduction, synaptogenesis and cell membrane formation, which are highlighted in our findings.

  5. Neonatal Diesel Exhaust Particulate Exposure Does Not Predispose Mice to Adult Cardiac Hypertrophy or Heart Failure

    PubMed Central

    Liu, Yonggang; Weldy, Chad S.; Chin, Michael T.

    2016-01-01

    Background: We have previously reported that in utero and early life exposure to diesel exhaust particulates predisposes mice to adult heart failure, and that in utero exposure alone is sufficient to confer this predisposition. This follow up study addresses whether neonatal exposure alone can also confer this predisposition. Methods: Newborn male C57BL/6 mice were exposed to diesel exhaust (DE) particulates immediately after birth until weaning at 21 days of age, whereupon they were transferred to filtered air (FA) conditions. At the age of 12 weeks, transverse aortic constriction (TAC) was performed followed by weekly echocardiography for three weeks. After the last echocardiogram, mice were euthanized for organ harvest, gravimetry and histology. Results: Neonatal exposure to DE particulates did not increase susceptibility to cardiac hypertrophy or heart failure after TAC when compared to FA exposed controls (ventricular weight/body weight ratio 7.505 vs. 7.517 mg/g, p = Not Significant (NS)). The left ventricular ejection fraction after TAC was similar between groups at one week, two weeks, and three weeks after procedure. Histological analysis showed no difference in the degree of cardiac hypertrophy or fibrosis. Conclusions: Neonatal exposure to DE particulates does not predispose mice to TAC-induced cardiac hypertrophy and heart failure in adulthood, in contrast to previously published results showing susceptibility due to in utero exposure. PMID:27886143

  6. CD1d Expression in Paneth Cells and Rat Exocrine Pancreas Revealed by Novel Monoclonal Antibodies Which Differentially Affect NKT Cell Activation

    PubMed Central

    Monzon-Casanova, Elisa; Steiniger, Birte; Schweigle, Stefanie; Clemen, Holger; Zdzieblo, Daniela; Starick, Lisa; Müller, Ingrid; Wang, Chyung-Ru; Rhost, Sara; Cardell, Susanna; Pyz, Elwira; Herrmann, Thomas

    2010-01-01

    Background CD1d is a nonpolymorphic MHC class I-like molecule which presents nonpeptide ligands, e.g. glycolipids, to NKT cells. These cells are known to have multiple effects on innate and adaptive immune responses and on the development of pathological conditions. In order to analyze CD1d expression and function in the rat, the first rat CD1d-specific monoclonal antibodies (mAbs) were generated. Methodology/Principal Findings Two mAbs, WTH-1 and WTH-2, were generated which bound equally well to cell surface-expressed rat and mouse CD1d. Their non-overlapping epitopes were mapped to the CD1d heavy chain. Flow cytometry and immunohistological analyses revealed a nearly identical degree and pattern of CD1d expression for hematopoieitic cells of both species. Notable is also the detection of CD1d protein in mouse and rat Paneth cells as well as the extremely high CD1d expression in acinar exocrine cells of the rat pancreas and the expression of CD4 on rat marginal zone B cells. Both mAbs blocked α-galactosylceramide recognition by primary rat and mouse NKT cells. Interestingly, the two mAbs differed in their impact on the activation of various autoreactive T cell hybridomas, including the XV19.2 hybridoma whose activation was enhanced by the WTH-1 mAb. Conclusions/Significance The two novel monoclonal antibodies described in this study, allowed the analysis of CD1d expression and CD1d-restricted T cell responses in the rat for the first time. Moreover, they provided new insights into mechanisms of CD1d-restricted antigen recognition. While CD1d expression by hematopoietic cells of mice and rats was extremely similar, CD1d protein was detected at not yet described sites of non-lymphatic tissues such as the rat exocrine pancreas and Paneth cells. The latter is of special relevance given the recently reported defects of Paneth cells in CD1d−/− mice, which resulted in an altered composition of the gut flora. PMID:20927351

  7. Genetic inducible fate mapping in adult mice using tamoxifen-dependent Cre recombinases.

    PubMed

    Feil, Susanne; Krauss, Jana; Thunemann, Martin; Feil, Robert

    2014-01-01

    The Cre/lox site-specific recombination system allows the control of gene activity in space and time in almost any tissue of the mouse. A major technical advance was the development of tamoxifen-dependent Cre recombinases, such as CreER(T2), that can be activated by administration of tamoxifen to the animal. This powerful tool greatly facilitates the study of gene functions and the generation of more realistic animal models of sporadic human diseases. Another important application of tamoxifen-dependent Cre recombinases is genetic inducible fate mapping (GIFM). In GIFM studies, the inducible Cre/lox system is used to genetically label a defined cell population at a selected time by irreversible activation of the expression of a Cre-responsive reporter transgene. Then, marked cells are detected at later time points to determine how the originally labeled progenitors contribute to specific structures and cell types during pre- and postnatal development. GIFM was initially applied during mouse embryogenesis, but is now increasingly used for cell lineage tracing in adult mice under physiological and pathophysiological conditions. Here we describe the design of GIFM experiments in adult mice as exemplified by CreER(T2)-assisted tracing of vascular smooth muscle cells during the development of atherosclerotic lesions. First, we give an overview of reporter transgenes available for genetic cell marking that are expressed from the Rosa26 locus, such as β-galactosidase and fluorescent proteins. Then we present detailed protocols for the generation of experimental mice for GIFM studies, the induction of cell labeling by tamoxifen treatment, and the detection of marked cells in fixed and live tissues. Each section also provides a discussion of limitations and common pitfalls of GIFM experiments. Most of the protocols can be easily adapted to other developmental stages, cell types, Cre recombinases, and reporter transgenes and, thus, can be used as general guidelines for GIFM

  8. Pleiotropic effects of extended blockade of CSF1R signaling in adult mice

    PubMed Central

    Sauter, Kristin A.; Pridans, Clare; Sehgal, Anuj; Tsai, Yi Ting; Bradford, Barry M.; Raza, Sobia; Moffat, Lindsey; Gow, Deborah J.; Beard, Philippa M.; Mabbott, Neil A.; Smith, Lee B.; Hume, David A.

    2014-01-01

    We investigated the role of CSF1R signaling in adult mice using prolonged treatment with anti-CSF1R antibody. Mutation of the CSF1 gene in the op/op mouse produces numerous developmental abnormalities. Mutation of the CSF1R has an even more penetrant phenotype, including perinatal lethality, because of the existence of a second ligand, IL-34. These effects on development provide limited insight into functions of CSF1R signaling in adult homeostasis. The carcass weight and weight of several organs (spleen, kidney, and liver) were reduced in the treated mice, but overall body weight gain was increased. Despite the complete loss of Kupffer cells, there was no effect on liver gene expression. The treatment ablated OCL, increased bone density and trabecular volume, and prevented the decline in bone mass seen in female mice with age. The op/op mouse has a deficiency in pancreatic β cells and in Paneth cells in the gut wall. Only the latter was reproduced by the antibody treatment and was associated with increased goblet cell number but no change in villus architecture. Male op/op mice are infertile as a result of testosterone insufficiency. Anti-CSF1R treatment ablated interstitial macrophages in the testis, but there was no sustained effect on testosterone or LH. The results indicate an ongoing requirement for CSF1R signaling in macrophage and OCL homeostasis but indicate that most effects of CSF1 and CSF1R mutations are due to effects on development. PMID:24652541

  9. α-Aminoadipate Induces Progenitor Cell Properties of Müller Glia in Adult Mice

    PubMed Central

    Takeda, Masumi; Takamiya, Akira; Jiao, Jian-wei; Cho, Kin-Sang; Trevino, Simon G.; Matsuda, Takahiko; Chen, Dong F.

    2008-01-01

    PURPOSE Retinal Müller glia in higher vertebrates have been reported to possess progenitor cell properties and the ability to generate new neurons after injury. This study was conducted to determine the signals that can activate this dormant capacity of Müller glia in adult mice, by studying their behavior during glutamate stimulation. METHODS Various concentrations of glutamate and its analogue α-aminoadipate, which specifically binds Müller glia, were injected subretinally in adult mice. Proliferating retinal cells were labeled by subretinal injection of 5′-bromo-2′-deoxyuridine (BrdU) followed by immunohistochemistry. Müller cell fates were analyzed in retinal sections by using double immunolabeling with primary antibodies against Müller and other retinaspecific cell markers. The effects of glutamate and α-aminoadipate were also determined in purified Müller cell cultures. RESULTS Although high levels of glutamate induce retinal damage, subtoxic levels of glutamate directly stimulate Müller glia to re-enter the cell cycle and induce neurogenesis in vivo and in purified Müller cell cultures. α-Aminoadipate, which selectively target glial cells, also induced expression of progenitor cell markers by Müller cells in vitro or stimulated Müller cell migration to the outer nuclear layer (ONL) and to differentiate into photoreceptors in vivo. CONCLUSIONS Mature Müller glia in adult mice can be induced to dedifferentiate, migrate, and generate new retinal neurons and photoreceptor cells by α-aminoadipate or glutamate signaling. The results of this study suggest a novel potential strategy for treating retinal neurodegeneration, including retinitis pigmentosa and age-related macular degeneration, without transplanting exogenous cells. PMID:18326742

  10. Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice

    PubMed Central

    Salvi, Rachele; Steigleder, Tobias; Schlachetzki, Johannes C. M.; Waldmann, Elisabeth; Schwab, Stefan; Winner, Beate; Winkler, Jürgen; Kohl, Zacharias

    2016-01-01

    While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ), recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g., the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA) receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX), and Ropinirole (ROP), on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2′-deoxyuridine (BrdU) a proliferation paradigm was performed in which two BrdU injections (100 mg/kg) were applied intraperitoneally within 12 h after a 14-days-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS)-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and Neuronal Nuclei (NeuN) 32 days after the last of five BrdU injections (50 mg/kg) applied at the beginning of 14-days DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX) in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active

  11. Nutritional and supranutritional levels of selenate differentially suppress prostate tumor growth in adult but not young nude mice.

    PubMed

    Holmstrom, Alexandra; Wu, Ryan T Y; Zeng, Huawei; Lei, K Y; Cheng, Wen-Hsing

    2012-09-01

    The inhibitory effect of oral methylseleninic acid or methylselenocysteine administration on cancer cell xenograft development in nude mice is well characterized; however, less is known about the efficacy of selenate and age on selenium chemoprevention. In this study, we tested whether selenate and duration on diets would regulate prostate cancer xenograft in nude mice. Thirty-nine homozygous NU/J nude mice were fed a selenium-deficient, Torula yeast basal diet alone (Se-) or supplemented with 0.15 (Se) or 1.0 (Se+) mg selenium/kg (as Na₂SeO₄) for 6 months in Experiment 1 and for 4 weeks in Experiment 2, followed by a 47-day PC-3 prostate cancer cell xenograft on the designated diet. In Experiment 1, the Se- diet enhanced the initial tumor development on days 11-17, whereas the Se+ diet suppressed tumor growth on days 35-47 in adult nude mice. Tumors grown in Se- mice were loosely packed and showed increased necrosis and inflammation as compared to those in Se and Se+ mice. In Experiment 2, dietary selenium did not affect tumor development or histopathology throughout the time course. In both experiments, postmortem plasma selenium concentrations in Se and Se+ mice were comparable and were twofold greater than those in Se- mice. Taken together, dietary selenate at nutritional and supranutritional levels differentially inhibit tumor development in adult, but not young, nude mice engrafted with PC-3 prostate cancer cells.

  12. Sensory deprivation disrupts homeostatic regeneration of newly generated olfactory sensory neurons after injury in adult mice.

    PubMed

    Kikuta, Shu; Sakamoto, Takashi; Nagayama, Shin; Kanaya, Kaori; Kinoshita, Makoto; Kondo, Kenji; Tsunoda, Koichi; Mori, Kensaku; Yamasoba, Tatsuya

    2015-02-11

    Although it is well known that injury induces the generation of a substantial number of new olfactory sensory neurons (OSNs) in the adult olfactory epithelium (OE), it is not well understood whether olfactory sensory input influences the survival and maturation of these injury-induced OSNs in adults. Here, we investigated whether olfactory sensory deprivation affected the dynamic incorporation of newly generated OSNs 3, 7, 14, and 28 d after injury in adult mice. Mice were unilaterally deprived of olfactory sensory input by inserting a silicone tube into their nostrils. Methimazole, an olfactotoxic drug, was also injected intraperitoneally to bilaterally ablate OSNs. The OE was restored to its preinjury condition with new OSNs by day 28. No significant differences in the numbers of olfactory marker protein-positive mature OSNs or apoptotic OSNs were observed between the deprived and nondeprived sides 0-7 d after injury. However, between days 7 and 28, the sensory-deprived side showed markedly fewer OSNs and mature OSNs, but more apoptotic OSNs, than the nondeprived side. Intrinsic functional imaging of the dorsal surface of the olfactory bulb at day 28 revealed that responses to odor stimulation were weaker in the deprived side compared with those in the nondeprived side. Furthermore, prevention of cell death in new neurons 7-14 d after injury promoted the recovery of the OE. These results indicate that, in the adult OE, sensory deprivation disrupts compensatory OSN regeneration after injury and that newly generated OSNs have a critical time window for sensory-input-dependent survival 7-14 d after injury.

  13. Comparative analysis of different oral approaches to treat Vibrio cholerae infection in adult mice.

    PubMed

    Jaiswal, Abhishek; Koley, Hemanta; Mitra, Soma; Saha, Dhira Rani; Sarkar, Banwarilal

    2014-05-01

    In this study, we have established an oral phage cocktail therapy in adult mice model and also performed a comparative analysis between phage cocktail, antibiotic and oral rehydration treatment for orally developed Vibrio cholerae infection. Four groups of mice were orally infected with Vibrio cholerae MAK 757 strain. Phage cocktail and antibiotic treated groups received 1×10(8) plaque forming unit/ml (once a daily) and 40mg/kg (once a daily) as an oral dose respectively for consecutive three days after bacterial infection. In case of oral rehydration group, the solution was supplied after bacterial infection mixed with the drinking water. To evaluate the better and safer approach of treatment, tissue and serum samples were collected. Here, phage cocktail treated mice reduced the log10 numbers of colony per gram by 3log10 (p<0.05); however, ciprofloxacin treated mice reduced the viable numbers up to 5log10 (p<0.05). Whereas, the oral rehydration solution application was not able to reduce the viable bacterial count but the disease progress was much more diminished (p>0.05). Besides, it was evident that antibiotic and phage cocktail treated group had a gradual decrease in both IL-6 and TNF-α level for 3 days (p<0.05) but the scenario was totally opposite in bacterial control and oral hydration treated group. Histological examinations also endorsed the phage cocktail and ciprofloxacin treatment in mice. Although, in this murine model of cholera ciprofloxacin was found to be a better antimicrobial agent, but from the safety and specificity point of view, a better method of application could fill the bridge and advances the phages as a valuable agent in treating Vibrio cholerae infection.

  14. CD1 mediated T cell recognition of glycolipids.

    PubMed

    Zajonc, Dirk M; Kronenberg, Mitchell

    2007-10-01

    Specialized subsets of T lymphocytes can distinguish the carbohydrate portions of microbial and self-glycolipids when they are presented by proteins in the CD1 family of antigen presenting molecules. Recent immunochemical and structural analyses indicate that the chemical composition of the presented carbohydrate, together with its precise orientation above the CD1 binding groove, determines if a particular T cell is activated. More recently, however, it has been shown that the lipid backbone of the glycolipid, buried inside the CD1 protein, also can have an impact on T cell activation. While glycolipid recognition is a relatively new category of T cell specificity, the powerful combination of microbial antigen discovery and structural biochemistry has provided great insight into the mechanism of carbohydrate recognition.

  15. Postnatal Loss of Hap1 Reduces Hippocampal Neurogenesis and Causes Adult Depressive-Like Behavior in Mice

    PubMed Central

    Xiang, Jianxing; Yan, Sen; Li, Shi-Hua; Li, Xiao-Jiang

    2015-01-01

    Depression is a serious mental disorder that affects a person’s mood, thoughts, behavior, physical health, and life in general. Despite our continuous efforts to understand the disease, the etiology of depressive behavior remains perplexing. Recently, aberrant early life or postnatal neurogenesis has been linked to adult depressive behavior; however, genetic evidence for this is still lacking. Here we genetically depleted the expression of huntingtin-associated protein 1 (Hap1) in mice at various ages or in selective brain regions. Depletion of Hap1 in the early postnatal period, but not later life, led to a depressive-like phenotype when the mice reached adulthood. Deletion of Hap1 in adult mice rendered the mice more susceptible to stress-induced depressive-like behavior. Furthermore, early Hap1 depletion impaired postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus and reduced the level of c-kit, a protein expressed in neuroproliferative zones of the rodent brain and that is stabilized by Hap1. Importantly, stereotaxically injected adeno-associated virus (AAV) that directs the expression of c-kit in the hippocampus promoted postnatal hippocampal neurogenesis and ameliorated the depressive-like phenotype in conditional Hap1 KO mice, indicating a link between postnatal-born hippocampal neurons and adult depression. Our results demonstrate critical roles for Hap1 and c-kit in postnatal neurogenesis and adult depressive behavior, and also suggest that genetic variations affecting postnatal neurogenesis may lead to adult depression. PMID:25875952

  16. Lgr5⁺ amacrine cells possess regenerative potential in the retina of adult mice.

    PubMed

    Chen, Mengfei; Tian, Shenghe; Glasgow, Nathan G; Gibson, Gregory; Yang, Xiaoling; Shiber, Christen E; Funderburgh, James; Watkins, Simon; Johnson, Jon W; Schuman, Joel S; Liu, Hongjun

    2015-08-01

    Current knowledge indicates that the adult mammalian retina lacks regenerative capacity. Here, we show that the adult stem cell marker, leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5), is expressed in the retina of adult mice. Lgr5(+) cells are generated at late stages of retinal development and exhibit properties of differentiated amacrine interneurons (amacrine cells). Nevertheless, Lgr5(+) amacrine cells contribute to regeneration of new retinal cells in the adult stage. The generation of new retinal cells, including retinal neurons and Müller glia from Lgr5(+) amacrine cells, begins in early adulthood and continues as the animal ages. Together, these findings suggest that the mammalian retina is not devoid of regeneration as previously thought. It is rather dynamic, and Lgr5(+) amacrine cells function as an endogenous regenerative source. The identification of such cells in the mammalian retina may provide new insights into neuronal regeneration and point to therapeutic opportunities for age-related retinal degenerative diseases.

  17. Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis.

    PubMed

    Garthe, Alexander; Roeder, Ingo; Kempermann, Gerd

    2016-02-01

    We here show that living in a stimulus-rich environment (ENR) improves water maze learning with respect to specific key indicators that in previous loss-of-function experiments have been shown to rely on adult hippocampal neurogenesis. Analyzing the strategies employed by mice to locate the hidden platform in the water maze revealed that ENR facilitated task acquisition by increasing the probability to use effective search strategies. ENR also enhanced the animals' behavioral flexibility, when the escape platform was moved to a new location. Treatment with temozolomide, which is known to reduce adult neurogenesis, abolished the effects of ENR on both acquisition and flexibility, while leaving other aspects of water maze learning untouched. These characteristic effects and interdependencies were not seen in parallel experiments with voluntary wheel running (RUN), a second pro-neurogenic behavioral stimulus. Since the histological assessment of adult neurogenesis is by necessity an end-point measure, the levels of neurogenesis over the course of the experiment can only be inferred and the present study focused on behavioral parameters as analytical endpoints. Although the correlation of physical activity with precursor cell proliferation and of learning and the survival of new neurons is well established, how the specific functional effects described here relate to dynamic changes in the stem cell niche remains to be addressed. Nevertheless, our findings support the hypothesis that adult neurogenesis is a critical mechanism underlying the beneficial effects of leading an active live, rich in experiences.

  18. Assessment of metabolic flexibility of old and adult mice using three noninvasive, indirect calorimetry-based treatments.

    PubMed

    Duivenvoorde, Loes P M; van Schothorst, Evert M; Swarts, Hans J M; Keijer, Jaap

    2015-03-01

    Indirect calorimetry (InCa) can potentially be used to noninvasively assess metabolic and age-related flexibility. To assess the use of InCa for this purpose, we tested the sensitivity and response stability over time of three InCa-based treatments in old versus adult mice. Diurnal patterns of respiratory exchange ratio were followed for 24 hours under standard conditions (Treatment 1), but the results were not stable between test periods. As a challenge, fasted mice received glucose to test switch-effectiveness from fat to glucose oxidation (Treatment 2). No differences between groups were observed, although old mice showed higher adiposity and lower white adipose tissue (WAT) mitochondrial density, indicative of age-impaired metabolic health. Lastly, adaptation to a challenge of oxygen restriction (OxR, 14.5% O2) was assessed as a novel approach (Treatment 3). This treatment stably detected significant differences: old mice did not maintain reduced oxygen consumption under OxR during both test periods, whereas adult mice did. Further biochemical and gene expression analyses showed that OxR affected glucose and lactate homeostasis in liver and WAT of adult mice, supporting the observed differences in oxygen consumption. In conclusion, InCa analysis of the response to OxR in mice is a sensitive and reproducible treatment to noninvasively measure age-impaired metabolic health.

  19. Acute social defeat stress increases the conditioned rewarding effects of cocaine in adult but not in adolescent mice.

    PubMed

    Montagud-Romero, S; Aguilar, M A; Maldonado, C; Manzanedo, C; Miñarro, J; Rodríguez-Arias, M

    2015-08-01

    Stressful experiences modify activity in areas of the brain involved in the rewarding effects of psychostimulants. In the present study we evaluated the influence of acute social defeat (ASD) on the conditioned rewarding effects of cocaine in adolescent (PND 29-32) and adult (PND 50-53) male mice in the conditioned place preference (CPP) paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1mg/kg or 25mg/kg of cocaine. The effects of social defeat on corticosterone levels were also evaluated. Adult mice exposed to ASD showed an increase in the conditioned reinforcing effects of cocaine. Only these mice developed cocaine-induced CPP with the subthreshold dose of cocaine, and they needed a higher number of extinction sessions for the 25mg/kg cocaine-induced CPP to be extinguished. In adolescent mice, on the other hand, ASD reduced the conditioned reinforcing effects of cocaine, since CPP was not produced with the lower dose of cocaine and was extinguished faster when they were conditioned with 25mg/kg. Adult mice exposed to social defeat displayed higher levels of corticosterone than their controls and adolescent mice. Our results confirm that the effect of social defeat stress on the acquisition and reinstatement of the CPP induced by cocaine varies depending on the age at which this stress is experienced.

  20. Glucose transporters GLUT4 and GLUT8 are upregulated after facial nerve axotomy in adult mice

    PubMed Central

    Gómez, Olga; Ballester-Lurbe, Begoña; Mesonero, José E; Terrado, José

    2011-01-01

    Peripheral nerve axotomy in adult mice elicits a complex response that includes increased glucose uptake in regenerating nerve cells. This work analyses the expression of the neuronal glucose transporters GLUT3, GLUT4 and GLUT8 in the facial nucleus of adult mice during the first days after facial nerve axotomy. Our results show that whereas GLUT3 levels do not vary, GLUT4 and GLUT8 immunoreactivity increases in the cell body of the injured motoneurons after the lesion. A sharp increase in GLUT4 immunoreactivity was detected 3 days after the nerve injury and levels remained high on Day 8, but to a lesser extent. GLUT8 also increased the levels but later than GLUT4, as they only rose on Day 8 post-lesion. These results indicate that glucose transport is activated in regenerating motoneurons and that GLUT4 plays a main role in this function. These results also suggest that metabolic defects involving impairment of glucose transporters may be principal components of the neurotoxic mechanisms leading to motoneuron death. PMID:21740425

  1. Perinatal exposure to methoxychlor enhances adult cognitive responses and hippocampal neurogenesis in mice

    PubMed Central

    Martini, Mariangela; Calandreau, Ludovic; Jouhanneau, Mélanie; Mhaouty-Kodja, Sakina; Keller, Matthieu

    2014-01-01

    During perinatal life, sex steroids, such as estradiol, have marked effects on the development and function of the nervous system. Environmental estrogens or xenoestrogens are man-made chemicals, which animal and human population encounter in the environment and which are able to disrupt the functioning of the endocrine system. Scientific interest in the effects of exposure to xenoestrogens has focused more on fertility and reproductive behaviors, while the effects on cognitive behaviors have received less attention. Therefore, the present study explored whether the organochlorine insecticide Methoxychlor (MXC), with known xenoestrogens properties, administered during the perinatal period (from gestational day 11 to postnatal day 8) to pregnant-lactating females, at an environmentally relevant dose (20 µg/kg (body weight)/day), would also affect learning and memory functions depending on the hippocampus of male and female offspring mice in adulthood. When tested in adulthood, MXC perinatal exposure led to an increase in anxiety-like behavior and in short-term spatial working memory in both sexes. Emotional learning was also assessed using a contextual fear paradigm and MXC treated male and female mice showed an enhanced freezing behavior compared to controls. These results were correlated with an increased survival of adult generated cells in the adult hippocampus. In conclusion, our results show that perinatal exposure to an environmentally relevant dose of MXC has an organizational effect on hippocampus-dependent memory and emotional behaviors. PMID:24982620

  2. Neurologic function during developmental and adult stages in Dab1(scm) (scrambler) mutant mice.

    PubMed

    Jacquelin, C; Strazielle, C; Lalonde, R

    2012-01-01

    Homozygous Dab1(scm) mouse mutants with cell ectopias in cerebellar cortex, hippocampus, and neocortex were compared to non-ataxic controls on the SHIRPA primary screening battery on postnatal days 8, 15, and 22, as well as in the adult period. Dab1(scm) mutants were distinguished from non-ataxic controls as early as postnatal day 8 based on body tremor, gait anomalies, and body weight. On postnatal day 15, motor coordination deficits were evident on horizontal bar and inclined or vertical grid tests in association with a weaker grip strength. Likewise, mutants were distinguished from controls on drop righting and hindpaw clasping tests. Further differences were detected on postnatal day 22 in the form of fewer visual placing, touch escape, trunk curl, freezing, and vocalization responses, as well as squares traversed in the open-field. Evaluation at the adult age demonstrated similar impairments, indicative of permanent motor alterations. Neuronal metabolic activity was estimated by cytochrome oxidase histochemistry on cerebellar sections. Cerebellar cortical layers and efferent deep nuclei of Dab1(scm) mice appeared hypometabolic relative to non-ataxic mice despite normal metabolism in both regular and ectopic Purkinje cells.

  3. Physical Exercise Preserves Adult Visual Plasticity in Mice and Restores it after a Stroke in the Somatosensory Cortex

    PubMed Central

    Kalogeraki, Evgenia; Pielecka-Fortuna, Justyna; Hüppe, Janika M.; Löwel, Siegrid

    2016-01-01

    The primary visual cortex (V1) is widely used to study brain plasticity, which is not only crucial for normal brain function, such as learning and memory, but also for recovery after brain injuries such as stroke. In standard cage (SC) raised mice, experience-dependent ocular dominance (OD) plasticity in V1 declines with age and is compromised by a lesion in adjacent and distant cortical regions. In contrast, mice raised in an enriched environment (EE), exhibit lifelong OD plasticity and are protected from losing OD plasticity after a stroke-lesion in the somatosensory cortex. Since SC mice with an access to a running wheel (RW) displayed preserved OD plasticity during aging, we investigated whether physical exercise might also provide a plasticity promoting effect after a cortical stroke. To this end, we tested if adult RW-raised mice preserved OD plasticity after stroke and also if short-term running after stroke restored OD plasticity to SC mice. Indeed, unlike mice without a RW, adult RW mice continued to show OD plasticity even after stroke, and a 2 weeks RW experience after stroke already restored lost OD plasticity. Additionally, the experience-enabled increase of the spatial frequency and contrast threshold of the optomotor reflex of the open eye, normally lost after a stroke, was restored in both groups of RW mice. Our data suggest that physical exercise alone can not only preserve visual plasticity into old age, but also restore it after a cortical stroke. PMID:27708575

  4. Physical Exercise Preserves Adult Visual Plasticity in Mice and Restores it after a Stroke in the Somatosensory Cortex.

    PubMed

    Kalogeraki, Evgenia; Pielecka-Fortuna, Justyna; Hüppe, Janika M; Löwel, Siegrid

    2016-01-01

    The primary visual cortex (V1) is widely used to study brain plasticity, which is not only crucial for normal brain function, such as learning and memory, but also for recovery after brain injuries such as stroke. In standard cage (SC) raised mice, experience-dependent ocular dominance (OD) plasticity in V1 declines with age and is compromised by a lesion in adjacent and distant cortical regions. In contrast, mice raised in an enriched environment (EE), exhibit lifelong OD plasticity and are protected from losing OD plasticity after a stroke-lesion in the somatosensory cortex. Since SC mice with an access to a running wheel (RW) displayed preserved OD plasticity during aging, we investigated whether physical exercise might also provide a plasticity promoting effect after a cortical stroke. To this end, we tested if adult RW-raised mice preserved OD plasticity after stroke and also if short-term running after stroke restored OD plasticity to SC mice. Indeed, unlike mice without a RW, adult RW mice continued to show OD plasticity even after stroke, and a 2 weeks RW experience after stroke already restored lost OD plasticity. Additionally, the experience-enabled increase of the spatial frequency and contrast threshold of the optomotor reflex of the open eye, normally lost after a stroke, was restored in both groups of RW mice. Our data suggest that physical exercise alone can not only preserve visual plasticity into old age, but also restore it after a cortical stroke.

  5. An animal model of adult T-cell leukemia: humanized mice with HTLV-1-specific immunity.

    PubMed

    Tezuka, Kenta; Xun, Runze; Tei, Mami; Ueno, Takaharu; Tanaka, Masakazu; Takenouchi, Norihiro; Fujisawa, Jun-ichi

    2014-01-16

    Human T-cell leukemia virus type 1 (HTLV-1) is causally associated with adult T-cell leukemia (ATL), an aggressive T-cell malignancy with a poor prognosis. To elucidate ATL pathogenesis in vivo, a variety of animal models have been established; however, the mechanisms driving this disorder remain poorly understood due to deficiencies in each of these animal models. Here, we report a novel HTLV-1-infected humanized mouse model generated by intra-bone marrow injection of human CD133(+) stem cells into NOD/Shi-scid/IL-2Rγc null (NOG) mice (IBMI-huNOG mice). Upon infection, the number of CD4(+) human T cells in the periphery increased rapidly, and atypical lymphocytes with lobulated nuclei resembling ATL-specific flower cells were observed 4 to 5 months after infection. Proliferation was seen in both CD25(-) and CD25(+) CD4 T cells with identical proviral integration sites; however, a limited number of CD25(+)-infected T-cell clones eventually dominated, indicating an association between clonal selection of infected T cells and expression of CD25. Additionally, HTLV-1-specific adaptive immune responses were induced in infected mice and might be involved in the control of HTLV-1-infected cells. Thus, the HTLV-1-infected IBMI-huNOG mouse model successfully recapitulated the development of ATL and may serve as an important tool for investigating in vivo mechanisms of ATL leukemogenesis and evaluating anti-ATL drug and vaccine candidates.

  6. Evaluation of neurotoxicity of repeated dermal application of chlorpyrifos on hippocampus of adult mice.

    PubMed

    Mitra, Nilesh K; Siong, How Hee; Nadarajah, Vishna D

    2008-01-01

    Dermal absorption of chlorpyrifos, an organophosphate insecticide is important because of its use in agriculture and control of household pests. The objectives of this study are to investigate firstly, the biochemical changes in the blood and secondly, histomorphometric changes in the hippocampus of adult mice following dermal application of chlorpyrifos in sub-toxic doses. Male Swiss albino mice (60 days) were segregated into one control and two treated groups (n=10). Chlorpyrifos, diluted with xylene, was applied in doses of 1/2 of LD(50) (E1) and 1/5 of LD(50) (E2) over the tail of mice of the two treated groups, 6 hours daily for 3 weeks. AChE levels in the serum and brain were estimated using a spectrophotometric method (Amplex Red reagent). Coronal serial sections were stained with 0.2 % thionin in acetate buffer and pyramidal neurons of Cornu Ammonis of hippocampus were counted at 400x magnification using Image Pro Express software. At the end of 3 weeks, body weights were reduced significantly in E1 group. Serum AChE concentrations were reduced by 97 % in E1 and 74 % in E2 groups compared to controls. The neurons of CA 3 and CA 1 in the hippocampus showed evidences of morphological damage in both treated groups. Furthermore, the neuronal count was significantly reduced in CA 3 layer of hippocampus in E1 group.

  7. Behavioural Effects of Adult Vitamin D Deficiency in BALB/c Mice Are not Associated with Proliferation or Survival of Neurons in the Adult Hippocampus

    PubMed Central

    Groves, Natalie J.; Bradford, DanaKai; Sullivan, Robert K. P.; Conn, Kyna-Anne; Aljelaify, Rasha Fahad; McGrath, John J.; Burne, Thomas H. J.

    2016-01-01

    Epidemiological studies have shown that up to one third of adults have insufficient levels of vitamin D and there is an association between low vitamin D concentrations and adverse brain outcomes, such as depression. Vitamin D has been shown to be involved in processes associated with neurogenesis during development. Therefore, the aim of this study was to test the hypothesis that adult vitamin D (AVD) deficiency in BALB/c mice was associated with (a) adult hippocampal neurogenesis at baseline, b) following 6 weeks of voluntary wheel running and (c) a depressive-like phenotype on the forced swim test (FST), which may be linked to alterations in hippocampal neurogenesis. We assessed proliferation and survival of adult born hippocampal neurons by counting the number of cells positive for Ki67 and doublecortin (DCX), and incorporation of 5-Bromo-2’-Deoxyuridine (BrdU) within newly born mature neurons using immunohistochemistry. There were no significant effects of diet on number of Ki67+, DCX+ or BrdU+ cells in the dentate gyrus. All mice showed significantly increased number of Ki67+ cells and BrdU incorporation, and decreased immobility time in the FST, after voluntary wheel running. A significant correlation was found in control mice between immobility time in the FST and level of hippocampal neurogenesis, however, no such correlation was found for AVD-deficient mice. We conclude that AVD deficiency was not associated with impaired proliferation or survival of adult born neurons in BALB/c mice and that the impact on rodent behaviour may not be due to altered neurogenesis per se, but to altered function of new hippocampal neurons or processes independent of adult neurogenesis. PMID:27043014

  8. Behavioural Effects of Adult Vitamin D Deficiency in BALB/c Mice Are not Associated with Proliferation or Survival of Neurons in the Adult Hippocampus.

    PubMed

    Groves, Natalie J; Bradford, DanaKai; Sullivan, Robert K P; Conn, Kyna-Anne; Aljelaify, Rasha Fahad; McGrath, John J; Burne, Thomas H J

    2016-01-01

    Epidemiological studies have shown that up to one third of adults have insufficient levels of vitamin D and there is an association between low vitamin D concentrations and adverse brain outcomes, such as depression. Vitamin D has been shown to be involved in processes associated with neurogenesis during development. Therefore, the aim of this study was to test the hypothesis that adult vitamin D (AVD) deficiency in BALB/c mice was associated with (a) adult hippocampal neurogenesis at baseline, b) following 6 weeks of voluntary wheel running and (c) a depressive-like phenotype on the forced swim test (FST), which may be linked to alterations in hippocampal neurogenesis. We assessed proliferation and survival of adult born hippocampal neurons by counting the number of cells positive for Ki67 and doublecortin (DCX), and incorporation of 5-Bromo-2'-Deoxyuridine (BrdU) within newly born mature neurons using immunohistochemistry. There were no significant effects of diet on number of Ki67+, DCX+ or BrdU+ cells in the dentate gyrus. All mice showed significantly increased number of Ki67+ cells and BrdU incorporation, and decreased immobility time in the FST, after voluntary wheel running. A significant correlation was found in control mice between immobility time in the FST and level of hippocampal neurogenesis, however, no such correlation was found for AVD-deficient mice. We conclude that AVD deficiency was not associated with impaired proliferation or survival of adult born neurons in BALB/c mice and that the impact on rodent behaviour may not be due to altered neurogenesis per se, but to altered function of new hippocampal neurons or processes independent of adult neurogenesis.

  9. Antagonistic effect of Lepidium meyenii (red maca) on prostatic hyperplasia in adult mice.

    PubMed

    Gonzales, G F; Gasco, M; Malheiros-Pereira, A; Gonzales-Castañeda, C

    2008-06-01

    The plants from the Lepidium gender have demonstrated to have effect on the size of the prostate. Lepidium meyenii (Maca) is a Peruvian plant that grows exclusively over 4000 m above sea level. The present study was designed to determine the effect of red maca (RM) in the prostate hyperplasia induced with testosterone enanthate (TE) in adult mice. Prostate hyperplasia was induced by administering TE, and then these animals (n = 6, each group) were treated with RM or Finasteride (positive control) for 21 days. There was an additional group without prostate hyperplasia (vehicle). Mice were killed on days 7, 14 and 21 after treatment with RM. Testosterone and oestradiol levels were measured on the last day of treatment. Prostatic stroma, epithelium and acini were measured histologically. RM reduced prostate weight at 21 days of treatment. Weights of seminal vesicles, testis and epididymis were not affected by RM treatment. The reduction in prostate size by RM was 1.59 times. Histological analysis showed that TE increased 2-fold the acinar area, effect prevented in the groups receiving TE + RM for 14 (P < 0.05) and 21 (P < 0.05) days and the group receiving TE + Finasteride for 21 days (P < 0.05). TE increased prostatic stroma area and this effect was prevented by treatment with RM since 7 days of treatment or Finasteride. The reduction in prostatic stroma area by RM was 1.42 times. RM has an anti-hyperplastic effect on the prostate of adult mice when hyperplasia was induced with TE acting first at prostatic stromal level.

  10. Rhinovirus exacerbates house-dust-mite induced lung disease in adult mice.

    PubMed

    Phan, Jennifer A; Kicic, Anthony; Berry, Luke J; Fernandes, Lynette B; Zosky, Graeme R; Sly, Peter D; Larcombe, Alexander N

    2014-01-01

    Human rhinovirus is a key viral trigger for asthma exacerbations. To date, murine studies investigating rhinovirus-induced exacerbation of allergic airways disease have employed systemic sensitisation/intranasal challenge with ovalbumin. In this study, we combined human-rhinovirus infection with a clinically relevant mouse model of aero-allergen exposure using house-dust-mite in an attempt to more accurately understand the links between human-rhinovirus infection and exacerbations of asthma. Adult BALB/c mice were intranasally exposed to low-dose house-dust-mite (or vehicle) daily for 10 days. On day 9, mice were inoculated with human-rhinovirus-1B (or UV-inactivated human-rhinovirus-1B). Forty-eight hours after inoculation, we assessed bronchoalveolar cellular inflammation, levels of relevant cytokines/serum antibodies, lung function and responsiveness/sensitivity to methacholine. House-dust-mite exposure did not result in a classical TH2-driven response, but was more representative of noneosinophilic asthma. However, there were significant effects of house-dust-mite exposure on most of the parameters measured including increased cellular inflammation (primarily macrophages and neutrophils), increased total IgE and house-dust-mite-specific IgG1 and increased responsiveness/sensitivity to methacholine. There were limited effects of human-rhinovirus-1B infection alone, and the combination of the two insults resulted in additive increases in neutrophil levels and lung parenchymal responses to methacholine (tissue elastance). We conclude that acute rhinovirus infection exacerbates house-dust-mite-induced lung disease in adult mice. The similarity of our results using the naturally occurring allergen house-dust-mite, to previous studies using ovalbumin, suggests that the exacerbation of allergic airways disease by rhinovirus infection could act via multiple or conserved mechanisms.

  11. Proteomic and transcriptomic study of brain microvessels in neonatal and adult mice

    PubMed Central

    Porte, Baptiste; Chatelain, Clémence; Hardouin, Julie; Derambure, Céline; Zerdoumi, Yasmine; Hauchecorne, Michèle; Dupré, Nicolas; Bekri, Soumeya; Gonzalez, Bruno; Marret, Stéphane; Cosette, Pascal

    2017-01-01

    Infants born before 29 weeks gestation incur a major risk of preterm encephalopathy and subependymal/intracerebral/intraventricular haemorrhage. In mice, an ontogenic window of haemorrhage risk was recorded up to 5 days after birth in serpine1 knock-out animals. Using proteome and transcriptome approaches in mouse forebrain microvessels, we previously described the remodelling of extracellular matrix and integrins likely strengthening the vascular wall between postnatal day 5 (P5) and P10. Haemorrhage is the ultimate outcome of vessel damage (i.e., during ischaemia), although discreet vessel insults may be involved in the aetiology of preterm encephalopathy. In this study, we examined proteins identified by mass spectrometry and segregating in gene ontology pathways in forebrain microvessels in P5, P10, and adult wild type mice. In parallel, comparative transcript levels were obtained using RNA hybridization microarrays and enriched biological pathways were extracted from genes exhibiting at least a two-fold change in expression. Five major biological functions were observed in those genes detected both as proteins and mRNA expression undergoing at least a two-fold change in expression in one or more age comparisons: energy metabolism, protein metabolism, antioxidant function, ion exchanges, and transport. Adult microvessels exhibited the highest protein and mRNA expression levels for a majority of genes. Energy metabolism–enriched gene ontology pathways pointed to the preferential occurrence of glycolysis in P5 microvessels cells versus P10 and adult preparations enriched in aerobic oxidative enzymes. Age-dependent levels of RNA coding transport proteins at the plasma membrane and mitochondria strengthened our findings based on protein data. The data suggest that immature microvessels have fewer energy supply alternatives to glycolysis than mature structures. In the context of high energy demand, this constraint might account for vascular damage and maintenance

  12. Delayed and transient increase of adult hippocampal neurogenesis by physical exercise in DBA/2 mice.

    PubMed

    Overall, Rupert W; Walker, Tara L; Leiter, Odette; Lenke, Sina; Ruhwald, Susann; Kempermann, Gerd

    2013-01-01

    This study builds on the findings that physical activity, such as wheel running in mice, enhances cell proliferation and neurogenesis in the adult hippocampus of the common mouse strain C57BL/6, and that the baseline level of neurogenesis varies by strain, being considerably lower in DBA/2. Because C57BL/6 and DBA/2 are important as the parental strains of the BXD recombinant inbred cross which allows the detection of genetic loci regulating phenotypes such as adult neurogenesis, we performed the current study to investigate the gene x environment interactions regulating neurogenesis. At equal distances and times run DBA/2J mice lacked the acute increase in precursor cell proliferation known from C57BL/6. In DBA/2J proliferation even negatively correlated with the distance run. This was neither due to a stress response (to running itself or single housing) nor differences in estrous cycle. DBA/2 animals exhibited a delayed and weaker pro-neurogenic response with a significant increase in numbers of proliferating cells first detectable after more than a week of wheel running. The proliferative response to running was transient in both strains, the effect being undetectable by 6 weeks. There was also a small transient increase in the production of new neurons in DBA/2J, although these extra cells did not survive. These findings indicate that the comparison between C57BL/6 and DBA/2, and by extension the BXD genetic reference population derived from these strains, should provide a powerful tool for uncovering the complex network of modifier genes affecting the activity-dependent regulation of adult hippocampal neurogenesis. More generally, our findings also describe how the external physical environment interacts with the internal genetic environment to produce different responses to the same behavioral stimuli.

  13. Cortical hypoplasia and ventriculomegaly of p73-deficient mice: Developmental and adult analysis.

    PubMed

    Medina-Bolívar, Carolina; González-Arnay, Emilio; Talos, Flaminia; González-Gómez, Miriam; Moll, Ute M; Meyer, Gundela

    2014-08-01

    Trp73, a member of the p53 gene family, plays a crucial role in neural development. We describe two main phenotypic variants of p73 deficiency in the brain, a severe one characterized by massive apoptosis in the cortex leading to early postnatal death and a milder, non-/low-apoptosis one in which 50% of pups may reach adulthood using an intensive-care breeding protocol. Both variants display the core triad of p73 deficiency: cortical hypoplasia, hippocampal malformations, and ventriculomegaly. We studied the development of the neocortex in p73 KO mice from early embryonic life into advanced age (25 months). Already at E14.5, the incipient cortical plate of the p73 KO brains showed a reduced width. Examination of adult neocortex revealed a generalized, nonprogressive reduction by 10-20%. Area-specific architectonic landmarks and lamination were preserved in all cortical areas. The surviving adult animals had moderate ventricular distension, whereas pups of the early lethal phenotypic variant showed severe ventriculomegaly. Ependymal cells of wild-type ventricles strongly express p73 and are particularly vulnerable to p73 deficiency. Ependymal denudation by apoptosis and reduction of ependymal cilia were already evident in young mice, with complete absence of cilia in older animals. Loss of p73 function in the ependyma may thus be one determining factor for chronic hydrocephalus, which leads to atrophy of subcortical structures (striatum, septum, amygdala). p73 Is thus involved in a variety of CNS activities ranging from embryonic regulation of brain size to the control of cerebrospinal fluid homeostasis in the adult brain via maintenance of the ependyma.

  14. Adolescent but not adult ethanol binge drinking modulates cocaine withdrawal symptoms in mice

    PubMed Central

    Aguilar, Maria A.; Giménez-Gómez, Pablo; Miñarro, José; Rodríguez-Arias, Marta

    2017-01-01

    Background Ethanol (EtOH) binge drinking is an increasingly common behavior among teenagers that induces long-lasting neurobehavioral alterations in adulthood. An early history of EtOH abuse during adolescence is highly correlated with cocaine addiction in adulthood. Abstinence of cocaine abuse can cause psychiatric symptoms, such as anxiety, psychosis, depression, and cognitive impairments. This study assessed the consequences of adolescent exposure to EtOH on the behavioral alterations promoted by cocaine withdrawal in adulthood. Methods We pretreated juvenile (34–47 days old) or adult (68–81 days old) mice with EtOH (1.25 g/kg) following a binge-drinking pattern. Then, after a three-week period without drug delivery, they were subjected to a chronic cocaine treatment in adulthood and tested under cocaine withdrawal by the ensuing paradigms: open field, elevated plus maze, prepulse inhibition, tail suspension test, and object recognition. Another set of mice were treated with the same EtOH binge-drinking procedure during adolescence and were tested immediately afterwards under the same behavioral paradigms. Results Adolescent EtOH pretreatment undermined the anxiogenic effects observed after cocaine abstinence, reduced prepulse inhibition, and increased immobility scores in the tail suspension test following cocaine withdrawal. Moreover, the memory deficits evoked by these substances when given separately were enhanced in cocaine-withdrawn mice exposed to EtOH during adolescence. EtOH binge drinking during adolescence also induced anxiety, depressive symptoms, and memory impairments when measured immediately afterwards. In contrast, neither EtOH nor cocaine alone or in combination altered any of these behaviors when given in adulthood. Conclusions EtOH binge drinking induces short- and long-term behavioral alterations and modulates cocaine withdrawal symptoms when given in adolescent mice. PMID:28291777

  15. Adolescent mice are less sensitive to the effects of acute nicotine on context pre-exposure than adults.

    PubMed

    Kutlu, Munir Gunes; Braak, David C; Tumolo, Jessica M; Gould, Thomas J

    2016-07-01

    Adolescence is a critical developmental period associated with both increased vulnerability to substance abuse and maturation of certain brain regions important for learning and memory such as the hippocampus. In this study, we employed a hippocampus-dependent learning context pre-exposure facilitation effect (CPFE) paradigm in order to test the effects of acute nicotine on contextual processing during adolescence (post-natal day (PND) 38) and adulthood (PND 53). In Experiment 1, adolescent or adult C57BL6/J mice received either saline or one of three nicotine doses (0.09, 0.18, and 0.36mg/kg) prior to contextual pre-exposure and testing. Our results demonstrated that both adolescent and adult mice showed CPFE in the saline groups. However, adolescent mice only showed acute nicotine enhancement of CPFE with the highest nicotine dose whereas adult mice showed the enhancing effects of acute nicotine with all three doses. In Experiment 2, to determine if the lack of nicotine's effects on CPFE shown by adolescent mice is specific to the age when they are tested, mice were either given contextual pre-exposure during adolescence or adulthood and received immediate shock and testing during adulthood after a 15day delay. We found that both adolescent and adult mice showed CPFE in the saline groups when tested during adulthood. However, like Experiment 1, mice that received contextual pre-exposure during adolescence did not show acute nicotine enhancement except at the highest dose (0.36mg/kg) whereas both low (0.09mg/kg) and high (0.36mg/kg) doses enhanced CPFE in adult mice. Finally, we showed that the enhanced freezing response found with 0.36mg/kg nicotine in the 15-day experiment may be a result of decreased locomotor activity as mice that received this dose of nicotine traveled shorter distances in an open field paradigm. Overall, our results indicate that while adolescent mice showed normal contextual processing when tested both during adolescence and adulthood, they

  16. Taurine release modified by GABAergic agents in hippocampal slices from adult and developing mice.

    PubMed

    Saransaari, P; Oja, S S

    2000-01-01

    In order to characterize the possible regulation of taurine release by GABAergic terminals, the effects of several agonists and antagonists of GABA receptors on the basal and K+-stimulated release of [3H]taurine were investigated in hippocampal slices from adult (3-month-old) and developing (7-day-old) mice using a superfusion system. Taurine release was concentration-dependently potentiated by GABA, which effect was reduced by phaclofen, saclofen and (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at both ages, suggesting regulation by both GABA(B) and GABA(C) receptors. The involvement of GABA(A) receptors could not be excluded since the antagonist bicuculline was able to affect both basal and K+-evoked taurine release. Furthermore, several GABA(B) receptor effectors were able to inhibit K+-stimulated taurine release in the adults, while the GABA(C) receptor agonists trans-4-aminocrotonic acid (TACA) and cis-4-aminocrotonic acid (CACA) potentiated this release. The potentiation of taurine release by agents acting on the three types of GABA receptors in both adult and developing hippocampus further indicates the involvement of transporters operating in an outward direction. This inference is corroborated by the moderate but significant inhibition of taurine uptake by the same compounds.

  17. Social Isolation Stress Induces Anxious-Depressive-Like Behavior and Alterations of Neuroplasticity-Related Genes in Adult Male Mice

    PubMed Central

    Ieraci, Alessandro; Mallei, Alessandra; Popoli, Maurizio

    2016-01-01

    Stress is a major risk factor in the onset of several neuropsychiatric disorders including anxiety and depression. Although several studies have shown that social isolation stress during postweaning period induces behavioral and brain molecular changes, the effects of social isolation on behavior during adulthood have been less characterized. Aim of this work was to investigate the relationship between the behavioral alterations and brain molecular changes induced by chronic social isolation stress in adult male mice. Plasma corticosterone levels and adrenal glands weight were also analyzed. Socially isolated (SI) mice showed higher locomotor activity, spent less time in the open field center, and displayed higher immobility time in the tail suspension test compared to group-housed (GH) mice. SI mice exhibited reduced plasma corticosterone levels and reduced difference between right and left adrenal glands. SI showed lower mRNA levels of the BDNF-7 splice variant, c-Fos, Arc, and Egr-1 in both hippocampus and prefrontal cortex compared to GH mice. Finally, SI mice exhibited selectively reduced mGluR1 and mGluR2 levels in the prefrontal cortex. Altogether, these results suggest that anxious- and depressive-like behavior induced by social isolation stress correlates with reduction of several neuroplasticity-related genes in the hippocampus and prefrontal cortex of adult male mice. PMID:26881124

  18. Social Isolation Stress Induces Anxious-Depressive-Like Behavior and Alterations of Neuroplasticity-Related Genes in Adult Male Mice.

    PubMed

    Ieraci, Alessandro; Mallei, Alessandra; Popoli, Maurizio

    2016-01-01

    Stress is a major risk factor in the onset of several neuropsychiatric disorders including anxiety and depression. Although several studies have shown that social isolation stress during postweaning period induces behavioral and brain molecular changes, the effects of social isolation on behavior during adulthood have been less characterized. Aim of this work was to investigate the relationship between the behavioral alterations and brain molecular changes induced by chronic social isolation stress in adult male mice. Plasma corticosterone levels and adrenal glands weight were also analyzed. Socially isolated (SI) mice showed higher locomotor activity, spent less time in the open field center, and displayed higher immobility time in the tail suspension test compared to group-housed (GH) mice. SI mice exhibited reduced plasma corticosterone levels and reduced difference between right and left adrenal glands. SI showed lower mRNA levels of the BDNF-7 splice variant, c-Fos, Arc, and Egr-1 in both hippocampus and prefrontal cortex compared to GH mice. Finally, SI mice exhibited selectively reduced mGluR1 and mGluR2 levels in the prefrontal cortex. Altogether, these results suggest that anxious- and depressive-like behavior induced by social isolation stress correlates with reduction of several neuroplasticity-related genes in the hippocampus and prefrontal cortex of adult male mice.

  19. Adolescent Chronic Unpredictable Stress Exposure Is a Sensitive Window for Long-Term Changes in Adult Behavior in Mice.

    PubMed

    Yohn, Nicole L; Blendy, Julie A

    2017-02-01

    Adolescence is a time period in development when the brain undergoes substantial remodeling in response to the environment. To determine whether a stressful experience during adolescence affects adult behavior, we exposed adolescent male and female C57BL/6J mice to chronic unpredictable stress (CUS) for 12 days starting at postnatal day 28 (PND28). We also exposed adult male and female mice to CUS for 12 days beginning at PND70 to determine whether adolescence is a sensitive time period when stress can have long-lasting effects on behavior. Regardless of when mice were exposed to stress, they were all tested exactly 30 days later in the marble burying task, elevated zero maze, acoustic startle response, and forced swim test. Adolescent stress exposure increased anxiety-like behaviors in adult male and female mice and decreased acoustic startle response in a sex-dependent manner. However, adult stress exposure did not change anxiety or response to an acoustic tone in adult male or female mice as compared with nonstressed animals. Of interest, increased depression-like behavior in the forced swim test was observed in all mice, regardless of when the stress occurred. Gene expression analysis showed significant upregulation of corticotropin releasing factor receptor 2 (CrfR2) in the amygdala of males subjected to CUS during adolescence, but not in males that experienced CUS during adulthood. In contrast, females, regardless of when they were exposed to CUS, were not affected. These data support clinical evidence suggesting that early-life stress may predispose individuals to increased anxiety and depression later in life.Neuropsychopharmacology advance online publication, 1 February 2017; doi:10.1038/npp.2017.11.

  20. Self administration of oxycodone alters synaptic plasticity gene expression in the hippocampus differentially in male adolescent and adult mice.

    PubMed

    Zhang, Y; Brownstein, A J; Buonora, M; Niikura, K; Ho, A; Correa da Rosa, J; Kreek, M J; Ott, J

    2015-01-29

    Abuse and addiction to prescription opioids such as oxycodone (a short-acting Mu opioid receptor (MOP-r) agonist) in adolescence is a pressing public health issue. We have previously shown differences in oxycodone self-administration behaviors between adolescent and adult C57BL/6J mice and expression of striatal neurotransmitter receptor genes, in areas involved in reward. In this study, we aimed to determine whether oxycodone self-administration differentially affects genes regulating synaptic plasticity in the hippocampus of adolescent compared to adult mice, since the hippocampus may be involved in learning aspects associated with chronic drug self administration. Hippocampus was isolated for mRNA analysis from mice that had self administered oxycodone (0.25 mg/kg/infusion) 2h/day for 14 consecutive days or from yoked saline controls. Gene expression was analyzed with real-time polymerase chain reaction (PCR) using a commercially available "synaptic plasticity" PCR array containing 84 genes. We found that adolescent and adult control mice significantly differed in the expression of several genes in the absence of oxycodone exposure, including those coding for mitogen-activated protein kinase, calcium/calmodulin-dependent protein kinase II gamma subunit, glutamate receptor, ionotropic AMPA2 and metabotropic 5. Chronic oxycodone self administration increased proviral integration site 1 (Pim1) and thymoma viral proto-oncogene 1 mRNA levels compared to controls in both age groups. Both Pim1 and cadherin 2 mRNAs showed a significant combined effect of Drug Condition and Age × Drug Condition. Furthermore, the mRNA levels of both cadherin 2 and cAMP response element modulators showed an experiment-wise significant difference between oxycodone and saline control in adult but not in adolescent mice. Overall, this study demonstrates for the first time that chronic oxycodone self-administration differentially alters synaptic plasticity gene expression in the hippocampus

  1. Evolution of mammalian CD1: marsupial CD1 is not orthologous to the eutherian isoforms and is a pseudogene in the opossum Monodelphis domestica.

    PubMed

    Baker, Michelle L; Miller, Robert D

    2007-05-01

    CD1 is a member of the major histocompatibility complex (MHC) class I family of proteins that present lipid antigens to T cells and natural killer (NK) T cells; it is found in both eutherian mammals and birds. In eutherians, duplication of the CD1 gene has resulted in multiple isoforms. A marsupial CD1 homologue was identified in a set of expressed sequence tags from the thymus of the bandicoot Isoodon macrourus. Southern blot and genomic sequence analyses revealed that CD1 is a single copy gene in both I. macrourus and a distantly related marsupial, the opossum Monodelphis domestica, which is currently the only marsupial species for which a whole genome sequence is available. We found that the opossum CD1 is located in a genomic region with a high degree of conserved synteny to the chromosomal regions containing human and mouse CD1. A phylogenetic analysis of mammalian CD1 revealed that marsupial CD1 is not orthologous to the eutherian CD1 isoforms, consistent with the latter having emerged by duplication after the separation of marsupials and eutherians 170-180 million years ago. The I. macrourus CD1 gene is actively transcribed and appears to encode a functional protein. In contrast, transcription of the M. domestica CD1 was not detected in any tissue and the predicted CD1 gene sequence contains a number of deletions that appear to render the locus a pseudogene.

  2. Molecular mechanisms mediating a deficit in recall of fear extinction in adult mice exposed to cocaine in utero.

    PubMed

    Kabir, Zeeba D; Katzman, Aaron C; Kosofsky, Barry E

    2013-01-01

    Prenatal cocaine exposure has been shown to alter cognitive processes of exposed individuals, presumed to be a result of long-lasting molecular alterations in the brain. In adult prenatal cocaine exposed (PCOC) mice we have identified a deficit in recall of fear extinction, a behavior that is dependent on the medial prefrontal cortex (mPFC) and the hippocampus. While we observed no change in the constitutive expression of brain derived neurotrophic factor (BDNF) protein and mRNA in the mPFC and hippocampus of adult PCOC mice, we observed blunted BDNF signaling in the mPFC of adult PCOC mice after fear extinction compared to the control animals. Specifically, during the consolidation phase of the extinction memory, we observed a decrease in BDNF protein and it's phospho-TrkB receptor expression. Interestingly, at this same time point there was a significant increase in total Bdnf mRNA levels in the mPFC of PCOC mice as compared with controls. In the Bdnf gene, we identified decreased constitutive binding of the transcription factors, MeCP2 and P-CREB at the promoters of Bdnf exons I and IV in the mPFC of PCOC mice, that unlike control mice remained unchanged when measured during the behavior. Finally, bilateral infusion of recombinant BDNF protein into the infralimbic subdivision of the mPFC during the consolidation phase of the extinction memory rescued the behavioral deficit in PCOC mice. In conclusion, these findings extend our knowledge of the neurobiologic impact of prenatal cocaine exposure on the mPFC of mice, which may lead to improved clinical recognition and treatment of exposed individuals.

  3. CD1-Restricted T Cells at the Crossroad of Innate and Adaptive Immunity

    PubMed Central

    Pereira, Catia S.

    2016-01-01

    Lipid-specific T cells comprise a group of T cells that recognize lipids bound to the MHC class I-like CD1 molecules. There are four isoforms of CD1 that are expressed at the surface of antigen presenting cells and therefore capable of presenting lipid antigens: CD1a, CD1b, CD1c, and CD1d. Each one of these isoforms has distinct structural features and cellular localizations, which promotes binding to a broad range of different types of lipids. Lipid antigens originate from either self-tissues or foreign sources, such as bacteria, fungus, or plants and their recognition by CD1-restricted T cells has important implications in infection but also in cancer and autoimmunity. In this review, we describe the characteristics of CD1 molecules and CD1-restricted lipid-specific T cells, highlighting the innate-like and adaptive-like features of different CD1-restricted T cell subtypes. PMID:28070524

  4. MECP2 regulates cortical plasticity underlying a learned behaviour in adult female mice

    PubMed Central

    Krishnan, Keerthi; Lau, Billy Y. B.; Ewall, Gabrielle; Huang, Z. Josh; Shea, Stephen D.

    2017-01-01

    Neurodevelopmental disorders are marked by inappropriate synaptic connectivity early in life, but how disruption of experience-dependent plasticity contributes to cognitive and behavioural decline in adulthood is unclear. Here we show that pup gathering behaviour and associated auditory cortical plasticity are impaired in female Mecp2het mice, a model of Rett syndrome. In response to learned maternal experience, Mecp2het females exhibited transient changes to cortical inhibitory networks typically associated with limited plasticity. Averting these changes in Mecp2het through genetic or pharmacological manipulations targeting the GABAergic network restored gathering behaviour. We propose that pup gathering learning triggers a transient epoch of inhibitory plasticity in auditory cortex that is dysregulated in Mecp2het. In this window of heightened sensitivity to sensory and social cues, Mecp2 mutations suppress adult plasticity independently from their effects on early development. PMID:28098153

  5. Serotonin signaling in the brain of adult female mice is required for sexual preference

    PubMed Central

    Zhang, Shasha; Liu, Yan; Rao, Yi

    2013-01-01

    A role for serotonin in male sexual preference was recently uncovered by our finding that male mutant mice lacking serotonin have lost sexual preference. Here we show that female mouse mutants lacking either central serotonergic neurons or serotonin prefer female over male genital odors when given a choice, and displayed increased female–female mounting when presented either with a choice of a male and a female target or only with a female target. Pharmacological manipulations and genetic rescue experiments showed that serotonin is required in adults. Behavioral changes caused by deficient serotonergic signaling were not due to changes in plasma concentrations of sex hormones. We demonstrate that a genetic manipulation reverses sexual preference without involving sex hormones. Our results indicate that serotonin controls sexual preference. PMID:23716677

  6. Unipotent, Atoh1+ progenitors maintain the Merkel cell population in embryonic and adult mice.

    PubMed

    Wright, Margaret C; Reed-Geaghan, Erin G; Bolock, Alexa M; Fujiyama, Tomoyuki; Hoshino, Mikio; Maricich, Stephen M

    2015-02-02

    Resident progenitor cells in mammalian skin generate new cells as a part of tissue homeostasis. We sought to identify the progenitors of Merkel cells, a unique skin cell type that plays critical roles in mechanosensation. We found that some Atoh1-expressing cells in the hairy skin and whisker follicles are mitotically active at embryonic and postnatal ages. Genetic fate-mapping revealed that these Atoh1-expressing cells give rise solely to Merkel cells. Furthermore, selective ablation of Atoh1(+) skin cells in adult mice led to a permanent reduction in Merkel cell numbers, demonstrating that other stem cell populations are incapable of producing Merkel cells. These data identify a novel, unipotent progenitor population in the skin that gives rise to Merkel cells both during development and adulthood.

  7. Transspinal direct current stimulation modulates migration and proliferation of adult newly born spinal cells in mice.

    PubMed

    Samaddar, Sreyashi; Vazquez, Kizzy; Ponkia, Dipen; Toruno, Pedro; Sahbani, Karim; Begum, Sultana; Abouelela, Ahmed; Mekhael, Wagdy; Ahmed, Zaghloul

    2017-02-01

    Direct current electrical fields have been shown to be a major factor in the regulation of cell proliferation, differentiation, migration, and survival, as well as in the maturation of dividing cells during development. During adulthood, spinal cord cells are continuously produced in both animals and humans, and they hold great potential for neural restoration following spinal cord injury. While the effects of direct current electrical fields on adult-born spinal cells cultured ex vivo have recently been reported, the effects of direct current electrical fields on adult-born spinal cells in vivo have not been characterized. Here, we provide convincing findings that a therapeutic form of transspinal direct current stimulation (tsDCS) affects the migration and proliferation of adult-born spinal cells in mice. Specifically, cathodal tsDCS attracted the adult-born spinal cells, while anodal tsDCS repulsed them. In addition, both tsDCS polarities caused a significant increase in cell number. Regarding the potential mechanisms involved, both cathodal and anodal tsDCS caused significant increases in expression of brain-derived neurotrophic factor, while expression of nerve growth factor increased and decreased, respectively. In the spinal cord, both anodal and cathodal tsDCS increased blood flow. Since blood flow and angiogenesis are associated with the proliferation of neural stem cells, increased blood flow may represent a major factor in the modulation of newly born spinal cells by tsDCS. Consequently, we propose that the method and novel findings presented in the current study have the potential to facilitate cellular, molecular, and/or bioengineering strategies to repair injured spinal cords.NEW & NOTEWORTHY Our results indicate that transspinal direct current stimulation (tsDCS) affects the migratory pattern and proliferation of adult newly born spinal cells, a cell population which has been implicated in learning and memory. In addition, our results suggest a

  8. Autologous Transplantation of Adult Mice Spermatogonial Stem Cells into Gamma Irradiated Testes

    PubMed Central

    Koruji, Morteza; Movahedin, Mansoureh; Mowla, Seyed Javad; Gourabi, Hamid; Pour-Beiranvand, Shahram; Jabbari Arfaee, Ali

    2012-01-01

    Objective: We evaluated structural and functional changes of fresh and frozen-thawed adult mouse spermatogonial stem cells following auto-transplantation into gamma-irradiated testes. Materials and Methods: In this experimental research, the right testes from adult mice (n=25) were collected, then Sertoli and spermatogonial cells were isolated using two-step enzymatic digestion, lectin immobilization and differential plating. Three weeks after cultivation, the Bromodeoxyuridine (BrdU)-labeled spermatogonial cells were transplanted, via rete testis, into the other testis of the same mouse, which had been irradiated with 14Gy. The mice were transplanted with: fresh cells (control 1), fresh cells co-cultured with Sertoli cells (control 2), the frozen-thawed cells (experimental 1) and frozen-thawed cells co-cultured with Sertoli cells (experimental 2). The morphological changes between different transplanted testes groups were compared in 8 weeks after transplantation. The statistical significance between mean values was determined by Kruskal Wallis and one-way analysis of variance in efficiency of transplantation. Results: The statistical analysis revealed significant increases in the mean percentage of testis weight and normal seminiferous tubules following spermatogonial stem cells transplantation in the recipient'fs testes. The normal seminiferous tubules percentage in the co-culture system with fresh cells and frozen-thawed groups were more than those in non-transplanted and fresh cell transplanted groups (p≤0.001). Conclusion: Our results demonstrated that spermatogonial stem cells in the colonies could result sperm production in the recipient’s testes after autologous transplantation. PMID:23507977

  9. Implanting Glass Spinal Cord Windows in Adult Mice with Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Fenrich, Keith K.; Weber, Pascal; Rougon, Genevieve; Debarbieux, Franck

    2013-01-01

    Experimental autoimmune encephalomyelitis (EAE) in adult rodents is the standard experimental model for studying autonomic demyelinating diseases such as multiple sclerosis. Here we present a low-cost and reproducible glass window implantation protocol that is suitable for intravital microscopy and studying the dynamics of spinal cord cytoarchitecture with subcellular resolution in live adult mice with EAE. Briefly, we surgically expose the vertebrae T12-L2 and construct a chamber around the exposed vertebrae using a combination of cyanoacrylate and dental cement. A laminectomy is performed from T13 to L1, and a thin layer of transparent silicone elastomer is applied to the dorsal surface of the exposed spinal cord. A modified glass cover slip is implanted over the exposed spinal cord taking care that the glass does not directly contact the spinal cord. To reduce the infiltration of inflammatory cells between the window and spinal cord, anti-inflammatory treatment is administered every 2 days (as recommended by ethics committee) for the first 10 days after implantation. EAE is induced only 2-3 weeks after the cessation of anti-inflammatory treatment. Using this approach we successfully induced EAE in 87% of animals with implanted windows and, using Thy1-CFP-23 mice (blue axons in dorsal spinal cord), quantified axonal loss throughout EAE progression. Taken together, this protocol may be useful for studying the recruitment of various cell populations as well as their interaction dynamics, with subcellular resolution and for extended periods of time. This intravital imaging modality represents a valuable tool for developing therapeutic strategies to treat autoimmune demyelinating diseases such as EAE. PMID:24378439

  10. Abnormal Cerebellar Cytoarchitecture and Impaired Inhibitory Signaling in Adult Mice Lacking Testicular Orphan Nuclear Receptor 4

    PubMed Central

    Chen, Yei-Tsung; Collins, Loretta L.; Uno, Hideo; Chou, Samuel M.; Meshul, Charles K.; Chang, Shu-Shi; Chang, Chawnshang

    2007-01-01

    Since Testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological functions remain largely unknown. In this study, the TR4 knockout (TR4−/−) mouse model was used to investigate the role of TR4 in the adult cerebellum. Behaviorally, these null mice exhibit unsteady gait, as well as involuntary postural and kinetic movements, indicating a disturbance of cerebellar function. In the TR4−/− brain, cerebellar restricted hypoplasia is severe and cerebellar vermal lobules VI and VII are underdeveloped, while no structural alterations in the cerebral cortex are observed. Histological analysis of the TR4−/− cerebellar cortex reveals reductions in granule cell density, as well as a decreased number of parallel fiber boutons that are enlarged in size. Further analyses reveal that the levels of GABA and GAD are decreased in both Purkinje cells and interneurons of the TR4−/− cerebellum, suggesting that the inhibitory circuits signaling within and from the cerebellum may be perturbed. In addition, in the TR4−/− cerebellum, immunoreactivity of GluR2/3 was reduced in Purkinje cells, but increased in the deep cerebellar nuclei. Together, these results suggest that the behavioral phenotype of TR4−/− mice may result from disrupted inhibitory pathways in the cerebellum. No progressive atrophy was observed at various adult stages in the TR4−/− brain, therefore the disturbances most likely originate from a failure to establish proper connections between principal neurons in the cerebellum during development. PMID:17706948

  11. Dynamics of cell proliferation in the adult dentate gyrus of two inbred strains of mice

    NASA Technical Reports Server (NTRS)

    Hayes, N. L.; Nowakowski, R. S.

    2002-01-01

    The output potential of proliferating populations in either the developing or the adult nervous system is critically dependent on the length of the cell cycle (T(c)) and the size of the proliferating population. We developed a new approach for analyzing the cell cycle, the 'Saturate and Survive Method' (SSM), that also reveals the dynamic behaviors in the proliferative population and estimates of the size of the proliferating population. We used this method to analyze the proliferating population of the adult dentate gyrus in 60 day old mice of two inbred strains, C57BL/6J and BALB/cByJ. The results show that the number of cells labeled by exposure to BUdR changes dramatically with time as a function of the number of proliferating cells in the population, the length of the S-phase, cell division, the length of the cell cycle, dilution of the S-phase label, and cell death. The major difference between C57BL/6J and BALB/cByJ mice is the size of the proliferating population, which differs by a factor of two; the lengths of the cell cycle and the S-phase and the probability that a newly produced cell will die within the first 10 days do not differ in these two strains. This indicates that genetic regulation of the size of the proliferating population is independent of the genetic regulation of cell death among those newly produced cells. The dynamic changes in the number of labeled cells as revealed by the SSM protocol also indicate that neither single nor repeated daily injections of BUdR accurately measure 'proliferation.'.

  12. Implanting glass spinal cord windows in adult mice with experimental autoimmune encephalomyelitis.

    PubMed

    Fenrich, Keith K; Weber, Pascal; Rougon, Genevieve; Debarbieux, Franck

    2013-12-21

    Experimental autoimmune encephalomyelitis (EAE) in adult rodents is the standard experimental model for studying autonomic demyelinating diseases such as multiple sclerosis. Here we present a low-cost and reproducible glass window implantation protocol that is suitable for intravital microscopy and studying the dynamics of spinal cord cytoarchitecture with subcellular resolution in live adult mice with EAE. Briefly, we surgically expose the vertebrae T12-L2 and construct a chamber around the exposed vertebrae using a combination of cyanoacrylate and dental cement. A laminectomy is performed from T13 to L1, and a thin layer of transparent silicone elastomer is applied to the dorsal surface of the exposed spinal cord. A modified glass cover slip is implanted over the exposed spinal cord taking care that the glass does not directly contact the spinal cord. To reduce the infiltration of inflammatory cells between the window and spinal cord, anti-inflammatory treatment is administered every 2 days (as recommended by ethics committee) for the first 10 days after implantation. EAE is induced only 2-3 weeks after the cessation of anti-inflammatory treatment. Using this approach we successfully induced EAE in 87% of animals with implanted windows and, using Thy1-CFP-23 mice (blue axons in dorsal spinal cord), quantified axonal loss throughout EAE progression. Taken together, this protocol may be useful for studying the recruitment of various cell populations as well as their interaction dynamics, with subcellular resolution and for extended periods of time. This intravital imaging modality represents a valuable tool for developing therapeutic strategies to treat autoimmune demyelinating diseases such as EAE.

  13. Dopaminergic Modulation of Excitatory Transmission in the Anterior Cingulate Cortex of Adult Mice.

    PubMed

    Darvish-Ghane, Soroush; Yamanaka, Manabu; Zhuo, Min

    2016-01-01

    Dopamine (DA) possesses potent neuromodulatory properties in the central nervous system. In the anterior cingulate cortex, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) are key ion channels in mediating nerve injury induced long-term potentiation (LTP) and chronic pain phenotype. In the present study, we reported the effects of DA on glutamate mediated excitatory post-synaptic currents (EPSCs) in pyramidal neurons of layer II/III of the ACC in adult mice. Bath application of DA (50 μM) caused a significant, rapid and reversible inhibition of evoked EPSCs (eEPSC). This inhibitory effect is dose-related and was absent in lower concentration of DA (5 μM). Furthermore, selective postsynaptic application of GDP-β-S (1.6 mM) in the internal solution completely abolished the inhibitory effects of DA (50 μM). We also investigated modulation of spontaneous EPSCs (sEPSCs) and TTX sensitive, miniature EPSCs (mEPSCs) by DA. Our results indicated mixed effects of potentiation and inhibition of frequency and amplitude for sEPSCs and mEPSCs. Furthermore, high doses of SCH23390 (100 μM) and sulpiride (100 μM) revealed that, inhibition of eEPSCs is mediated by postsynaptic D2-receptors (D2R). Our finding posits a pre- and postsynaptic mode of pyramidal neuron EPSC modulation in mice ACC by DA.

  14. Efficiency of AUY922 in mice with adult T-cell leukemia/lymphoma

    PubMed Central

    ISHIKAWA, CHIE; SENBA, MASACHIKA; MORI, NAOKI

    2016-01-01

    Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATLL is associated with poor prognosis mainly due to resistance to chemotherapy, which highlights the requirement for alternative therapies. The chaperone heat shock protein (HSP) 90 assist proteins involved in the onset and progression of ATLL. In the present study, the efficacy of a second generation HSP90 inhibitor termed AUY922 was investigated in ATLL. In vitro, AUY922 induced marked inhibition of cell viability in the HTLV-1-infected T-cell lines HUT-102 and MT-4. In immunodeficient mice bearing HUT-102 xenotransplants, AUY922 markedly retarded tumor growth, compared with the control group. Apoptosis was evident in hematoxylin and eosin stained- and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-labeled tissue sections from AUY922-treated mice. In addition, AUY922 significantly reduced the serum levels of the surrogate tumor markers soluble interleukin-2 receptor and soluble cluster of differentiation 30. Overall, the present results demonstrate that AUY922 has potent anti-ATLL activity, thus providing a rationale for continuing the clinical development of HSP90 inhibitors in clinical trials for the treatment of patients with ATLL. PMID:27347156

  15. Maternal separation facilitates extinction of social fear in adult male mice.

    PubMed

    Zoicas, Iulia; Neumann, Inga D

    2016-01-15

    Early life stress, such as child abuse or neglect, is a risk factor for the development of psychopathologies characterized by abnormal social and emotional behaviors. In rodents, long-lasting changes in stress coping and emotional behavior can be induced by separating pups from their mother. We used maternal separation (MS; 3h daily on postnatal days 1-14) to test whether early life stress alters acquisition and extinction of social fear in adult male mice as studied in a specific model of social fear, i.e., in the social fear conditioning paradigm. We show that MS facilitated extinction of social fear without altering acquisition or expression of social fear. This facilitatory effect of MS on social fear extinction was not due to improved social learning and memory abilities or to increased social interest, as MS rather impaired social memory in the social discrimination test and did not alter social preference in the social preference-avoidance test. In contrast, MS did not alter acquisition and extinction of non-social, cued fear, or non-social memory as assessed in the object discrimination test and non-social anxiety as assessed in the elevated plus-maze. These results suggest that a social stress like MS in early life may improve coping with and recovery from a traumatic social experience in adulthood in mice.

  16. Prenatal cocaine alters later responses to morphine in adult male mice.

    PubMed

    Estelles, Josefina; Rodríguez-Arias, Marta; Maldonado, Concepción; Manzanedo, Carmen; Aguilar, María A; Miñarro, José

    2006-08-30

    Mice prenatally exposed to cocaine (25 mg/kg), physiological saline or non-treated during the last 6 days of pregnancy were evaluated as adults for the rewarding properties of 2 mg/kg of morphine, using the conditioned place preference (CPP) procedure. Likewise, isolated animals underwent a social interaction test with conspecifics after receiving the same morphine dose. Unlike control or animals pre-treated with saline, subjects prenatally treated with cocaine did not develop CPP with this dose of morphine. Only cocaine-exposed animals showed increased threat, avoidance and fleeing during the social encounter. No differences in motor effects of morphine were observed. Analysis of monoamines revealed effects of housing conditions, isolated animals having fewer DOPAC but higher levels of HVA than those grouped, but in both groups there was a decrease in DOPAC in cocaine- and saline-treated mice. Prenatal cocaine exposure decreases the response to the rewarding properties of drugs in mature offspring. They also implicate cocaine consumption during pregnancy could affect the response of offspring to take other drugs of abuse.

  17. Effect of Selenium on Neurotoxicity in Adult Male Mice Exposed to Formaldehyde

    PubMed Central

    Mohammadi, Shabnam

    2014-01-01

    Background: Formaldehyde is used in medicine and industry, and it is known to have detrimental effects on various systems including the nervous system, by increasing oxidative stress. However, data are scarce related to substances that can protect against the neurotoxicity induced by formaldehyde. Therefore, this study was designed to assess the protective effects of selenium against the toxic effect of this compound. Methods: A total of 48 adult male mice were divided randomly into six groups, i.e., (1) control, (2) treated with formaldehyde, (3) treated with formaldehyde plus 0.1 mg/kg selenium, (4) treated with formaldehyde plus 0.2 mg/kg selenium, (5) treated with formaldehyde plus 0.4 mg/kg selenium, and (6) treated with formaldehyde plus 0.8 mg/kg selenium. At the end of 14 days, the cerebellums were removed for histological evaluation. Morphological changes were examined using Image J software. The data were analyzed using SPSS software version 20.0 and analysis of variance (ANOVA). Results: Formaldehyde caused a reduction in the numbers and sizes of Purkinje cells and granular cells; in addition, the thickness of the granular layer was thinner than that in the control mice (P < 0.05). Treatment with 0.1 mg/kg selenium resulted in an increase in the number of Purkinje cells as well as the area of the gray matter compared to those of the control mice. Conclusion: Formaldehyde-induced neuronal damage was prevented by the administration of 0.1 mg/kg selenium, hence this treatment shows therapeutic potential for the treatment of neurotoxicity PMID:25763172

  18. Postanesthetic Effects of Isoflurane on Behavioral Phenotypes of Adult Male C57BL/6J Mice

    PubMed Central

    Asakura, Ayako; Kobayashi, Ayako; Takase, Kenkichi; Goto, Takahisa

    2015-01-01

    Isoflurane was previously the major clinical anesthetic agent but is now mainly used for veterinary anesthesia. Studies have reported widespread sites of action of isoflurane, suggesting a wide array of side effects besides sedation. In the present study, we phenotyped isoflurane-treated mice to investigate the postanesthetic behavioral effects of isoflurane. We applied comprehensive behavioral test batteries comprising sensory test battery, motor test battery, anxiety test battery, depression test battery, sociability test battery, attention test battery, and learning test battery, which were started 7 days after anesthesia with 1.8% isoflurane. In addition to the control group, we included a yoked control group that was exposed to the same stress of handling as the isoflurane-treated animals before being anesthetized. Our comprehensive behavioral test batteries revealed impaired latent inhibition in the isoflurane-treated group, but the concentration of residual isoflurane in the brain was presumably negligible. The yoked control group and isoflurane-treated group exhibited higher anxiety in the elevated plus-maze test and impaired learning function in the cued fear conditioning test. No influences were observed in sensory functions, motor functions, antidepressant behaviors, and social behaviors. A number of papers have reported an effect of isoflurane on animal behaviors, but no systematic investigation has been performed. To the best of our knowledge, this study is the first to systematically investigate the general health, neurological reflexes, sensory functions, motor functions, and higher behavioral functions of mice exposed to isoflurane as adults. Our results suggest that the postanesthetic effect of isoflurane causes attention deficit in mice. Therefore, isoflurane must be used with great care in the clinical setting and veterinary anesthesia. PMID:25806517

  19. Cellular origins of cold-induced brown adipocytes in adult mice.

    PubMed

    Lee, Yun-Hee; Petkova, Anelia P; Konkar, Anish A; Granneman, James G

    2015-01-01

    This work investigated how cold stress induces the appearance of brown adipocytes (BAs) in brown and white adipose tissues (WATs) of adult mice. In interscapular brown adipose tissue (iBAT), cold exposure increased proliferation of endothelial cells and interstitial cells expressing platelet-derived growth factor receptor, α polypeptide (PDGFRα) by 3- to 4-fold. Surprisingly, brown adipogenesis and angiogenesis were largely restricted to the dorsal edge of iBAT. Although cold stress did not increase proliferation in inguinal white adipose tissue (ingWAT), the percentage of BAs, defined as multilocular adipocytes that express uncoupling protein 1, rose from undetectable to 30% of total adipocytes. To trace the origins of cold-induced BAs, we genetically tagged PDGFRα(+) cells and adipocytes prior to cold exposure, using Pdgfra-Cre recombinase estrogen receptor T2 fusion protein (CreER(T2)) and adiponectin-CreER(T2), respectively. In iBAT, cold stress triggered the proliferation and differentiation of PDGFRα(+) cells into BAs. In contrast, all newly observed BAs in ingWAT (5207 out of 5207) were derived from unilocular adipocytes tagged by adiponectin-CreER(T2)-mediated recombination. Surgical denervation of iBAT reduced cold-induced brown adipogenesis by >85%, whereas infusion of norepinephrine (NE) mimicked the effects of cold in warm-adapted mice. NE-induced de novo brown adipogenesis in iBAT was eliminated in mice lacking β1-adrenergic receptors. These observations identify a novel tissue niche for brown adipogenesis in iBAT and further define depot-specific mechanisms of BA recruitment.

  20. Adult but Not Aged C57BL/6 Male Mice Are Capable of Using Geometry for Orientation

    ERIC Educational Resources Information Center

    Schachner, Melitta; Morellini, Fabio; Fellini, Laetitia

    2006-01-01

    Geometry, e.g., the shape of the environment, can be used by numerous animal species to orientate, but data concerning the mouse are lacking. We addressed the question of whether mice are capable of using geometry for navigating. To test whether aging could affect searching strategies, we compared adult (3- to 5-mo old) and aged (20- to 21-mo old)…

  1. Galanin synaptic input to gonadotropin-releasing hormone perikarya in juvenile and adult female mice: implications for sexual maturity.

    PubMed

    Rajendren, G; Li, X

    2001-11-26

    Changes in connectivity of the gonadotropin-releasing hormone (GnRH) neuronal system are believed to occur during the transition from juvenile to adulthood in females. Experiments were designed to investigate whether there is any difference in the number of galanin inputs to GnRH cells located in the organum vasculosum of lamina terminalis-rostral preoptic area (OVLT-rPOA) between juvenile (2 weeks old) and adult (10 weeks old) female mice. Triple label immunofluorescence staining of brain sections for galanin, GnRH and the presynaptic vesicle marker synaptophysin coupled with confocal microscopy was employed to identify galanin synapses to GnRH perikarya. The number of galanin synapses to GnRH cells and the proportion of GnRH cells with galanin input were significantly higher in adults than in juvenile mice. In adult mice, the proportions of GnRH cells with 0, 1, 2, 3, 4, 5 or 6 galanin synapses/cell were comparable to each other whereas in the juveniles the vast majority of them received no galanin synaptic input. A greater number of galanin synapses in adult as compared with juvenile female mice suggests a functional role for galanin in the maturation of the GnRH system.

  2. MECHANISTIC DESCRIPTION OF DOSE-DEPENDENT URINARY ELIMINATION OF PBDE-47 IN ADULT MICE USING A PHYSIOLOGICAL BASED PHARMACOKINETIC MODEL

    EPA Science Inventory

    Abstract Polybrominated diphenyl ethers (PBDEs) are used as additive flame-retardants. In North America, scientists have noted continuing increases in human body burdens. Our laboratory has previously described urinary elimination of parent compound in adult mice for at l...

  3. Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CDl Mice.

    EPA Science Inventory

    Inorganic arsenic exposure is carcinogenic in humans and rodents. When pregnant mice are exposed to inorganic arsenic in the drinking water their offspring, when adults, develop tumors and proliferative lesions at several sites, such as lung, liver, adrenal, uterus, ovary and ovi...

  4. REPRODUCTIVE EFFECTS OF THE WATER DISINFECTANT BYPRODUCT BROMOCHLOROACETIC ACID (BCA) IN ADULT AND JUVENILE MALE C57BL/6 MICE

    EPA Science Inventory

    REPRODUCTIVE EFFECTS OF THE WATER DISINFECTANT BYPRODUCT BROMOCHLOROACETIC ACID (BCA) IN ADULT AND JUVENILE MALE C57BL/6 MICE.
    JC Rockett, JC Luft, JB Garges and DJ Dix. Reproductive Toxicology Division, USEPA, RTP, NC, USA.
    Sponsor: G Klinefelter
    The development of wate...

  5. Antigen-Induced Increases in Pulmonary Mast Cell Progenitor Numbers Depend on IL-9 and CD1d-Restricted NKT Cells1

    PubMed Central

    Jones, Tatiana G.; Hallgren, Jenny; Humbles, Alison; Burwell, Timothy; Finkelman, Fred D.; Alcaide, Pilar; Austen, K. Frank; Gurish, Michael F.

    2009-01-01

    Pulmonary mast cell progenitor (MCp) numbers increase dramatically in sensitized and aerosolized Ag-challenged mice. This increase depends on CD4+ T cells, as no MCp increase occurs in the lungs of sensitized wild-type (WT) mice after mAb depletion of CD4+ but not CD8+ cells before aerosol Ag challenge. Neither the genetic absence of IL-4, IL-4Rα chain, STAT-6, IFN-γ, or IL-12p40 nor mAb blockade of IFN-γ, IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17A, IL-12p40, or IL-12p40Rβ1 before Ag challenge in WT mice reduces the pulmonary MCp increase. However, sensitized and Ag-challenged IL-9-deficient mice and sensitized WT mice given mAb to IL-9 just before Ag challenge show significant reductions in elicited lung MCp/106 mononuclear cells of 47 and 66%, respectively. CD1d-deficient mice and WT mice receiving anti-CD1d before Ag challenge also show significant reductions of 65 and 59%, respectively, in elicited lung MCp/106 mononuclear cells, revealing an additional requirement for MCp recruitment. However, in Jα18-deficient mice, which lack only type 1 or invariant NKT cells, the increase in the numbers of lung MCp with Ag challenge was intact, indicating that their recruitment must be mediated by type 2 NKT cells. Furthermore, anti-CD1d treatment of IL-9-deficient mice or anti-IL-9 treatment of CD1d-deficient mice does not further reduce the significant partial impairment of MCp recruitment occurring with a single deficiency. These findings implicate type 2 NKT cells and IL-9 as central regulators that function in the same pathway mediating the Ag-induced increase in numbers of pulmonary MCp. PMID:19783672

  6. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality.

    PubMed

    Chae, T; Kwon, Y T; Bronson, R; Dikkes, P; Li, E; Tsai, L H

    1997-01-01

    The adult mammalian cortex is characterized by a distinct laminar structure generated through a well-defined pattern of neuronal migration. Successively generated neurons are layered in an "inside-out" manner to produce six cortical laminae. We demonstrate here that p35, the neuronal-specific activator of cyclin-dependent kinase 5, plays a key role in proper neuronal migration. Mice lacking p35, and thus p35/cdk5 kinase activity, display severe cortical lamination defects and suffer from sporadic adult lethality and seizures. Histological examination reveals that the mutant mice lack the characteristic laminated structure of the cortex. Neuronal birth-dating experiments indicate a reversed packing order of cortical neurons such that earlier born neurons reside in superficial layers and later generated neurons occupy deep layers. The phenotype of p35 mutant mice thus demonstrates that the formation of cortical laminar structure depends on the action of the p35/cdk5 kinase.

  7. Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

    PubMed

    Jara, Adam; Liu, Xingbo; Sim, Don; Benner, Chance M; Duran-Ortiz, Silvana; Qian, Yanrong; List, Edward O; Berryman, Darlene E; Kim, Jason K; Kopchick, John J

    2016-05-01

    GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1.

  8. Methods for the Isolation, Culture, and Functional Characterization of Sinoatrial Node Myocytes from Adult Mice

    PubMed Central

    Sharpe, Emily J.; St Clair, Joshua R.; Proenza, Catherine

    2016-01-01

    Sinoatrial node myocytes (SAMs) act as the natural pacemakers of the heart, initiating each heart beat by generating spontaneous action potentials (APs). These pacemaker APs reflect the coordinated activity of numerous membrane currents and intracellular calcium cycling. However the precise mechanisms that drive spontaneous pacemaker activity in SAMs remain elusive. Acutely isolated SAMs are an essential preparation for experiments to dissect the molecular basis of cardiac pacemaking. However, the indistinct anatomy, complex microdissection, and finicky enzymatic digestion conditions have prevented widespread use of acutely isolated SAMs. In addition, methods were not available until recently to permit longer-term culture of SAMs for protein expression studies. Here we provide a step-by-step protocol and video demonstration for the isolation of SAMs from adult mice. A method is also demonstrated for maintaining adult mouse SAMs in vitro and for expression of exogenous proteins via adenoviral infection. Acutely isolated and cultured SAMs prepared via these methods are suitable for a variety of electrophysiological and imaging studies. PMID:27805586

  9. Taste Bud Labeling in Whole Tongue Epithelial Sheet in Adult Mice.

    PubMed

    Venkatesan, Nandakumar; Boggs, Kristin; Liu, Hong-Xiang

    2016-04-01

    Molecular labeling in whole-mount tissues provides an efficient way to obtain general information about the formation, maintenance, degeneration, and regeneration of many organs and tissues. However, labeling of lingual taste buds in whole tongue tissues in adult mice has been problematic because of the strong permeability barrier of the tongue epithelium. In this study, we present a simple method for labeling taste buds in the intact tongue epithelial sheet of an adult mouse. Following intralingual protease injection and incubation, immediate fixation of the tongue on mandible in 4% paraformaldehyde enabled the in situ shape of the tongue epithelium to be well maintained after peeling. The peeled epithelium was accessible to taste bud labeling with a pan-taste cell marker, keratin 8, and a type II taste cell marker, α-gustducin, in all three types of taste papillae, that is, fungiform, foliate, and circumvallate. Overnight incubation of tongue epithelial sheets with primary and secondary antibodies was sufficient for intense labeling of taste buds with both fluorescent and DAB visualizations. Labeled individual taste buds were easy to identify and quantify. This protocol provides an efficient way for phenotypic analyses of taste buds, especially regarding distribution pattern and number.

  10. Retinoid-related orphan receptor γ (RORγ) adult induced knockout mice develop lymphoblastic lymphoma.

    PubMed

    Liljevald, Maria; Rehnberg, Maria; Söderberg, Magnus; Ramnegård, Marie; Börjesson, Jenny; Luciani, Donatella; Krutrök, Nina; Brändén, Lena; Johansson, Camilla; Xu, Xiufeng; Bjursell, Mikael; Sjögren, Anna-Karin; Hornberg, Jorrit; Andersson, Ulf; Keeling, David; Jirholt, Johan

    2016-11-01

    RORγ is a nuclear hormone receptor which controls polarization of naive CD4(+) T-cells into proinflammatory Th17 cells. Pharmacological antagonism of RORγ has therapeutic potential for autoimmune diseases; however, this mechanism may potentially carry target-related safety risks, as mice deficient in Rorc, the gene encoding RORγ, develop T-cell lymphoma with 50% frequency. Due to the requirement of RORγ during development, the Rorc knockout (KO) animals lack secondary lymphoid organs and have a dysregulation in the generation of CD4+ and CD8+ T cells. We wanted to extend the evaluation of RORγ deficiency to address the question whether lymphomas, similar to those observed in the Rorc KO, would develop in an animal with an otherwise intact adult immune system. Accordingly, we designed a conditional RORγ knockout mouse (Rorc CKO) where the Rorc locus could be deleted in adult animals. Based on these studies we can confirm that these animals also develop lymphoma in a similar time frame as embryonic Rorc knockouts. This study also suggests that in animals where the gene deletion is incomplete, the thymus undergoes a rapid selection process replacing Rorc deficient cells with remnant thymocytes carrying a functional Rorc locus and that subsequently, these animals do not develop lymphoblastic lymphoma.

  11. Supporting cells remove and replace sensory receptor hair cells in a balance organ of adult mice

    PubMed Central

    Bucks, Stephanie A; Cox, Brandon C; Vlosich, Brittany A; Manning, James P; Nguyen, Tot B; Stone, Jennifer S

    2017-01-01

    Vestibular hair cells in the inner ear encode head movements and mediate the sense of balance. These cells undergo cell death and replacement (turnover) throughout life in non-mammalian vertebrates. However, there is no definitive evidence that this process occurs in mammals. We used fate-mapping and other methods to demonstrate that utricular type II vestibular hair cells undergo turnover in adult mice under normal conditions. We found that supporting cells phagocytose both type I and II hair cells. Plp1-CreERT2-expressing supporting cells replace type II hair cells. Type I hair cells are not restored by Plp1-CreERT2-expressing supporting cells or by Atoh1-CreERTM-expressing type II hair cells. Destruction of hair cells causes supporting cells to generate 6 times as many type II hair cells compared to normal conditions. These findings expand our understanding of sensorineural plasticity in adult vestibular organs and further elucidate the roles that supporting cells serve during homeostasis and after injury. DOI: http://dx.doi.org/10.7554/eLife.18128.001 PMID:28263708

  12. Prenatal diethylstilbestrol induces malformation of the external genitalia of male and female mice and persistent second-generation developmental abnormalities of the external genitalia in two mouse strains

    PubMed Central

    Mahawong, Phitsanu; Sinclair, Adriane; Li, Yi; Schlomer, Bruce; Rodriguez, Esequiel; Max, Ferretti M.; Liu, Baomei; Baskin, Laurence S.; Cunha, Gerald R.

    2014-01-01

    Potential trans-generational influence of diethylstilbestrol (DES) exposure emerged with reports of effects in grandchildren of DES-treated pregnant women and of reproductive tract tumors in offspring of mice exposed in utero to DES. Accordingly, we examined the trans-generational influence of DES on development of external genitalia (ExG) and compared effects of in utero DES exposure in CD-1 and C57BL/6 mice injected with oil or DES every other day from gestational days 12 to 18. Mice were examined at birth, and on 5 to 120 days postnatal to evaluate ExG malformations. Of 23 adult (≥60 days) prenatally DES-exposed males, features indicative of urethral meatal hypospadias (see text for definitions) ranged from 18 to 100% in prenatally DES-exposed CD-1 males and 31 to 100% in prenatally DES-exposed C57BL/6 males. Thus, the strains differed in the incidence of male urethral hypospadias. Ninety-one percent of DES-exposed CD-1 females and 100% of DES-exposed C57BL/6 females had urethral-vaginal fistula. All DES-exposed CD-1 and C57BL/6 females lacked an os clitoris. None of the prenatally oil-treated CD-1 and C57BL/6 male and female mice had ExG malformations. For the second-generation study, 10 adult CD-1 males and females, from oil- and DES-exposed groups, respectively, were paired with untreated CD-1 mice for 30 days, and their offspring evaluated for ExG malformations. None of the F1 DES-treated females were fertile. Nine of 10 prenatally DES-exposed CD-1 males sired offspring with untreated females, producing 55 male and 42 female pups. Of the F2 DES-lineage adult males, 20% had exposed urethral flaps, a criterion of urethral meatal hypospadias. Five of 42 (11.9%) F2 DES lineage females had urethral-vaginal fistula. In contrast, all F2 oil-lineage males and all oil-lineage females were normal. Thus, prenatal DES exposure induces malformations of ExG in both sexes and strains of mice, and certain malformations are transmitted to the second-generation. PMID

  13. The CB₁ receptor antagonist SR141716A reverses adult male mice overweight and metabolic alterations induced by early stress.

    PubMed

    Valenzuela, Carina A; Castillo, Valeska A; Aguirre, Carolina A; Ronco, Ana M; Llanos, Miguel N

    2011-01-01

    Perinatal stress may cause metabolic and hormonal disruptions during adulthood. The aim of this study was to evaluate the effects of early postnatal nociceptive stimulation (NS) on body weight and other metabolic parameters during adulthood and to determine whether CB₁ endocannabinoid receptors (CB₁Rs) may be involved in these effects. Male mice were subjected to NS during lactation with a daily subcutaneous injection of saline solution. Subsequently, both control and NS-mice were treated from day 40 to 130, with an oral dose (1 µg/g body weight) of SR141716A, a specific CB₁R antagonist/inverse agonist. Mice body weight and food intake was periodically evaluated. Adult animals were then killed to evaluate epididymal fat pads and metabolic parameters. NS did not influence food intake in adult animals, but caused significant increases in body weight, epididymal fat pads, and circulating levels of leptin, corticosterone, and triglycerides (TGs). Chronic treatment with SR141716A normalized these parameters, with the exception of corticosterone levels. This treatment also reduced plasma levels of glucose, insulin, and total cholesterol in both adult control and NS-mice. In addition, fatty acid (FA) amide hydrolase (FAAH) activity (the enzyme able to hydrolyze endocannabinoids) from liver and epididymal fat of adult NS-mice was decreased by 40-50% in comparison to activities found in same tissues of control mice. Results suggest that overactive liver and epididymal fat CB₁R due to early NS may be involved in late metabolic alterations, which are sensitive to chronic treatment with SR141716A.

  14. Modulation by Ethanol of Cigarette Smoke Clastogenicity in Cells of Adult Mice and of Transplacentally Exposed Fetuses

    PubMed Central

    Balansky, Roumen; La Maestra, Sebastiano; Micale, Rosanna T.; Iltcheva, Marietta; Kirov, Krassimir; De Flora, Silvio

    2016-01-01

    Cigarette smoke (CS) and ethanol (EtOH) are known to synergize in the causation of cancers of the upper aerodigestive tract and of the liver. Little is known about possible interactions between these agents in other organs. These premises prompted us to evaluate the clastogenic effects resulting from the inhalation for 3 weeks of mainstream CS and oral administration of EtOH, which were tested either individually or in combination in cells of adult BDF1 mice and their fetuses. CS exerted clastogenic effects in haematopoietic cells of adult male mice by increasing the frequency of micronucleated erythroid cells both in bone marrow and in peripheral blood as well as the frequency of micronucleated and polynucleated pulmonary alveolar macrophages. Likewise, exposure to CS of pregnant mice resulted in a clastogenic damage in maternal bone marrow cells and in the liver and peripheral blood of their fetuses. Under all experimental conditions, EtOH was consistently devoid of clastogenic effects when given alone. In adult mice, EtOH exhibited a mild stimulating effect on the clastogenicity of CS in haematopoietic cells, while an opposite effect was observed in the respiratory tract, where EtOH attenuated the cytogenetic alterations induced by CS in pulmonary alveolar macrophages. At variance with the mild synergism observed in haematopoietic cells of adult mice, EtOH inhibited the clastogenicity of CS in the liver and peripheral blood cells of transplacentally exposed fetuses. Therefore, the effects of EtOH in CS-exposed mice show different trends depending both on the life stage and on the cells analyzed. PMID:27907070

  15. Initial results of the CD-1 reliable multicast experiment

    SciTech Connect

    Agarwal, D.; Stead, R.; Coan, B.; Burns, J. E.; Shah, N.; Kyriakopoulos, N.

    2000-09-29

    During the past year, an experiment has been underway to test use of reliable multicast capabilities for transmission of continuous data in the Global Communication Infrastructure. For the experiment a version of the CD-1 protocol was multicast enabled. The experiment has demonstrated the feasibility of transmitting data in a multicast mode over the GCI. In the case of the Comprehensive Nuclear Test-Ban Treaty the sender could be the station and the receivers the International Data Center (IDC) and one or more National Data Centers (NDC). The potential advantages of multicasting include (a) the timely receipt of the data by the IDC and the host NDC and (b) the simultaneous availability of the raw station data at, at least, two locations. The latter, by introducing redundant data paths, decreases the probability of loss of station data due to a potential failure of a single data receiver. This experiment is only one element of a needed more thorough assessment of the reliability and cost-effectiveness of introducing redundancies in the data transmission paths and the data sinks of the IMS. The next stage of the multicast experiment planned is installation of the multicast-enabled CD-1 software at the GERES IMS station, at the German NDC and at the IDC for further experiments with actual IMS station data. This stage of the experiment is waiting on installation of a GCI link to the German NDC. Negotiations regarding price for this installation have been on going between the Global Communication Infrastructure (GCI) contractor and the German NDC with no resolution. Current development of the CD-x protocol is proceeding in two complementary directions. Along with the work on a multicast enabled version of CD-1 there is also work to develop CD-1.1, which will add end-to-end reliability to the CD-1 protocol among other things. A possible future activity would be to combine the reliable multicast and the end-to-end reliability mechanisms into one CD-x protocol version.

  16. Low intensity, long term exposure to tobacco smoke inhibits hippocampal neurogenesis in adult mice.

    PubMed

    Csabai, Dávid; Csekő, Kata; Szaiff, Lilla; Varga, Zsófia; Miseta, Attila; Helyes, Zsuzsanna; Czéh, Boldizsár

    2016-04-01

    Previous data have shown that high dose of nicotine administration or tobacco smoke exposure can reduce cell formation and the survival rate of adult-born neurons in the dentate gyrus. Here, we subjected adult mice to low intensity cigarette smoke exposure over long time periods. We did a 2×30min/day smoke exposure with two cigarettes per occasion over 1- or 2-months. Subsequently, we carried out a systematic quantitative histopathological analysis to assess the number of newborn neurons in the dentate gyrus. To investigate cell proliferation, the exogenous marker 5-bromo-2'-deoxyuridine (BrdU) was administered on the last experimental day and animals were sacrificed 2h later. To investigate the effect of tobacco smoke on the population of immature neurons, we quantified the number of doublecortin-positive (DCX+) neurons in the same animals. We found that exposing animals to cigarette smoke for 1- or 2-months had no influence on cell proliferation rate, but significantly reduced the number of DCX-positive immature neurons. Our tobacco smoke exposure regimen caused no substantial changes in respiratory functions, but histopathological analysis of the pulmonary tissue revealed a marked perivascular/peribronchial edema formation after 1-month and signs of chronic pulmonary inflammation after 2-months of cigarette smoke exposure. These data demonstrate that even mild exposure to cigarette smoke, without significantly affecting respiratory functions, can have a negative effect on adult-born neurons in the dentate gyrus, when applied over longer time periods. Our data indicate that besides nicotine other factors, such as inflammatory mediators, may also contribute to this effect.

  17. Isoflurane does not cause neuroapoptosis but reduces astroglial processes in young adult mice

    PubMed Central

    2011-01-01

    Background Isoflurane, a volatile anesthetic widely used clinically, has been implicated to be both neuroprotective and neurotoxic. The claim about isoflurane causing neural apoptosis remains controversial. In this study, we investigated the effects of isoflurane exposures on apoptotic and anti-apoptotic signals, cell proliferation and neurogenesis, and astroglial processes in young adult mouse brains. Methods Sixty 6-week-old mice were randomly assigned to four anesthetic concentration groups (0 as control and 0.6%, 1.3%, and 2%) with four recovery times (2 h and 1, 6, and 14 d) after 2-h isoflurane exposure. Immunohistochemistry measurements of activated caspase-3 and Bcl-xl for apoptotic and anti-apoptotic signals, respectively, glial fibrillary acidic protein (GFAP) and vimentin for reactive astrocytosis, doublecortin (Dcx) for neurogenesis, and BrdU for cell proliferation were performed. Results Contrary to the previous conclusion derived from studies with neonatal rodents, we found no evidence of isoflurane-induced apoptosis in the adult mouse brain. Neurogenesis in the subgranule zone of the dentate gyrus was not affected by isoflurane. However, there is a tendency of reduced cell proliferation after 2% isoflurane exposure. VIM and GFAP staining showed that isoflurane exposure caused a delayed reduction of astroglial processes in the hippocampus and dentate gyrus. Conclusion Two-hour exposure to isoflurane did not cause neuroapoptosis in adult brains. The delayed reduction in astroglial processes after isoflurane exposure may explain why some volatile anesthetics can confer neuroprotection after experimental stroke because reduced glial scarring facilitates better long-term neuronal recoveries. PMID:22146123

  18. Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice

    SciTech Connect

    Fox, Donald A.; Hamilton, W. Ryan; Johnson, Jerry E.; Xiao, Weimin; Chaney, Shawntay; Mukherjee, Shradha; Miller, Diane B.; O'Callaghan, James P.

    2011-11-15

    Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was {<=} 1, {<=} 10, {approx} 25 and {approx} 40 {mu}g/dL, respectively, on PN10 and by PN30 all were {<=} 1 {mu}g/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity. -- Highlights: Black-Right-Pointing-Pointer Peak [BPb] in control, low-, moderate- and high-dose newborn mice with gestational lead exposure: {<=} 1, {<=} 10, 25 and 40 {mu}g/dL Black

  19. A direct relationship between aggressive behavior in the resident/intruder test and cell oxidative status in adult male mice.

    PubMed

    Rammal, Hassan; Bouayed, Jaouad; Soulimani, Rachid

    2010-02-10

    Disturbances in oxidative metabolism are involved in many acute and chronic diseases, as well as in several other conditions. The objective of the present study was to examine the relationship between the level of intracellular reactive oxygen species in the peripheral blood granulocytes of mice, as evaluated by 2',7'-dichlorofluorescin diacetate (DCFH-DA), a sensor of reactive oxygen species, and the aggressive behavior of these mice, as estimated by the resident/intruder test. Our results showed a significant, linear and positive relationship (P<0.001) between the intracellular redox status of peripheral blood granulocytes and the aggressive behavior levels of adult male mice (correlation coefficients (R(2)) ranging from 0.75 to 0.77). This suggests that the granulocytes of aggressively behaving mice have high levels of oxidative stress.

  20. Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging.

    PubMed

    Kang, S; Louboutin, J-P; Datta, P; Landel, C P; Martinez, D; Zervos, A S; Strayer, D S; Fernandes-Alnemri, T; Alnemri, E S

    2013-02-01

    mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals.

  1. MeCP2 Related Studies Benefit from the Use of CD1 as Genetic Background

    PubMed Central

    Cobolli Gigli, Clementina; Scaramuzza, Linda; Gandaglia, Anna; Bellini, Elisa; Gabaglio, Marina; Parolaro, Daniela; Kilstrup-Nielsen, Charlotte; Bedogni, Francesco

    2016-01-01

    MECP2 mutations cause a number of neurological disorders of which Rett syndrome (RTT) represents the most thoroughly analysed condition. Many Mecp2 mouse models have been generated through the years; their validity is demonstrated by the presence of a broad spectrum of phenotypes largely mimicking those manifested by RTT patients. These mouse models, between which the C57BL/6 Mecp2tm1.1Bird strain probably represents the most used, enabled to disclose much of the roles of Mecp2. However, small litters with little viability and poor maternal care hamper the maintenance of the colony, thus limiting research on such animals. For this reason, past studies often used Mecp2 mouse models on mixed genetic backgrounds, thus opening questions on whether modifier genes could be responsible for at least part of the described effects. To verify this possibility, and facilitate the maintenance of the Mecp2 colony, we transferred the Mecp2tm1.1Bird allele on the stronger CD1 background. The CD1 strain is easier to maintain and largely recapitulates the phenotypes already described in Mecp2-null mice. We believe that this mouse model will foster the research on RTT. PMID:27097329

  2. Single and repeated sevoflurane or desflurane exposure does not impair spatial memory performance of young adult mice.

    PubMed

    Kilicaslan, Alper; Belviranli, Muaz; Okudan, Nilsel; Nurullahoglu Atalik, Esra

    2013-12-01

    Volatile anesthetics are known to disturb the spatial memory in aged rodents, but there is insufficient information on their effects on young adult rodents. The aim of this study was to compare the effects of single and repeated exposure to desflurane and sevoflurane on spatial learning and memory functions in young adult mice. Balb/c mice (2 months old) were randomly divided into six equal groups (n = 8). The groups with single inhalation were exposed to 3.3% sevoflurane or 7.8% desflurane or vehicle gas for 4 h, respectively. The groups with repeated inhalation were exposed to 3.3% sevoflurane or 7.8% desflurane or vehicle gas for 2 h a day during 5 consecutive days. Spatial learning and memory were tested in the Morris water maze 24 h after exposure. In the learning phase, the parameters associated with finding the hidden platform and swimming speed, and in the memory phase, time spent in the target quadrant and the adjacent quadrants, were assessed and compared between the groups. In the 4-day learning process, there was no significant difference between the groups in terms of mean latency to platform, mean distance traveled and average speed (P > 0.05). During the memory-test phase, all mice exhibited spatial memory, but there was no significant difference between the groups in terms of time spent in the target quadrant (P > 0.05). Sevoflurane and desflurane anesthesia did not impair acquisition learning and retention memory in young adult mice.

  3. Sod1 gene ablation in adult mice leads to physiological changes at the neuromuscular junction similar to changes that occur in old wild-type mice.

    PubMed

    Ivannikov, Maxim V; Van Remmen, Holly

    2015-07-01

    Reactive oxygen species (ROS) are believed to be important mediators of muscle atrophy and weakness in aging and many degenerative conditions. However, the mechanisms and physiological processes specifically affected by elevated ROS in neuromuscular units that contribute to muscle weakness during aging are not well defined. Here we investigate the effects of chronic oxidative stress on neurotransmission and excitation-contraction (EC) coupling mechanisms in the levator auris longus (LAL) muscle from young (4-8 months) and old (22-28 months) wild-type mice and young adult Cu-Zn superoxide dismutase 1 knockout (Sod1(-/-)) mice. The frequency of spontaneous neurotransmitter release and the amplitude of evoked neurotransmitter release in young Sod1(-/-) and old wild-type LAL neuromuscular junctions were significantly reduced from the young wild-type values, and those declines were mirrored by decreases in synaptic vesicle pool size. Presynaptic cytosolic calcium concentration and mitochondrial calcium uptake amplitudes showed substantial increases in stimulated young Sod1(-/-) and old axon terminals. Surprisingly, LAL muscle fibers from old mice showed a greater excitability than fibers from either young wild-type or young Sod1(-/-) LAL. Both evoked excitatory junction potential (EJP) and spontaneous mini EJP amplitudes were considerably higher in LAL muscles from old mice than in fibers from young Sod1(-/-) LAL muscle. Despite a greater excitability, sarcoplasmic calcium influx in both old wild-type and young Sod1(-/-) LAL muscle fibers was significantly less. Sarcoplasmic reticulum calcium levels were also reduced in both old wild-type and young Sod1(-/-) mice, but the difference was not statistically significant in muscle fibers from old wild-type mice. The protein ratio of triad calcium channels RyR1/DHPR was not different in all groups. However, fibers from both young Sod1(-/-) and old mice had substantially elevated levels of protein carbonylation and S

  4. Immunosuppression in early postnatal days induces persistent and allergen-specific immune tolerance to asthma in adult mice.

    PubMed

    Chen, Yan; Zhang, Jin; Lu, Yong; Wang, Libo

    2015-01-01

    Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV) was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs) were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma.

  5. In Utero Exposure to Benzo[a]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

    PubMed Central

    Meier, Matthew J.; O’Brien, Jason M.; Beal, Marc A.; Allan, Beverly; Yauk, Carole L.; Marchetti, Francesco

    2016-01-01

    Background: Mosaicism, the presence of genetically distinct cell populations within an organism, has emerged as an important contributor to disease. Mutational events occurring during embryonic development can cause mosaicism in any tissue, but the influence of environmental factors on levels of mosaicism is unclear. Objectives: We investigated whether in utero exposure to the widespread environmental mutagen benzo[a]pyrene (BaP) has an impact on the burden and distribution of mutations in adult mice. Methods: We used the Muta™Mouse transgenic rodent model to quantify and characterize mutations in the offspring of pregnant mice exposed to BaP during postconception days 7 through 16, covering the major period of organogenesis in mice. Next-generation DNA sequencing was then used to determine the spectrum of mutations induced in adult mice that were exposed to BaP during fetal development. Results: Mutation frequency was significantly increased in the bone marrow, liver, brain, and sperm of first filial generation (F1) males. Developing embryos accumulated more mutations and exhibited higher proportions of mosaicism than exposed adults, particularly in the brain. Decreased sperm count and motility revealed additional negative impacts on the reproductive function of F1 males. Conclusion: In utero exposure to environmental mutagens contributes to somatic and germline mosaicism, permanently affecting both the genetic health of the F1 and the population gene pool. Citation: Meier MJ, O’Brien JM, Beal MA, Allan B, Yauk CL, Marchetti F. 2017. In utero exposure to benzo[a]pyrene increases mutation burden in the soma and sperm of adult mice. Environ Health Perspect 125:82–88; http://dx.doi.org/10.1289/EHP211 PMID:27448386

  6. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water.

    PubMed

    Krishna, Saritha; Dodd, Celia A; Hekmatyar, Shahryar K; Filipov, Nikolay M

    2014-01-01

    Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e., mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) levels, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post-Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure.

  7. Sex and Laterality Differences in Medial Amygdala Neurons and Astrocytes of Adult Mice

    PubMed Central

    Pfau, Daniel R.; Hobbs, Nicholas J.; Breedlove, S. Marc; Jordan, Cynthia L.

    2016-01-01

    The posterodorsal aspect of the medial amygdala (MePD) in rats is sexually dimorphic, being larger and containing more and larger neurons in males than in females. It is also highly lateralized, with the right MePD larger than the left in both sexes, but with the smaller left MePD actually containing more and larger neurons than the larger right. Astrocytes are also strikingly sexually differentiated, with male-biased numbers and lateralized favoring the right in the rat MePD. However, comparable information is scant for mice where genetic tools offer greater experimental power. Hence, we examined the MePD from adult male and female C57Bl/6J mice. We now report that the MePD is larger in males than in females, with the MePD in males containing more astrocytes and neurons than in females. However, we did not find sex differences in astrocyte complexity or overall glial number nor effects of laterality in either measure. While the mouse MePD is generally less lateralized than in rats, we did find that the sex difference in astrocyte number is only on the right because of a significant lateralization in females, with significantly fewer astrocytes on the right than the left but only in females. A sex difference in neuronal soma size favoring males was also evident, but only on the left. Sex differences in the number of neurons and astrocytes common to both rodent species may represent core morphological features that critically underlie the expression of sex-specific behaviors that depend on the MePD. PMID:26780286

  8. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water

    PubMed Central

    Saritha, Krishna; Celia, Dodd A.; Shahryar, Hekmatyar K.; Nikolay, Filipov M.

    2013-01-01

    Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e. mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) level, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure. PMID:23832297

  9. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

    PubMed Central

    Pristerà, Alessandro; Lin, Wei; Kaufmann, Anna-Kristin; Brimblecombe, Katherine R.; Threlfell, Sarah; Dodson, Paul D.; Magill, Peter J.; Fernandes, Cathy; Cragg, Stephanie J.; Ang, Siew-Lan

    2015-01-01

    Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice. We show that deletion of Foxa1/2 results in down-regulation of tyrosine hydroxylase, the rate-limiting enzyme of dopamine (DA) biosynthesis, specifically in dopaminergic neurons of the substantia nigra pars compacta (SNc). In addition, DA synthesis and striatal DA transmission were reduced after Foxa1/2 deletion. Furthermore, the burst-firing activity characteristic of SNc mDA neurons was drastically reduced in the absence of FOXA1/2. These molecular and functional alterations lead to a severe feeding deficit in adult Foxa1/2 mutant mice, independently of motor control, which could be rescued by l-DOPA treatment. FOXA1/2 therefore control the maintenance of molecular and physiological properties of SNc mDA neurons and impact on feeding behavior in adult mice. PMID:26283356

  10. Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

    PubMed

    Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-05-01

    We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model.

  11. CD1d(hi)CD5+ B cells expanded by GM-CSF in vivo suppress experimental autoimmune myasthenia gravis.

    PubMed

    Sheng, Jian Rong; Quan, Songhua; Soliven, Betty

    2014-09-15

    IL-10-competent subset within CD1d(hi)CD5(+) B cells, also known as B10 cells, has been shown to regulate autoimmune diseases. Whether B10 cells can prevent or suppress the development of experimental autoimmune myasthenia gravis (EAMG) has not been studied. In this study, we investigated whether low-dose GM-CSF, which suppresses EAMG, can expand B10 cells in vivo, and whether adoptive transfer of CD1d(hi)CD5(+) B cells would prevent or suppress EAMG. We found that treatment of EAMG mice with low-dose GM-CSF increased the proportion of CD1d(hi)CD5(+) B cells and B10 cells. In vitro coculture studies revealed that CD1d(hi)CD5(+) B cells altered T cell cytokine profile but did not directly inhibit T cell proliferation. In contrast, CD1d(hi)CD5(+) B cells inhibited B cell proliferation and its autoantibody production in an IL-10-dependent manner. Adoptive transfer of CD1d(hi)CD5(+) B cells to mice could prevent disease, as well as suppress EAMG after disease onset. This was associated with downregulation of mature dendritic cell markers and expansion of regulatory T cells resulting in the suppression of acetylcholine receptor-specific T cell and B cell responses. Thus, our data have provided significant insight into the mechanisms underlying the tolerogenic effects of B10 cells in EAMG. These observations suggest that in vivo or in vitro expansion of CD1d(hi)CD5(+) B cells or B10 cells may represent an effective strategy in the treatment of human myasthenia gravis.

  12. Effects of tamoxifen on autosomal genes regulating ovary maintenance in adult mice.

    PubMed

    Yu, Mingxi; Liu, Wei; Wang, Jingyun; Qin, Junwen; Wang, Yongan; Wang, Yu

    2015-12-01

    Environmental endocrine-disrupting chemicals (EDCs), known to bind to estrogen/androgen receptors and mimic native estrogens, have been implicated as a main source for increasing human reproductive and developmental deficiencies and diseases. Tamoxifen (TAM) is one of the most well-known antiestrogens with defined adverse effects on the female reproductive tract, but the mechanisms related to autosomal gene regulation governing ovary maintenance in mammals remain unclear. The expression pattern and levels of key genes and proteins involved in maintaining the ovarian phenotype in mice were analyzed. The results showed that TAM induced significant upregulation of Sox9, which is the testis-determining factor gene. The results showed that TAM induced significant upregulation of Sox9, the testis-determining factor gene, and the expression level of Sox9 mRNA in the ovaries of mice exposed to 75 or 225 mg/kg bw TAM was 2- and 10-fold that in the control group, respectively (p < 0.001). Furthermore, the testicular fibroblast growth factor gene, Fgf9, was also elevated in TAM-treated ovaries. Accordingly, expression of the ovary development marker, forkhead transcription factor (FOXL2), and WNT4/FST signaling, were depressed. The levels of protein expression changed consistently with the target genes. Moreover, the detection of platelet/endothelial cell adhesion molecule 1 (PECAM-1) in TAM-treated ovaries suggested the formation of vascular endothelial cells, which is a further evidence for the differentiation of the ovaries to a testis-like phenotype. During this period, the level of 17β-estradiol, progesterone, and luteinizing hormone decreased, while that of testosterone increased by 3.3-fold (p = 0.013). The activation of a testis-specific molecular signaling cascade was a potentially important mechanism contributing to the gender disorder induced by TAM, which resulted in the differentiation of the ovaries to a testis-like phenotype in adult mice. Limited with

  13. Effect of dietary selenium and cancer cell xenograft on peripheral T and B lymphocytes in adult nude mice.

    PubMed

    Cheng, Wen-Hsing; Holmstrom, Alexandra; Li, Xiangdong; Wu, Ryan T Y; Zeng, Huawei; Xiao, Zhengguo

    2012-05-01

    Selenium (Se) is known to regulate tumorigenesis and immunity at the nutritional and supranutritional levels. Because the immune system provides critical defenses against cancer and the athymic, immune-deficient NU/J nude mice are known to gradually develop CD8(+) and CD4(+) T cells, we investigated whether B and T cell maturation could be modulated by dietary Se and by tumorigenesis in nude mice. Fifteen homozygous nude mice were fed a Se-deficient, Torula yeast basal diet alone (Se-) or supplemented with 0.15 (Se+) or 1.0 (Se++) mg Se/kg (as Na(2)SeO(4)) for 6 months, followed by a 7-week time course of PC-3 prostate cancer cell xenograft (2 × 10(6) cells/site, 2 sites/mouse). Here, we show that peripheral B cell levels decreased in nude mice fed the Se -  or Se++ diet and the CD4(+) T cell levels increased in mice fed the Se++ diet. During the PC-3 cell tumorigenesis, dietary Se status did not affect peripheral CD4(+) or CD8(+) T cells in nude mice whereas mice fed with the Se++ diet appeared to exhibit greater peripheral CD25(+)CD4(+) T cells on day 9. Dietary Se status did not affect spleen weight in nude mice 7 weeks after the xenograft. Spleen weight was associated with frequency of peripheral CD4(+), but not CD8(+) T cells. Taken together, dietary Se at the nutritional and supranutritional levels regulates peripheral B and T cells in adult nude mice before and after xenograft with PC-3 prostate cancer cells.

  14. Action of the noradrenergic system on adult-born cells is required for olfactory learning in mice.

    PubMed

    Moreno, Melissa M; Bath, Kevin; Kuczewski, Nicola; Sacquet, Joëlle; Didier, Anne; Mandairon, Nathalie

    2012-03-14

    We have previously shown that an experience-driven improvement in olfactory discrimination (perceptual learning) requires the addition of newborn neurons in the olfactory bulb (OB). Despite this advance, the mechanisms which govern the selective survival of newborn OB neurons following learning remain largely unknown. We propose that activity of the noradrenergic system is a critical mediator providing a top-down signal to control the selective survival of newly born cells and support perceptual learning. In adult mice, we used pharmacological means to manipulate the noradrenergic system and neurogenesis and to assess their individual and additive effects on behavioral performance on a perceptual learning task. We then looked at the effects of these manipulations on regional survival of adult-born cells in the OB. Finally, using confocal imaging and electrophysiology, we investigated potential mechanisms by which noradrenaline could directly influence the survival of adult-born cells. Consistent with our hypotheses, direct manipulation of noradrenergic transmission significantly effect on adult-born cell survival and perceptual learning. Specifically, learning required both the presence of adult-born cell and noradrenaline. Finally, we provide a mechanistic link between these effects by showing that adult-born neurons receive noradrenergic projections and are responsive to noradrenaline. Based upon these data we argue that noradrenergic transmission is a key mechanism selecting adult-born neurons during learning and demonstrate that top-down neuromodulation acts on adult-born neuron survival to modulate learning performance.

  15. Learning and Memory Deficits in Male Adult Mice Treated with a Benzodiazepine Sleep-Inducing Drug during the Juvenile Period

    PubMed Central

    Furukawa, Yusuke; Tanemura, Kentaro; Igarashi, Katsuhide; Ideta-Otsuka, Maky; Aisaki, Ken-Ichi; Kitajima, Satoshi; Kitagawa, Masanobu; Kanno, Jun

    2016-01-01

    Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, is also known to be important for brain development. Therefore, disturbances of GABA receptor (GABA-R) mediated signaling (GABA-R signal) during brain development may influence normal brain maturation and cause late-onset brain malfunctions. In this study, we examined whether the stimulation of the GABA-R signal during brain development induces late-onset adverse effects on the brain in adult male mice. To stimulate the GABA-R signal, we used either the benzodiazepine sleep-inducing drug triazolam (TZ) or the non-benzodiazepine drug zolpidem (ZP). We detected learning and memory deficits in mice treated with TZ during the juvenile period, as seen in the fear conditioning test. On the other hand, ZP administration during the juvenile period had little effect. In addition, decreased protein expression of GluR1 and GluR4, which are excitatory neurotransmitter receptors, was detected in the hippocampi of mice treated with TZ during the juvenile period. We measured mRNA expression of the immediate early genes (IEGs), which are neuronal activity markers, in the hippocampus shortly after the administration of TZ or ZP to juvenile mice. Decreased IEG expression was detected in mice with juvenile TZ administration, but not in mice with juvenile ZP administration. Our findings demonstrate that TZ administration during the juvenile period can induce irreversible learning and memory deficits in adult mice. It may need to take an extra care for the prescription of benzodiazepine sleep-inducing drugs to juveniles because it might cause learning and memory deficits. PMID:27489535

  16. Transcription levels of sirtuin family in neural stem cells and brain tissues of adult mice.

    PubMed

    Wang, H F; Li, Q; Feng, R L; Wen, T Q

    2012-09-10

    Neural stem cells (NSCs) has been used as a well-known model to investigate apoptosis, differentiation, maintenance of stem cells status, and therapy of neurological disease. The C17.2 NSCs line was produced after v-myc transformation of neural progenitor from mouse cerebellar cortex. Sirtuin family plays important roles involved in neuronal differentiation, genomic stability, lifespan, cell survival. However, little is known about gene expression variation of sirtuin family in C17.2 NSCs, primary NSCs, and different brain tissues in adult mice. Here, we confirmed that the mRNA expression levels of sirt2, 3, 4, 5, and 7 in E14.5 NSCs were significantly higher than in C17.2 NSCs, whereas that sirt 6 displayed an opposing mode. Moreover, a higher mRNA level of sirtuin family was observed in the adult mouse brain compared to C17.2 NSCs. In addition, histone deacetylase (HDAC) inhibitors nicotinamide and Trichostatin A (TSA) were used to explore differential changes at the transcriptional level of sirtuins. Results indicated that the expression of sirt1, sirt5 and sirt6 was significant downregulated by nicotinamide treatment. Whereas, a significant downregulation in sirt1 and sirt3 and a significant upregulation in sirt2, sirt4, sirt6, and sirt7 were observed in the treatment of TSA. Thus our studies indicate different sirtuin mRNA expression profiles between C17.2 NSCs, E14.5 NSCs and brain tissues, suggesting the transcriptional regulation of sirtuin family could be mediated by different histone acetylation.

  17. Culture and adenoviral infection of sinoatrial node myocytes from adult mice

    PubMed Central

    St. Clair, Joshua R.; Sharpe, Emily J.

    2015-01-01

    Pacemaker myocytes in the sinoatrial node of the heart initiate each heartbeat by firing spontaneous action potentials. However, the molecular processes that underlie pacemaking are incompletely understood, in part because of our limited ability to manipulate protein expression within the native cellular context of sinoatrial node myocytes (SAMs). Here we describe a new method for the culture of fully differentiated SAMs from adult mice, and we demonstrate that robust expression of introduced proteins can be achieved within 24–48 h in vitro via adenoviral gene transfer. Comparison of morphological and electrophysiological characteristics of 48 h-cultured versus acutely isolated SAMs revealed only minor changes in vitro. Specifically, we found that cells tended to flatten in culture but retained an overall normal morphology, with no significant changes in cellular dimensions or membrane capacitance. Cultured cells beat spontaneously and, in patch-clamp recordings, the spontaneous action potential firing rate did not differ between cultured and acutely isolated cells, despite modest changes in a subset of action potential waveform parameters. The biophysical properties of two membrane currents that are critical for pacemaker activity in SAMs, the “funny current” (If) and voltage-gated Ca2+ currents (ICa), were also indistinguishable between cultured and acutely isolated cells. This new method for culture and adenoviral infection of fully-differentiated SAMs from the adult mouse heart expands the range of experimental techniques that can be applied to study the molecular physiology of cardiac pacemaking because it will enable studies in which protein expression levels can be modified or genetically encoded reporter molecules expressed within SAMs. PMID:26001410

  18. Embryonic exposure to dimethoate and/or deltamethrin impairs sexual development and programs reproductive success in adult male offspring mice.

    PubMed

    Ben Slima, A; Ben Abdallah, F; Keskes-Ammar, L; Mallek, Z; El Feki, A; Gdoura, R

    2012-05-01

    Pesticides can be toxic to desirable plants and animals, including humans. The aim of this study was to investigate the reproductive effects of low doses of pesticides on male offspring of exposed pregnant mice. Three groups of five female mice were treated daily by oral gavage with dimethoate (5 mg kg(-1) per day), deltamethrin (5 mg kg(-1) per day) and their mixture at 5 mg kg(-1) per day from day 3 to day 21 of pregnancy. Fertility, sexual behaviour and a number of reproductive endpoints, such as organ weights, sperm evaluations and testicular histology, were examined on four adult male offspring of exposed pregnant mice. When compared with control, a dose of deltamethrin 5 mg kg j(-1) causes a decrease in the absolute and relative weight of the testes of exposed mice and it affects their fertility by reducing the density, mobility and vitality of sperm and increasing the number of abnormal forms of these cells (P ≤ 0.01). The same results were obtained in mice exposed to a dose of 5 mg kg j(-1) combination of dimethoate and deltamethrin. This study demonstrated that deltamethrin and combination of dimethoate and deltamethrin caused a decrease in the absolute and relative weight of the testes, which affected the sperm parameters of male offspring of exposed mice to a low dose of these pesticides during pregnancy.

  19. Botulism in metronidazole- treated conventional adult mice challenged orogastrically with spores of Clostridium botulinum type A or B.

    PubMed Central

    Wang, Y; Sugiyama, H

    1984-01-01

    Conventional adult mice were pretreated with metronidazole to make their intestinal tracts receptive to colonization by Clostridium botulinum. These mice, in groups of 10, were fed 0 (controls), 10(2), 10(3), 10(4), or 10(5) C. botulinum type B spores and were placed for observation in filter-lid cages whose screen floors minimized the amounts of feces available for coprophagy. The opportunity to eat feces was made equal for all mouse groups by placing one mouse of every group in each of 10 cages. Mice given a spore inoculum began to develop botulism after incubation periods of slightly less than 2.75 days. Morbidity rates, which reached maxima within 5 days of challenge, were related to inocula levels. Mortality rates were also dose related. Mice given 10(5) spores and then type B antitoxin intraperitoneally, a treatment not affecting intraintestinal toxin production, remained healthy. Morbidity among control mice was seldom more than 10% and could be ascribed to toxin ingested with feces. A C. botulinum type A spore suspension gave similar results, although morbidity and mortality rates were generally lower than after challenge with a comparable number of type B spores. Mice challenged with 10(2) or 10(5) spores had similar toxin levels in their large intestines 48 h later. Morbidity rates correlated better with toxin levels in the small intestines. PMID:6389360

  20. Influence of Botulinumtoxin A on the Expression of Adult MyHC Isoforms in the Masticatory Muscles in Dystrophin-Deficient Mice (Mdx-Mice)

    PubMed Central

    Todorov, Teodor

    2016-01-01

    The most widespread animal model to investigate Duchenne muscular dystrophy is the mdx-mouse. In contrast to humans, phases of muscle degeneration are replaced by regeneration processes; hence there is only a restricted time slot for research. The aim of the study was to investigate if an intramuscular injection of BTX-A is able to break down muscle regeneration and has direct implications on the gene expression of myosin heavy chains in the corresponding treated and untreated muscles. Therefore, paralysis of the right masseter muscle was induced in adult healthy and dystrophic mice by a specific intramuscular injection of BTX-A. After 21 days the mRNA expression and protein content of MyHC isoforms of the right and left masseter, temporal, and the tongue muscle were determined using quantitative RT-PCR and Western blot technique. MyHC-IIa and MyHC-I-mRNA expression significantly increased in the paralyzed masseter muscle of control-mice, whereas MyHC-IIb and MyHC-IIx/d-mRNA were decreased. In dystrophic muscles no effect of BTX-A could be detected at the level of MyHC. This study suggests that BTX-A injection is a suitable method to simulate DMD-pathogenesis in healthy mice but further investigations are necessary to fully analyse the BTX-A effect and to generate sustained muscular atrophy in mdx-mice. PMID:27689088

  1. Salidroside, a Bioactive Compound of Rhodiola Rosea, Ameliorates Memory and Emotional Behavior in Adult Mice.

    PubMed

    Palmeri, Agostino; Mammana, Leonardo; Tropea, Maria Rosaria; Gulisano, Walter; Puzzo, Daniela

    2016-02-26

    Rhodiola Rosea (R. Rosea) is a plant used in traditional popular medicine to enhance cognition and physical performance. R. Rosea medicinal properties have been related to its capability to act as an adaptogen, i.e., a substance able to increase the organism's resistance to a variety of chemical, biological, and physical stressors in a non-specific way. These adaptogen properties have been mainly attributed to the glycoside salidroside, one of the bioactive compounds present in the standardized extracts of R. Rosea. Here, we aimed to investigate whether a single dose of salidroside is able to affect memory and emotional behavior in wild type adult mice. We performed fear conditioning to assess cued and contextual memory, elevated plus maze and open field to evaluate anxiety, and tail suspension test to evaluate depression. Our results showed that a single i.p. administration of salidroside was able to enhance fear memory and exerted an anxiolytic and antidepressant effect. These data confirmed the adaptogenic effect of R. Rosea bioactive compounds in animal models and suggest that salidroside might represent an interesting pharmacological tool to ameliorate cognition and counteract mood disorders.

  2. The Protein Kinase KIS Impacts Gene Expression during Development and Fear Conditioning in Adult Mice

    PubMed Central

    Manceau, Valérie; Kremmer, Elisabeth; Nabel, Elizabeth G.; Maucuer, Alexandre

    2012-01-01

    The brain-enriched protein kinase KIS (product of the gene UHMK1) has been shown to phosphorylate the human splicing factor SF1 in vitro. This phosphorylation in turn favors the formation of a U2AF65-SF1-RNA complex which occurs at the 3′ end of introns at an early stage of spliceosome assembly. Here, we analyzed the effects of KIS knockout on mouse SF1 phosphorylation, physiology, adult behavior, and gene expression in the neonate brain. We found SF1 isoforms are differently expressed in KIS-ko mouse brains and fibroblasts. Re-expression of KIS in fibroblasts restores a wild type distribution of SF1 isoforms, confirming the link between KIS and SF1. Microarray analysis of transcripts in the neonate brain revealed a subtle down-regulation of brain specific genes including cys-loop ligand-gated ion channels and metabolic enzymes. Q-PCR analyses confirmed these defects and point to an increase of pre-mRNA over mRNA ratios, likely due to changes in splicing efficiency. While performing similarly in prepulse inhibition and most other behavioral tests, KIS-ko mice differ in spontaneous activity and contextual fear conditioning. This difference suggests that disregulation of gene expression due to KIS inactivation affects specific brain functions. PMID:22937132

  3. Nicotine-Cadmium Interaction Alters Exploratory Motor Function and Increased Anxiety in Adult Male Mice

    PubMed Central

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

    2014-01-01

    In this study we evaluated the time dependence in cadmium-nicotine interaction and its effect on motor function, anxiety linked behavioural changes, serum electrolytes, and weight after acute and chronic treatment in adult male mice. Animals were separated randomly into four groups of n = 6 animals each. Treatment was done with nicotine, cadmium, or nicotine-cadmium for 21 days. A fourth group received normal saline for the same duration (control). Average weight was determined at 7-day interval for the acute (D1-D7) and chronic (D7-D21) treatment phases. Similarly, the behavioural tests for exploratory motor function (open field test) and anxiety were evaluated. Serum electrolytes were measured after the chronic phase. Nicotine, cadmium, and nicotine-cadmium treatments caused no significant change in body weight after the acute phase while cadmium-nicotine and cadmium caused a decline in weight after the chronic phase. This suggests the role of cadmium in the weight loss observed in tobacco smoke users. Both nicotine and cadmium raised serum Ca2+ concentration and had no significant effect on K+ ion when compared with the control. In addition, nicotine-cadmium treatment increased bioaccumulation of Cd2+ in the serum which corresponded to a decrease in body weight, motor function, and an increase in anxiety. PMID:26317007

  4. CD1 Mouse Retina Is Shielded From Iron Overload Caused by a High Iron Diet

    PubMed Central

    Bhoiwala, Devang L.; Song, Ying; Cwanger, Alyssa; Clark, Esther; Zhao, Liang-liang; Wang, Chenguang; Li, Yafeng; Song, Delu; Dunaief, Joshua L.

    2015-01-01

    Purpose High RPE iron levels have been associated with age-related macular degeneration. Mutation of the ferroxidase ceruloplasmin leads to RPE iron accumulation and degeneration in patients with aceruloplasminemia; mice lacking ceruloplasmin and its homolog hephaestin have a similar RPE degeneration. To determine whether a high iron diet (HID) could cause RPE iron accumulation, possibly contributing to RPE oxidative stress in AMD, we tested the effect of dietary iron on mouse RPE iron. Methods Male CD1 strain mice were fed either a standard iron diet (SID) or the same diet with extra iron added (HID) for either 3 months or 10 months. Mice were analyzed with immunofluorescence and Perls' histochemical iron stain to assess iron levels. Levels of ferritin, transferrin receptor, and oxidative stress gene mRNAs were measured by quantitative PCR (qPCR) in neural retina (NR) and isolated RPE. Morphology was assessed in plastic sections. Results Ferritin immunoreactivity demonstrated a modest increase in the RPE in 10-month HID mice. Analysis by qPCR showed changes in mRNA levels of iron-responsive genes, indicating moderately increased iron in the RPE of 10-month HID mice. However, even by age 18 months, there was no Perls' signal in the retina or RPE and no retinal degeneration. Conclusions These findings indicate that iron absorbed from the diet can modestly increase the level of iron deposition in the wild-type mouse RPE without causing RPE or retinal degeneration. This suggests regulation of retinal iron uptake at the blood-retinal barriers. PMID:26275132

  5. Toll-like receptor 2 mediates ischemia-reperfusion injury of the small intestine in adult mice.

    PubMed

    Watanabe, Toshio; Tanigawa, Tetsuya; Kobata, Atsushi; Takeda, Shogo; Nadatani, Yuji; Otani, Koji; Yamagami, Hirokazu; Shiba, Masatsugu; Tominaga, Kazunari; Fujiwara, Yasuhiro; Arakawa, Tetsuo

    2014-01-01

    Toll-like receptor 2 (TLR2) recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R) injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO), a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory mediators

  6. Neonatal Whisker Trimming Impairs Fear/Anxiety-Related Emotional Systems of the Amygdala and Social Behaviors in Adult Mice.

    PubMed

    Soumiya, Hitomi; Godai, Ayumi; Araiso, Hiromi; Mori, Shingo; Furukawa, Shoei; Fukumitsu, Hidefumi

    2016-01-01

    Abnormalities in tactile perception, such as sensory defensiveness, are common features in autism spectrum disorder (ASD). While not a diagnostic criterion for ASD, deficits in tactile perception contribute to the observed lack of social communication skills. However, the influence of tactile perception deficits on the development of social behaviors remains uncertain, as do the effects on neuronal circuits related to the emotional regulation of social interactions. In neonatal rodents, whiskers are the most important tactile apparatus, so bilateral whisker trimming is used as a model of early tactile deprivation. To address the influence of tactile deprivation on adult behavior, we performed bilateral whisker trimming in mice for 10 days after birth (BWT10 mice) and examined social behaviors, tactile discrimination, and c-Fos expression, a marker of neural activation, in adults after full whisker regrowth. Adult BWT10 mice exhibited significantly shorter crossable distances in the gap-crossing test than age-matched controls, indicating persistent deficits in whisker-dependent tactile perception. In contrast to controls, BWT10 mice exhibited no preference for the social compartment containing a conspecific in the three-chamber test. Furthermore, the development of amygdala circuitry was severely affected in BWT10 mice. Based on the c-Fos expression pattern, hyperactivity was found in BWT10 amygdala circuits for processing fear/anxiety-related responses to height stress but not in circuits for processing reward stimuli during whisker-dependent cued learning. These results demonstrate that neonatal whisker trimming and concomitant whisker-dependent tactile discrimination impairment severely disturbs the development of amygdala-dependent emotional regulation.

  7. Early postnatal GFAP-expressing cells produce multilineage progeny in cerebrum and astrocytes in cerebellum of adult mice.

    PubMed

    Guo, Zhibao; Wang, Xijuan; Xiao, Jun; Wang, Yihui; Lu, Hong; Teng, Junfang; Wang, Wei

    2013-09-26

    Early postnatal GFAP-expressing cells are thought to be immature astrocytes. However, it is not clear if they possess multilineage capacity and if they can generate different lineages (astrocytes, neurons and oligodendrocytes) in the brain of adult mice. In order to identify the fate of astroglial cells in the postnatal brain, hGFAP-Cre-ER(T2) transgenic mice were crossed with the R26R Cre reporter mouse strains which exhibit constitutive expression of β-galactosidase (β-gal). Mice carrying the hGFAP-Cre-ER(T2)/R26R transgene were treated with Tamoxifen to induce Cre recombination in astroglial cells at postnatal (P) day 6 and Cre recombinase-expressing cells were identified by X-gal staining. Immunohistochemical staining was used to identify the type(s) of these reporter-tagged cells. Sixty days after recombination, X-gal-positive cells in different cerebral regions of the adult mice expressed the astroglial markers Blbp and GFAP, the neuronal marker NeuN, the oligodendrocyte precursor cell marker NG2 and the mature oligodendrocyte marker CC1. X-gal-positive cells in the cerebellum coexpressed the astroglial marker Blbp, but not the granule cell marker NeuN, Purkinje cell marker Calbindin or oligodendrocyte precursor cell marker NG2. Our genetic fate mapping data demonstrated that early postnatal GFAP-positive cells possessed multilineage potential and eventually differentiated into neurons, astrocytes, and oligodendrocyte precursor cells in the cerebrum and into astrocytes (including Bergmann glia) in the cerebellum of adult mice.

  8. Neonatal Whisker Trimming Impairs Fear/Anxiety-Related Emotional Systems of the Amygdala and Social Behaviors in Adult Mice

    PubMed Central

    Soumiya, Hitomi; Godai, Ayumi; Araiso, Hiromi; Mori, Shingo; Furukawa, Shoei; Fukumitsu, Hidefumi

    2016-01-01

    Abnormalities in tactile perception, such as sensory defensiveness, are common features in autism spectrum disorder (ASD). While not a diagnostic criterion for ASD, deficits in tactile perception contribute to the observed lack of social communication skills. However, the influence of tactile perception deficits on the development of social behaviors remains uncertain, as do the effects on neuronal circuits related to the emotional regulation of social interactions. In neonatal rodents, whiskers are the most important tactile apparatus, so bilateral whisker trimming is used as a model of early tactile deprivation. To address the influence of tactile deprivation on adult behavior, we performed bilateral whisker trimming in mice for 10 days after birth (BWT10 mice) and examined social behaviors, tactile discrimination, and c-Fos expression, a marker of neural activation, in adults after full whisker regrowth. Adult BWT10 mice exhibited significantly shorter crossable distances in the gap-crossing test than age-matched controls, indicating persistent deficits in whisker-dependent tactile perception. In contrast to controls, BWT10 mice exhibited no preference for the social compartment containing a conspecific in the three-chamber test. Furthermore, the development of amygdala circuitry was severely affected in BWT10 mice. Based on the c-Fos expression pattern, hyperactivity was found in BWT10 amygdala circuits for processing fear/anxiety-related responses to height stress but not in circuits for processing reward stimuli during whisker-dependent cued learning. These results demonstrate that neonatal whisker trimming and concomitant whisker-dependent tactile discrimination impairment severely disturbs the development of amygdala-dependent emotional regulation. PMID:27362655

  9. Effects of social isolation and enriched environment on behavior of adult Swiss mice do not require hippocampal neurogenesis.

    PubMed

    Silva, Cristiane Felisbino; Duarte, Filipe Silveira; Lima, Thereza Christina Monteiro De; de Oliveira, Cilene Lino

    2011-11-20

    Housing conditions are important determinants of animal behavior. Their impact on behavioral output depends on the behavior of interest, species, strain, and age of the animal evaluated. In the present study, male Swiss mice reared from weaning up to 8 weeks in social isolation (SI8), in enriched environment (EE8) or in standard environment (SE8) were evaluated in the elevated plus-maze (EPM), open-field (OFT) and tail-suspension (TST) tests. The effect of housing for 6 weeks in EE followed by 2 weeks in SI (EE6SI2) and the opposite condition (SI6EE2) was also studied. Housing conditions are reported to affect hippocampal neurogenesis; therefore, the expression of doublecortin (DCX) in the dentate gyrus of the hippocampus (DG) of these mice was monitored. Data showed that SI8, EE8 and EE6SI2 reduced the stretching-attend postures in the EPM and explored more the center of the apparatus when compared to SE8. The time and the number of entries in the closed arms of the EPM was not affected indicating that effects of housing conditions in the EPM were not consequence of motor activity alteration. Accordingly, EE8 mice exploration of the OFT was similar to SE8. However, the SI8 mice explored the OFT more than the EE8 mice, suggesting hyperactivity induced by isolation. Behavior of Swiss mice in the TST was not altered, indicating that this test was not sensitive to the environmental changes in this mice strain. Compared to SE8, EE8 did not affect the number of DCX cells, whereas SI8, EE6SI2, and SI6EE2 decreased it. Taken together, our data suggest that the behavior of adult Swiss mice in the EPM and OFT was affected by environmental changes but that these changes seem to be independent of hippocampal neurogenesis.

  10. CD1A, D and E gene polymorphisms in a North African population from Morocco.

    PubMed

    Aureli, Anna; Oumhani, Khadija; Del Beato, Tiziana; El Aouad, Rajae; Piancatelli, Daniela

    2016-07-01

    CD1 molecules are specialized in capturing and presenting lipids and glycolipids to distinct subsets of T and NKT cells. Glycolipid presentation could play a significant role in the immune response against microbial infections. There are five closely linked CD1 genes in humans, named CD1A, B, C, D, and E, which all show a limited polymorphism. In this study, exon 2 polymorphisms of CD1A, CD1D and CD1E were investigated and allele, genotype and haplotype frequencies of these loci were reported in a Moroccan population. A comparison with allele, genotype and haplotype frequencies observed in other geographic areas was also performed. Results confirmed the presence of ethnic differences in CD1 polymorphism, mainly in CD1D (in this population two additional CD1D variant alleles, CD1D(∗)03 and CD1D(∗)04, were described) and E genes. These data could be useful to evaluate a possible pathogenetic role of CD1 in diseases. Increasing the knowledge in this field may offer possibilities for the development of new immunotherapeutic approaches.

  11. Characteristics of Multi-Organ Lymphangiectasia Resulting from Temporal Deletion of Calcitonin Receptor-Like Receptor in Adult Mice

    PubMed Central

    Hoopes, Samantha L.; Willcockson, Helen H.; Caron, Kathleen M.

    2012-01-01

    Adrenomedullin (AM) and its receptor complexes, calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2/3, are highly expressed in lymphatic endothelial cells and are required for embryonic lymphatic development. To determine the role of Calcrl in adulthood, we used an inducible Cre-loxP system to temporally and ubiquitously delete Calcrl in adult mice. Following tamoxifen injection, Calcrlfl/fl/CAGGCre-ER™ mice rapidly developed corneal edema and inflammation that was preceded by and persistently associated with dilated corneoscleral lymphatics. Lacteals and submucosal lymphatic capillaries of the intestine were also dilated, while mesenteric collecting lymphatics failed to properly transport chyle after an acute Western Diet, culminating in chronic failure of Calcrlfl/fl/CAGGCre-ER™ mice to gain weight. Dermal lymphatic capillaries were also dilated and chronic edema challenge confirmed significant and prolonged dermal lymphatic insufficiency. In vivo and in vitro imaging of lymphatics with either genetic or pharmacologic inhibition of AM signaling revealed markedly disorganized lymphatic junctional proteins ZO-1 and VE-cadherin. The maintenance of AM signaling during adulthood is required for preserving normal lymphatic permeability and function. Collectively, these studies reveal a spectrum of lymphatic defects in adult Calcrlfl/fl/CAGGCre-ER™ mice that closely recapitulate the clinical symptoms of patients with corneal, intestinal and peripheral lymphangiectasia. PMID:23028890

  12. Altered resistance to Trichinella spiralis infection following subchronic exposure of adult mice to chemicals of environmental concern

    SciTech Connect

    Luebke, R.W.

    1981-01-01

    The effects of subchronic chemical exposure on expulsion of adult Trichinella spiralis from the small intestine of mice and encystment of newborn larvae in the host's musculature were investigated. Exposure to diethylstilbestrol, benzo(a)pyrene, tris-(1,3-dichloro-2-propyl) phosphate, cyclophosphamide, phorbol myristate acetate, and dimethylvinylchloride prior to infection of mice with 200 infective larvae resulted in larger worm burdens in treated animals than in controls 14 days after infection. Worm expulsion was not affected by exposure to tris-(2,3-dibromopropyl)phosphate, orthophenylphenol, and indomethacin. Increased burdens of muscle-phase larvae were found in animals that maintained significant numbers of adult worms in the gut at 14 days, except in mice administered diethylstilbestrol and dimethylvinylchloride. Exposure to diethylstilbestrol and cyclophosphamide resulted in decreased inflammatory reactions in the tissues of the small intestine and development of bone marrow eosinophilia in infected mice. Marrow eosinophilia was likewise decreased in mice given tris-(1,3-dichloro-2-propyl)phosphate before infection. Additional studies with diethylstilbestrol administered either before, at the time of, or after infection showed inhibition of worm expulsion. Drug exposure during a primary infection inhibited the expulsion of a second T. spiralis infection, but did not affect worm elimination when given during a second infection. Treatment with diethylstilbestrol after artificial sensitization of mice with Trichinella antigens decreased delayed hypersensitivity responses to the sensitizing antigen. Immune functions, assessed by lymphoproliferative responses to mitogens and antibody responses to sheep red blood cells, generally correlated with altered host resistance to T. spiralis infection.

  13. Cardiac structure/function, protein expression, and DNA methylation are changed in adult female mice exposed to diethylstilbestrol in utero.

    PubMed

    Haddad, Rami; Kasneci, Amanda; Sebag, Igal A; Chalifour, Lorraine E

    2013-09-01

    The detrimental effects of in utero exposure to the non-steroidal estrogen diethylstilbestrol (DES) are particularly marked in women. Fetal hearts express estrogen receptors, making them potentially responsive to DES. To examine whether gestational exposure to DES would impact the heart, we exposed pregnant C57bl/6n dams to DES (0.1, 1.0, and 10.0 μg·(kg body mass)(-1)·day(-1)) on gestation days 11.5-14.5, and examined the measured cardiac structure/function and calcium homeostasis protein expression in adult females. At baseline, echocardiography revealed eccentric hypertrophy in mice treated with 10.0 μg·(kg body mass)(-1)·day(-1) DES, and immunoblots showed increased SERCA2a in all DES-treated mice. Mice were swim-trained to assess cardiac remodeling. Swim-trained vehicle-treated mice developed eccentric hypertrophy without changing SERCA2 or calsequestrin 2 expression. In contrast, no DES-treated mice hypertrophied, and all increased in SERCA2a and calsequestrin 2 expression after training. To determine whether DES-induced changes in DNA methylation is part of the mechanism for its long-term effects, we measured DNA methyltransferase expression and DNA methylation. Global DNA methylation and DNA methyltransferase 3a expression were unchanged. However, DES-treated mice had increased DNA methylation in the calsequestrin 2 promoter. Thus, gestational exposure to DES altered female ventricular DNA, cardiac structure/function, and calcium homeostasis protein expression. We conclude that gestational exposure to estrogenizing compounds may impact cardiac structure/function in adult females.

  14. Knock-out of HCN1 subunit flattens dorsal-ventral frequency gradient of medial entorhinal neurons in adult mice.

    PubMed

    Giocomo, Lisa M; Hasselmo, Michael E

    2009-06-10

    Layer II stellate cells at different locations along the dorsal to ventral axis of medial entorhinal cortex show differences in the frequency of intrinsic membrane potential oscillations and resonance (Giocomo et al., 2007). The frequency differences scale with differences in the size and spacing of grid-cell firing fields recorded in layer II of the medial entorhinal cortex in behaving animals. To determine the mechanism for this difference in intrinsic frequency, we analyzed oscillatory properties in adult control mice and adult mice with a global deletion of the HCN1 channel. Data from whole-cell patch recordings show that the oscillation frequency gradient along the dorsal-ventral axis previously shown in juvenile rats also appears in control adult mice, indicating that the dorsal-ventral gradient generalizes across age and species. Knock-out of the HCN1 channel flattens the dorsal-ventral gradient of the membrane potential oscillation frequency, the resonant frequency, the time constant of the "sag" potential and the amplitude of the sag potential. This supports a role of the HCN1 subunit in the mechanism of the frequency gradient in these neurons. These findings have important implications for models of grid cells and generate predictions for future in vivo work on entorhinal grid cells.

  15. The anaesthetic combination of ketamine/midazolam does not alter the acquisition of spatial and motor tasks in adult mice.

    PubMed

    Valentim, A M; Olsson, I A S; Antunes, L M

    2013-01-01

    The ketamine/midazolam association of a dissociative with a sedative agent is used for the induction and maintenance of anaesthesia in laboratory animals. Anaesthesia may interfere with research results through side-effects on the nervous system, such as memory impairment. It is known that ketamine and midazolam affect cognition; however, their effects have not been clarified when used in a context of balanced anaesthesia. Thus, this study evaluated the effects of ketamine/midazolam on the acquisition of motor and of a spatial memory task in adult mice. Twenty-eight C57BL/6 adult male mice were divided into three groups: untreated control, treated with ketamine/midazolam (75 mg/kg / 10 mg/kg) and treated with midazolam (10 mg/kg) groups. Respiratory rate, heart rate and systolic pressure were measured every 5 min in the animals treated with ketamine/midazolam, as this was the only group that exhibited loss of the righting reflex. One day after treatment, animals were tested in the open field, rotarod and radial arm maze. There were no differences between treatments regarding open-field activity, rotarod performance or number of working and reference memory errors in the radial arm maze task. In conclusion, the learning process of spatial and motor tasks was not disrupted by the anaesthetic combination of ketamine/midazolam. These results suggest its safe use in adult mice in projects where acquisition of a spatial and motor task is necessary.

  16. Developmental dioxin exposure of either parent is associated with an increased risk of preterm birth in adult mice.

    PubMed

    Ding, Tianbing; McConaha, Melinda; Boyd, Kelli L; Osteen, Kevin G; Bruner-Tran, Kaylon L

    2011-04-01

    We have previously described diminished uterine progesterone response and increased uterine sensitivity to inflammation in adult female mice with a history of developmental exposure to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin). Since parturition in mammals is an inflammatory process mediated in part by a decline in progesterone action, toxicant-mediated disruption of progesterone receptor (PR) expression at the maternal-fetal interface would likely impact the timing of birth. Therefore, in the current study, we examined pregnancy outcomes in adult female mice with a similar in utero exposure to TCDD. We also examined the impact of in utero TCDD exposure of male mice on pregnancy outcomes in unexposed females since the placenta, a largely paternally derived organ, plays a major role in the timing of normal parturition via inflammatory signaling. Our studies indicate that developmental exposure of either parent to TCDD is associated with preterm birth in a subsequent adult pregnancy due to altered PR expression and placental inflammation.

  17. Postnatal Proteasome Inhibition Induces Neurodegeneration and Cognitive Deficiencies in Adult Mice: A New Model of Neurodevelopment Syndrome

    PubMed Central

    Romero-Granados, Rocío; Fontán-Lozano, Ángela; Aguilar-Montilla, Francisco Javier; Carrión, Ángel Manuel

    2011-01-01

    Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering proteasome inhibitors daily during the first 10 days of life, affects the behaviour of adult mice. We found that this regime of exposure to the proteasome inhibitors MG132 or lactacystin did not produce significant behavioural or morphological changes in the first 15 days of life. However, towards the end of the treatment with proteasome inhibitors, there was a loss of mitochondrial markers and activity, and an increase in DNA oxidation. On reaching adulthood, the memory of mice that were injected with proteasome inhibitors postnatally was impaired in hippocampal and amygdala-dependent tasks, and they suffered motor dysfunction and imbalance. These behavioural deficiencies were correlated with neuronal loss in the hippocampus, amygdala and brainstem, and with diminished adult neurogenesis. Accordingly, impairing proteasome activity at early postnatal ages appears to cause morphological and behavioural alterations in adult mice that resemble those associated with certain neurodegenerative diseases and/or syndromes of mental retardation. PMID:22174927

  18. Donor states in a semimagnetic Cd1 -xinMnxin Te /Cd1 -xoutMnxout Te Double Quantum Well

    NASA Astrophysics Data System (ADS)

    Kalpana, Panneer Selvam; Nithiananthi, Perumal; Jayakumar, Kalyanasundaram

    2017-02-01

    The theoretical investigation has been carried out on the binding energy of donor associated with the electrons confined in a Cd1 -xinMnxin Te /Cd1 -xoutMnxout Te Double Quantum Well (DQW) as a function of central barrier width for various well dimensions and impurity locations in the barrier and the well. The magnetic field can act as a tool to continuously change the interwell coupling inside this DQW systems and its effect on donor binding has also been studied. Moreover, the polaronic corrections, which is due to the strong exchange interaction between the magnetic moment of Mn2+ ion and the spin of the confined carrier, to the binding energy of the hydrogenic donor impurity has also been estimated with and without the application of magnetic field. The binding energy of the donor impurity is determined by solving the Schrodinger equation variationally in the effective mass approximation and the effect due to Bound Magnetic Polaron (BMP) is included using mean field theory with the modified Brillouin function. The results are reported and discussed.

  19. Impaired Memory in OT-II Transgenic Mice Is Associated with Decreased Adult Hippocampal Neurogenesis Possibly Induced by Alteration in Th2 Cytokine Levels

    PubMed Central

    Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-il; Moon, Minho

    2016-01-01

    Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic. PMID:27432189

  20. Impaired Memory in OT-II Transgenic Mice Is Associated with Decreased Adult Hippocampal Neurogenesis Possibly Induced by Alteration in Th2 Cytokine Levels.

    PubMed

    Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-Il; Moon, Minho

    2016-08-31

    Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic.

  1. Brain-derived neurotrophic factor signaling does not stimulate subventricular zone neurogenesis in adult mice and rats.

    PubMed

    Galvão, Rui P; Garcia-Verdugo, José Manuel; Alvarez-Buylla, Arturo

    2008-12-10

    In rodents, the adult subventricular zone (SVZ) generates neuroblasts which migrate to the olfactory bulb (OB) and differentiate into interneurons. Recent work suggests that the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) can enhance adult SVZ neurogenesis, but the mechanism by which it acts is unknown. Here, we analyzed the role of BDNF and its receptor TrkB in adult SVZ neurogenesis. We found that TrkB is the most prominent neurotrophin receptor in the mouse SVZ, but only the truncated, kinase-negative isoform (TrkB-TR) was detected. TrkB-TR is expressed in SVZ astrocytes and ependymal cells, but not in neuroblasts. TrkB mutants have reduced SVZ proliferation and survival and fewer new OB neurons. To test whether this effect is cell-autonomous, we grafted SVZ cells from TrkB knock-out mice (TrkB-KO) into the SVZ of wild-type mice (WT). Grafted progenitors generated neuroblasts that migrated to the OB in the absence of TrkB. The survival and differentiation of granular interneurons and Calbindin(+) periglomerular interneurons seemed unaffected by the loss of TrkB, whereas dopaminergic periglomerular neurons were reduced. Intra-ventricular infusion of BDNF yielded different results depending on the animal species, having no effect on neuron production from mouse SVZ, while decreasing it in rats. Interestingly, mice and rats also differ in their expression of the neurotrophin receptor p75. Our results indicate that TrkB is not essential for adult SVZ neurogenesis and do not support the current view that delivering BDNF to the SVZ can enhance adult neurogenesis.

  2. The crystal structure of avian CD1 reveals a smaller, more primordial antigen-binding pocket compared to mammalian CD1

    PubMed Central

    Zajonc, Dirk M.; Striegl, Harald; Dascher, Christopher C.; Wilson, Ian A.

    2008-01-01

    The molecular details of glycolipid presentation by CD1 antigen-presenting molecules are well studied in mammalian systems. However, little is known about how these non-classical MHC class I (MHCI) molecules diverged from the MHC locus to create a more complex, hydrophobic binding groove that binds lipids rather than peptides. To address this fundamental question, we have determined the crystal structure of an avian CD1 (chCD1–2) that shares common ancestry with mammalian CD1 from ≈310 million years ago. The chCD1–2 antigen-binding site consists of a compact, narrow, central hydrophobic groove or pore rather than the more open, 2-pocket architecture observed in mammalian CD1s. Potential antigens then would be restricted in size to single-chain lipids or glycolipids. An endogenous ligand, possibly palmitic acid, serves to illuminate the mode and mechanism of ligand interaction with chCD1–2. The palmitate alkyl chain is inserted into the relatively shallow hydrophobic pore; its carboxyl group emerges at the receptor surface and is stabilized by electrostatic and hydrogen bond interactions with an arginine residue that is conserved in all known CD1 proteins. In addition, other novel features, such as an A′ loop that interrupts and segments the normally long, continuous α1 helix, are unique to chCD1–2 and contribute to the unusually narrow binding groove, thereby limiting its size. Because birds and mammals share a common ancestor, but the rate of evolution is slower in birds than in mammals, the chCD1–2-binding groove probably represents a more primordial CD1-binding groove. PMID:19004781

  3. Agonistic behavior in males and females: effects of an estrogen receptor beta agonist in gonadectomized and gonadally intact mice

    PubMed Central

    Allen, Amy E. Clipperton; Cragg, Cheryl L.; Wood, Alexis J.; Pfaff, Donald W.; Choleris, Elena

    2010-01-01

    Summary Affiliative and agonistic social interactions are mediated by gonadal hormones. Research with estrogen receptor alpha (ERα) or beta (ERβ) knockout (KO) mice show that long-term inactivation of ERα decreases, while inactivation of ERβ increases, male aggression. Opposite effects were found in female αERKO and βERKO mice. The role of acute activation of ERα or ERβ in the agonistic responses of adult non-KO mice is unknown. We report here the effects of the ERβ selective agonist WAY-200070 on agonistic and social behavior in gonadally intact and gonadectomized (gonadex) male and female CD-1 mice towards a gonadex, same-sex intruder. All 15 min resident-intruder tests were videotaped for comprehensive behavioral analysis. Separate analyses assessed: 1) effects of WAY-200070 on each sex and gonadal condition; 2) differences between sexes, and between gonadally intact and gonadex mice, in untreated animals. Results show that in gonadally intact male and female mice WAY-200070 increased agonistic behaviors such as pushing down and aggressive grooming, while leaving attacks unaffected. In untreated mice, males attacked more than females, and gonadex animals showed less agonistic behavior than same-sex, gonadally intact mice. Overall, our detailed behavioral analysis suggested that in gonadally intact male and female mice, ERβ mediates patterns of agonistic behavior that are not directly involved in attacks. This suggests that specific aspects of aggressive behavior are acutely mediated by ERβ in adult mice. Our results also showed that, in resident-intruder tests, female mice spend as much time in intrasexual agonistic interactions as males, but use agonistic behaviors that involve extremely low levels of direct attacks. This non-attack aggression in females is increased by acute activation of ERβ. Thus, acute activation of ERβ similarly mediates agonistic behavior in adult male and female CD-1 mice. PMID:20129736

  4. Crystal structure of human CD1e reveals a groove suited for lipid-exchange processes.

    PubMed

    Garcia-Alles, Luis F; Giacometti, Gaelle; Versluis, Cees; Maveyraud, Laurent; de Paepe, Diane; Guiard, Julie; Tranier, Samuel; Gilleron, Martine; Prandi, Jacques; Hanau, Daniel; Heck, Albert J R; Mori, Lucia; De Libero, Gennaro; Puzo, Germain; Mourey, Lionel; de la Salle, Henri

    2011-08-09

    CD1e is the only human CD1 protein existing in soluble form in the late endosomes of dendritic cells, where it facilitates the processing of glycolipid antigens that are ultimately recognized by CD1b-restricted T cells. The precise function of CD1e remains undefined, thus impeding efforts to predict the participation of this protein in the presentation of other antigens. To gain insight into its function, we determined the crystal structure of recombinant CD1e expressed in human cells at 2.90-Å resolution. The structure revealed a groove less intricate than in other CD1 proteins, with a significantly wider portal characterized by a 2 Å-larger spacing between the α1 and α2 helices. No electron density corresponding to endogenous ligands was detected within the groove, despite the presence of ligands unequivocally established by native mass spectrometry in recombinant CD1e. Our structural data indicate that the water-exposed CD1e groove could ensure the establishment of loose contacts with lipids. In agreement with this possibility, lipid association and dissociation processes were found to be considerably faster with CD1e than with CD1b. Moreover, CD1e was found to mediate in vitro the transfer of lipids to CD1b and the displacement of lipids from stable CD1b-antigen complexes. Altogether, these data support that CD1e could have evolved to mediate lipid-exchange/editing processes with CD1b and point to a pathway whereby the repertoire of lipid antigens presented by human dendritic cells might be expanded.

  5. Neonatal respiratory syncytial virus infection has an effect on lung inflammation and the CD4(+) CD25(+) T cell subpopulation during ovalbumin sensitization in adult mice.

    PubMed

    Comas-García, A; López-Pacheco, C P; García-Zepeda, E A; Soldevila, G; Ramos-Martínez, P; Ramos-Castañeda, J

    2016-08-01

    In BALB/c adult mice, respiratory syncytial virus (RSV) infection enhances the degree of lung inflammation before and/or after ovalbumin (OVA) respiratory sensitization. However, it is unclear whether RSV infection in newborn mice has an effect on the immune response to OVA respiratory sensitization in adult mice. The aim of this study was to determine if RSV neonatal infection alters T CD4(+) population and lung inflammation during OVA respiratory sensitization in adult mice. BALB/c mice were infected with RSV on the fourth day of life and challenged by OVA 4 weeks later. We found that in adult mice, RSV neonatal infection prior to OVA sensitization reduces the CD4(+) CD25(+) and CD4(+) CD25(+) forkhead protein 3 (FoxP3)(+) cell populations in the lungs and bronchoalveolar lavage. Furthermore, it also attenuates the inflammatory infiltrate and cytokine/chemokine expression levels in the mouse airways. In conclusion, the magnitude of the immune response to a non-viral respiratory perturbation in adult mice is not enhanced by a neonatal RSV infection.

  6. Feeding Pregnant and Lactating Mice Rhodiola kirilowii Extracts helps to Preserve Thymus Function of their Adult Progeny.

    PubMed

    Bień, K; Lewicki, S; Zdanowski, R; Skopinska-Różewska, E; Krzyżowska, M

    2016-09-01

    Plants belonging to Rhodiola kirilowii species, members of Rhodiola genus and Crassulaceae family, grow wildly in Tibet, Mongolia and China mountains and are traditionally used as adaptogens, antidepressants and anti-inflammatory remedies. Nowadays, R. kirilowii is cultivated in some countries, also in Poland. In our previous papers we reported immuno- and angio-modulatory effects of aqueous and hydro-alcoholic extracts of radix and rhizome of this plant in non-pregnant and pregnant mice. The aim of the present study was to evaluate the effect of feeding pregnant and further lactating mice these extracts on selected thymus function parameters in adult progeny. The counts of M-30+ apoptotic cells, in the thymuses obtained from progeny of mice fed during pregnancy and lactation water or 50% water-alcoholic extract of Rhodiola kirilowii, were significantly lower (p<0.05) than apoptotic cells counts observed in the control mice. No significant differences in the counts of IL-7-positive cells in the thymuses obtained from progeny of the control mice and mothers treated with water or hydro-alcohol extracts of Rhodiola kirilowii were observed.

  7. Loss of endothelial-ARNT in adult mice contributes to dampened circulating proangiogenic cells and delayed wound healing.

    PubMed

    Han, Yu; Tao, Jiayi; Gomer, Alla; Ramirez-Bergeron, Diana L

    2014-12-01

    The recruitment and homing of circulating bone marrow-derived cells include endothelial progenitor cells (EPCs) that are critical to neovascularization and tissue regeneration of various vascular pathologies. We report here that conditional inactivation of hypoxia-inducible factor's (HIF) transcriptional activity in the endothelium of adult mice (Arnt(ΔiEC) mice) results in a disturbance of infiltrating cells, a hallmark of neoangiogenesis, during the early phases of wound healing. Cutaneous biopsy punches show distinct migration of CD31(+) cells into wounds of control mice by 36 hours. However, a significant decline in numbers of infiltrating cells with immature vascular markers, as well as decreased transcript levels of genes associated with their expression and recruitment, were identified in wounds of Arnt(ΔiEC) mice. Matrigel plug assays further confirmed neoangiogenic deficiencies alongside a reduction in numbers of proangiogenic progenitor cells from bone marrow and peripheral blood samples of recombinant vascular endothelial growth factor-treated Arnt(ΔiEC) mice. In addition to HIF's autocrine requirements in endothelial cells, our data implicate that extrinsic microenvironmental cues provided by endothelial HIF are pivotal for early migration of proangiogenic cells, including those involved in wound healing.

  8. [Effect of amantadine or 3-cyclopentyl adamantanamine on the immobility of adult or aged mice, in the forced swim test].

    PubMed

    Vamvakidès, A

    2000-12-01

    Amantadine (AMA), an antiparkinsonian drug, (20 mg/Kg, ip) or 3-cyclopentyl adamantanamine (AdCP), an AMA derivative synthesized recently, (20 mg/Kg, ip) induced an anti-immobility effect-comparable to those of imipramine (IMI), an antidepressive drug, (30 mg/Kg, ip) - in the forced swim test (FST), on adult (4 months) Balb-C mice. In contrast, on aged (10 months) Balb-C mice, only AdCP (20 or 40 mg/Kg, ip) was active in the FST. It is suggested that the inactivity of AMA or IMI on the aged Balb-C mice could be the consequence of their NMDA (i.e., N-methyl-D-aspartic acid sensitive) receptors failure. This NMDA receptors dysfunction could render non significant the antagonism of the mice immobility in the FST, induced by AMA or IMI, which could result (in part for IMI) from the anti-NMDA effect of these drugs. In contrast AdCP, which may principally act by glycinergic A (strychnine sensitive) effect, inhibiting the release of the brain monoamines and glutamate, conserved its activity in the FST on aged mice. In conclusion, it seems that the neurochemical profile of the drugs studied in the FST, could be useful for understanding their anti-immobility effect and for a rational approach of their possible clinical use as antidepressant.

  9. PENTACHLOROPHENOL POTENTIATES BENZO[A]PYRENE DNA ADDUCT FORMATION IN ADULT BUT NOT INFANT B6C3F1 MALE MICE

    EPA Science Inventory

    Abstract

    The objective of this study is to determine whether pentachlorophenol (PCP) alters benzo[a]pyrene (B[a]P) induced DNA adduct formation in infant and adult B6C3Fl mice. Mice were exposed to 55 ug B[a]P/g body weight (BW) alone and in combination with several dose...

  10. Evaluation of antioxidant effects of crocin on sperm quality in cyclophosphamide treated adult mice

    PubMed Central

    Bakhtiary, Zahra; Shahrooz, Rasoul; Ahmadi, Abbas; Zarei, Leila

    2014-01-01

    Cyclophosphamide (CP) is one of the anti-neoplastic drugs. Despite its numerous clinical applications, it has devastating effects on the testicles and declines the sperm quality in treated patients. This study was aimed to investigate the protective effect of crocin in improving the toxicity induced by CP in reproductive system. In this study, 24 male adult mice (6 to 8 weeks) were randomly divided into three groups, control group received normal saline (0.1 mL, IP, daily), the CP group received CP (15 mg kg-1, IP, weekly) and the CP + crocin group received CP along with crocin (200 mg kg-1, IP, daily). After 35 days of treatment, animals were sacrificed. The samples of epididymis in human tubal fluid medium incubated for 30 min in 5% CO2 for flotation of sperm. Sperm were obtained from caudal epididymis using dissecting method. Then, the parameters of sperm quality including sperm count, motility, viability, DNA damage, nuclear maturation, and sperm morphology were evaluated. In CP group, the sperm count, motility, viability, nuclear maturation and sperm morphology were significantly decreased compared to control group (p < 0.05) and in the CP + crocin group all of these parameters significantly increased compared to CP group (p < 0.05). The percentage of sperm with DNA damage in the CP group significantly increased compared to other groups (p < 0.05). The results of this study indicated that the crocin was able to suppress free radicals and enhance the quality of sperm in CP treated animals. PMID:25568721

  11. Cerebral Cell Renewal in Adult Mice Controls the Onset of Obesity

    PubMed Central

    Gouazé, Alexandra; Brenachot, Xavier; Rigault, Caroline; Krezymon, Alice; Rauch, Camille; Nédélec, Emmanuelle; Lemoine, Aleth; Gascuel, Jean; Bauer, Sylvian; Pénicaud, Luc; Benani, Alexandre

    2013-01-01

    The hypothalamus plays a crucial role in the control of the energy balance and also retains neurogenic potential into adulthood. Recent studies have reported the severe alteration of the cell turn-over in the hypothalamus of obese animals and it has been proposed that a neurogenic deficiency in the hypothalamus could be involved in the development of obesity. To explore this possibility, we examined hypothalamic cell renewal during the homeostatic response to dietary fat in mice, i.e., at the onset of diet-induced obesity. We found that switching to high-fat diet (HFD) accelerated cell renewal in the hypothalamus through a local, rapid and transient increase in cell proliferation, peaking three days after introducing the HFD. Blocking HFD-induced cell proliferation by central delivery of an antimitotic drug prevented the food intake normalization observed after HFD introduction and accelerated the onset of obesity. This result showed that HFD-induced dividing brain cells supported an adaptive anorectic function. In addition, we found that the percentage of newly generated neurons adopting a POMC-phenotype in the arcuate nucleus was increased by HFD. This observation suggested that the maturation of neurons in feeding circuits was nutritionally regulated to adjust future energy intake. Taken together, these results showed that adult cerebral cell renewal was remarkably responsive to nutritional conditions. This constituted a physiological trait required to prevent severe weight gain under HFD. Hence this report highlighted the amazing plasticity of feeding circuits and brought new insights into our understanding of the nutritional regulation of the energy balance. PMID:23967273

  12. Tetrahydrohyperforin increases adult hippocampal neurogenesis in wild-type and APPswe/PS1ΔE9 mice.

    PubMed

    Abbott, Ana C; Calderon Toledo, Carla; Aranguiz, Florencia C; Inestrosa, Nibaldo C; Varela-Nallar, Lorena

    2013-01-01

    Tetrahydrohyperforin (IDN5706), a semi-synthetic derivative of hyperforin, has shown neuroprotective properties preventing the impairment of synaptic plasticity and cognitive decline in an in vivo model of Alzheimer's disease (AD). Considering the reported role of adult neurogenesis in the plasticity of the hippocampal network, we investigated whether IDN5706 affects adult neurogenesis and hippocampal function. In hippocampal progenitors cultured from adult rats, IDN5706 increased proliferation. Moreover, treatment with IDN5706 for 4 weeks increased cell proliferation in the subgranular zone (SGZ) of the hippocampus in 2 month-old wild-type mice in vivo. As determined by double labeling with BrdU and neuronal markers, IDN5706 treatment increased the number of immature neurons and newborn mature neurons in the adult dentate gyrus. In addition, IDN5706 treatment improved long-term memory in a hippocampal-dependent spatial memory task. Finally, IDN5706 treatment increased cell proliferation and neural commitment in the SGZ of the double transgenic APPswe/PS1ΔE9 mouse model of AD. These results indicate that IDN5706 increases adult hippocampal neurogenesis and may have therapeutic value in neurological disorders in which adult neurogenesis is impaired.

  13. Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

    PubMed Central

    Mansour, Salah; Tocheva, Anna S.; Cave-Ayland, Chris; Machelett, Moritz M.; Sander, Barbara; Lissin, Nikolai M.; Molloy, Peter E.; Baird, Mark S.; Stübs, Gunthard; Schröder, Nicolas W. J.; Schumann, Ralf R.; Rademann, Jörg; Postle, Anthony D.; Jakobsen, Bent K.; Marshall, Ben G.; Gosain, Rajendra; Elkington, Paul T.; Elliott, Tim; Skylaris, Chris-Kriton; Essex, Jonathan W.; Tews, Ivo; Gadola, Stephan D.

    2016-01-01

    Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors. PMID:26884207

  14. T cell receptor recognition of CD1b presenting a mycobacterial glycolipid

    PubMed Central

    Gras, Stephanie; Van Rhijn, Ildiko; Shahine, Adam; Cheng, Tan-Yun; Bhati, Mugdha; Tan, Li Lynn; Halim, Hanim; Tuttle, Kathryn D.; Gapin, Laurent; Le Nours, Jérôme; Moody, D. Branch; Rossjohn, Jamie

    2016-01-01

    CD1 proteins present microbial lipids to T cells. Germline-encoded mycolyl lipid-reactive (GEM) T cells with conserved αβ T cell receptors (TCRs) recognize CD1b presenting mycobacterial mycolates. As the molecular basis underpinning TCR recognition of CD1b remains unknown, here we determine the structure of a GEM TCR bound to CD1b presenting glucose-6-O-monomycolate (GMM). The GEM TCR docks centrally above CD1b, whereby the conserved TCR α-chain extensively contacts CD1b and GMM. Through mutagenesis and study of T cells from tuberculosis patients, we identify a consensus CD1b footprint of TCRs present among GEM T cells. Using both the TCR α- and β-chains as tweezers to surround and grip the glucose moiety of GMM, GEM TCRs create a highly specific mechanism for recognizing this mycobacterial glycolipid. PMID:27807341

  15. Tandem repeats modify the structure of the canine CD1D gene.

    PubMed

    Looringh van Beeck, F A; Leegwater, P A J; Herrmann, T; Broere, F; Rutten, V P M G; Willemse, T; Van Rhijn, I

    2013-06-01

    Among the CD1 proteins that present lipid antigens to T cells, CD1d is the only one that stimulates a population of T cells with an invariant T-cell receptor known as NKT cells. Sequencing of a 722 nucleotide gap in the dog (Canis lupus familiaris) genome revealed that the canine CD1D gene lacks a sequence homologous to exon 2 of human CD1D, coding for the start codon and signal peptide. Also, the canine CD1D gene contains three different short tandem repeats that disrupt the expected gene structure. Because canine CD1D cDNA lacks sequences homologous to human exon 2 and 3, the functionality of canine CD1d protein may be affected, and this could have consequences for the development and activation of canine NKT cells.

  16. In Utero Environmental Tobacco Smoke Exposure Alters Gene Expression in Lungs of Adult BALB/c Mice

    PubMed Central

    Rouse, Rodney L.; Boudreaux, Marc J.; Penn, Arthur L.

    2007-01-01

    Background In utero environmental tobacco smoke (ETS) exposure exacerbates initial lung responses of adult mice to ovalbumin (OVA), a common allergen in rodent models of allergic asthma. Objective We tested the hypothesis that in utero ETS exposure alters expression of genes (including asthma-related and inflammatory genes) in the lungs of adult mice and that this differential expression is reflected in differential respiratory and immune responses to nontobacco allergens. Methods Using Affymetrix Mouse Genome 430 2.0 arrays, we examined gene expression changes in lungs of BALB/c mice exposed to ETS in utero, OVA, or saline aerosol at weeks 7–8, and OVA sensitization and challenge at weeks 11–15. Data sets were filtered by transcript p-value (≤ 0.05), false discovery rate (≤ 0.05), and fold change (≥ 1.5). Differential expression of selected genes was confirmed by polymerase chain reaction (PCR). Results Genes differentially expressed as a result of in utero ETS exposure are involved in regulation of biological processes (immune response, cell proliferation, apoptosis, cell metabolism) through altered cytoskeleton, adhesion, transcription, and enzyme molecules. A number of genes prominent in lung inflammation were differentially expressed on PCR but did not pass selection criteria for microarray, including arginase (Arg1), chitinases (Chia, Chi3l3, Chi3l4), eotaxins (Ccl11, Ccl24), small proline-rich protein 2a (Sprr2a), and cytokines (Il4, Il6, Il10, Il13, Tnfa) . Conclusion The differential lung gene expression reported here is consistent with previously reported functional changes in lungs of mice exposed in utero to ETS and as adults to the nontobacco allergen OVA. PMID:18087596

  17. Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

    PubMed Central

    Mingote, Susana; Masson, Justine; Gellman, Celia; Thomsen, Gretchen M.; Lin, Chyuan-Sheng; Merker, Robert J.; Gaisler-Salomon, Inna; Wang, Yvonne; Ernst, Rachel; Hen, René; Rayport, Stephen

    2016-01-01

    Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAGERT2cre∕+ mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction—mimicking pharmacological inhibition—strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel

  18. Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice.

    PubMed

    Mingote, Susana; Masson, Justine; Gellman, Celia; Thomsen, Gretchen M; Lin, Chyuan-Sheng; Merker, Robert J; Gaisler-Salomon, Inna; Wang, Yvonne; Ernst, Rachel; Hen, René; Rayport, Stephen

    2015-01-01

    Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG(ERT2cre∕+) mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction-mimicking pharmacological inhibition-strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target

  19. Presynaptic size of associational/commissural CA3 synapses is controlled by fibroblast growth factor 22 in adult mice.

    PubMed

    Pasaoglu, Taliha; Schikorski, Thomas

    2016-02-01

    Associational/commissural CA3-CA3 synapses define the recurrent CA3 network that generates the input to CA1 pyramidal neurons. We quantified the fine structure of excitatory synapses in the stratum radiatum of the CA3d area in adult wild type (WT) and fibroblast growth factor 22 knock-out (FGF22KO) mice by using serial 3D electron microscopy. WT excitatory CA3 synapses are rather small yet range 10 fold in size. Spine size, however, was small and uniform and did not correlate with the size of the synaptic junction. To reveal mechanisms that regulate presynaptic structure, we investigated the role of FGF22, a target-derived signal specific for the distal part of area CA3 (CA3d). In adult FGF22KO mice, postsynaptic properties of associational CA3 synapses were unaltered. Presynaptically, the number of synaptic vesicles (SVs), the bouton volume, and the number of vesicles in axonal regions (the super pool) were reduced. This concurrent decrease suggests concerted control by FGF22 of presynaptic size. This hypothesis is supported by the finding that WT presynapses in the proximal part of area CA3 (CA3p) that do not receive FGF22 signaling in WT mice were smaller than presynapses in CA3d in WT but of comparable size in CA3d of FGF22KO mice. Docked SV density was decreased in CA1, CA3d, and CA3p in FGF22KO mice. Because CA1 and CA3p are not directly affected by the loss of FGF22, the smaller docked SV density may be an adaptation to activity changes in the CA3 network. Thus, docked SV density potentially is a long-term regulator for the synaptic release probability and/or the strength of short-term depression in vivo.

  20. Post-training, intrahippocampal HDAC inhibition differentially impacts neural circuits underlying spatial memory in adult and aged mice.

    PubMed

    Dagnas, Malorie; Micheau, Jacques; Decorte, Laurence; Beracochea, Daniel; Mons, Nicole

    2015-07-01

    Converging evidence indicates that pharmacologically elevating histone acetylation using post-training, systemic or intrahippocampal, administration of histone deacetylase inhibitor (HDACi) can enhance memory consolidation processes in young rodents but it is not yet clear, whether such treatment is sufficient to prevent memory impairments associated with aging. To address this question, we used a 1-day massed spatial learning task in the water maze to investigate the effects of immediate post-training injection of the HDACi trichostatin A (TSA) into the dorsal hippocampus on long-term memory consolidation in 3-4 and 18-20 month-old mice. We show that TSA improved the 24 h-memory retention for the hidden platform location in young-adults, but failed to rescue memory impairments in older mice. The results further indicate that Young-TSA mice sacrificed 1 h after training had a robust increase in histone H4 acetylation in the dorsal hippocampal CA1 region (dCA1) and the dorsomedial part of the striatum (DMS), a structure important for spatial information processing. Importantly, TSA infusion in aged mice completely rescued altered H4 acetylation in the dCA1 but failed to alleviate age-associated decreased H4 acetylation in the DMS. Moreover, intrahippocampal TSA infusion produced concomitant decreases (in adults) or increases (in older mice) of acetylated histone levels in the ventral hippocampus (vCA1 and vCA3) and the lateral amygdala, two structures critically involved in stress and emotional responses. These data suggest that the failure of post-training, intrahippocampal TSA injection to reverse age-associated memory impairments may be related to an inability to recruit appropriate circuit-specific epigenetic patterns during early consolidation processes.

  1. Peripubertal Vitamin D3 Deficiency Delays Puberty and Disrupts the Estrous Cycle in Adult Female Mice1

    PubMed Central

    Dicken, Cary L.; Israel, Davelene D.; Davis, Joe B.; Sun, Yan; Shu, Jun; Hardin, John; Neal-Perry, Genevieve

    2012-01-01

    ABSTRACT The mechanism(s) by which vitamin D3 regulates female reproduction is minimally understood. We tested the hypothesis that peripubertal vitamin D3 deficiency disrupts hypothalamic-pituitary-ovarian physiology. To test this hypothesis, we used wild-type mice and Cyp27b1 (the rate-limiting enzyme in the synthesis of 1,25-dihydroxyvitamin D3) null mice to study the effect of vitamin D3 deficiency on puberty and reproductive physiology. At the time of weaning, mice were randomized to a vitamin D3-replete or -deficient diet supplemented with calcium. We assessed the age of vaginal opening and first estrus (puberty markers), gonadotropin levels, ovarian histology, ovarian responsiveness to exogenous gonadotropins, and estrous cyclicity. Peripubertal vitamin D3 deficiency significantly delayed vaginal opening without affecting the number of GnRH-immunopositive neurons or estradiol-negative feedback on gonadotropin levels during diestrus. Young adult females maintained on a vitamin D3-deficient diet after puberty had arrested follicular development and prolonged estrous cycles characterized by extended periods of diestrus. Ovaries of vitamin D3-deficient Cyp27b1 null mice responded to exogenous gonadotropins and deposited significantly more oocytes into the oviducts than mice maintained on a vitamin D3-replete diet. Estrous cycles were restored when vitamin D3-deficient Cyp27b1 null young adult females were transferred to a vitamin D3-replete diet. This study is the first to demonstrate that peripubertal vitamin D3 sufficiency is important for an appropriately timed pubertal transition and maintenance of normal female reproductive physiology. These data suggest vitamin D3 is a key regulator of neuroendocrine and ovarian physiology. PMID:22572998

  2. Induced Wnt5a expression perturbs embryonic outgrowth and intestinal elongation, but is well-tolerated in adult mice.

    PubMed

    Bakker, Elvira R M; Raghoebir, Lalini; Franken, Patrick F; Helvensteijn, Werner; van Gurp, Léon; Meijlink, Frits; van der Valk, Martin A; Rottier, Robbert J; Kuipers, Ernst J; van Veelen, Wendy; Smits, Ron

    2012-09-01

    Wnt5a is essential during embryonic development, as indicated by mouse Wnt5a knockout embryos displaying outgrowth defects of multiple structures including the gut. The dynamics of Wnt5a involvement in these processes is unclear, and perinatal lethality of Wnt5a knockout embryos has hampered investigation of Wnt5a during postnatal stages in vivo. Although in vitro studies have suggested a relevant role for Wnt5a postnatally, solid evidence for a significant impact of Wnt5a within the complexity of an adult organism is lacking. We generated a tightly-regulated inducible Wnt5a transgenic mouse model and investigated the effects of Wnt5a induction during different time-frames of embryonic development and in adult mice, focusing on the gastrointestinal tract. When induced in embryos from 10.5 dpc onwards, Wnt5a expression led to severe outgrowth defects affecting the gastrointestinal tracts, limbs, facial structures and tails, closely resembling the defects observed in Wnt5a knockout mice. However, Wnt5a induction from 13.5 dpc onwards did not cause this phenotype, indicating that the most critical period for Wnt5a in embryonic development is prior to 13.5 dpc. In adult mice, induced Wnt5a expression did not reveal abnormalities, providing the first in vivo evidence that Wnt5a has no major impact on mouse intestinal homeostasis postnatally. Protein expression of Wnt5a receptor Ror2 was strongly reduced in adult intestine compared to embryonic stages. Moreover, we uncovered a regulatory process where induction of Wnt5a causes downregulation of its receptor Ror2. Taken together, our results indicate a role for Wnt5a during a restricted time-frame of embryonic development, but suggest no impact during homeostatic postnatal stages.

  3. Residual sarcoplasmic reticulum Ca2+ concentration after Ca2+ release in skeletal myofibers from young adult and old mice.

    PubMed

    Wang, Zhong-Min; Tang, Shen; Messi, María Laura; Yang, Jenny J; Delbono, Osvaldo

    2012-04-01

    Contrasting information suggests either almost complete depletion of sarcoplasmic reticulum (SR) Ca(2+) or significant residual Ca(2+) concentration after prolonged depolarization of the skeletal muscle fiber. The primary obstacle to resolving this controversy is the lack of genetically encoded Ca(2+) indicators targeted to the SR that exhibit low-Ca(2+) affinity, a fast biosensor: Ca(2+) off-rate reaction, and can be expressed in myofibers from adult and older adult mammalian species. This work used the recently designed low-affinity Ca(2+) sensor (Kd = 1.66 mM in the myofiber) CatchER (calcium sensor for detecting high concentrations in the ER) targeted to the SR, to investigate whether prolonged skeletal muscle fiber depolarization significantly alters residual SR Ca(2+) with aging. We found CatchER a proper tool to investigate SR Ca(2+) depletion in young adult and older adult mice, consistently tracking SR luminal Ca(2+) release in response to brief and repetitive stimulation. We evoked SR Ca(2+) release in whole-cell voltage-clamped flexor digitorum brevis muscle fibers from young and old FVB mice and tested the maximal SR Ca(2+) release by directly activating the ryanodine receptor (RyR1) with 4-chloro-m-cresol in the same myofibers. Here, we report for the first time that the Ca(2+) remaining in the SR after prolonged depolarization (2 s) in myofibers from aging (~220 μM) was larger than young (~132 μM) mice. These experiments indicate that SR Ca(2+) is far from fully depleted under physiological conditions throughout life, and support the concept of excitation-contraction uncoupling in functional senescent myofibers.

  4. Neonatal Bacillus Calmette-Guérin vaccination alleviates lipopolysaccharide-induced neurobehavioral impairments and neuroinflammation in adult mice

    PubMed Central

    Yang, Junhua; Qi, Fangfang; Yao, Zhibin

    2016-01-01

    The Bacillus Calmette-Guérin (BCG) vaccine is routinely administered to human neonates worldwide. BCG has recently been identified as a neuroprotective immune mediator in several neuropathological conditions, exerting neuroprotection in a mouse model of Parkinson's disease and slowing the progression of clinically isolated syndrome in patients with multiple sclerosis. The immune system is significantly involved in brain development, and several types of neonatal immune activations exert influences on the brain and behavior following a secondary immune challenge in adulthood. However, whether the neonatal BCG vaccination affects the brain in adulthood remains to be elucidated. In the present study, newborn C57BL/6 mice were injected subcutaneously with BCG (105 colony forming units) or phosphate-buffered saline (PBS). A total of 12 weeks later, the mice were injected intraperitoneally with 330 µg/kg lipopolysaccharide (LPS) or PBS. The present study reported that the neonatal BCG vaccination alleviated sickness, anxiety and depression-like behavior, lessened the impairments in hippocampal cell proliferation and downregulated the proinflammatory responses in the serum and brain that were induced by the adult LPS challenge. However, BCG vaccination alone had no evident influence on the brain and behavior in adulthood. In conclusion, the neonatal BCG vaccination alleviated the neurobehavioral impairments and neuroinflammation induced by LPS exposure in adult mice, suggesting a potential neuroprotective role of the neonatal BCG vaccination in adulthood. PMID:27357155

  5. Adult Gli2+/–;Gli3Δ699/+ Male and Female Mice Display a Spectrum of Genital Malformation

    PubMed Central

    He, Fei; Akbari, Pedram; Mo, Rong; Zhang, Jennifer J.; Hui, Chi-Chung; Kim, Peter C.; Farhat, Walid A.

    2016-01-01

    Disorders of sexual development (DSD) encompass a broad spectrum of urogenital malformations and are amongst the most common congenital birth defects. Although key genetic factors such as the hedgehog (Hh) family have been identified, a unifying postnatally viable model displaying the spectrum of male and female urogenital malformations has not yet been reported. Since human cases are diagnosed and treated at various stages postnatally, equivalent mouse models enabling analysis at similar stages are of significant interest. Additionally, all non-Hh based genetic models investigating DSD display normal females, leaving female urogenital development largely unknown. Here, we generated compound mutant mice, Gli2+/–;Gli3Δ699/+, which exhibit a spectrum of urogenital malformations in both males and females upon birth, and also carried them well into adulthood. Analysis of embryonic day (E)18.5 and adult mice revealed shortened anogenital distance (AGD), open ventral urethral groove, incomplete fusion of scrotal sac, abnormal penile size and structure, and incomplete testicular descent with hypoplasia in male mice, whereas female mutant mice displayed reduced AGD, urinary incontinence, and a number of uterine anomalies such as vaginal duplication. Male and female fertility was also investigated via breeding cages, and it was identified that male mice were infertile while females were unable to deliver despite becoming impregnated. We propose that Gli2+/–;Gli3Δ699/+ mice can serve as a genetic mouse model for common DSD such as cryptorchidism, hypospadias, and incomplete fusion of the scrotal sac in males, and a spectrum of uterine and vaginal abnormalities along with urinary incontinence in females, which could prove essential in revealing new insights into their equivalent diseases in humans. PMID:27814383

  6. Increased nitric oxide bioavailability in adult GRK2 hemizygous mice protects against angiotensin II-induced hypertension.

    PubMed

    Avendaño, María S; Lucas, Elisa; Jurado-Pueyo, María; Martínez-Revelles, Sonia; Vila-Bedmar, Rocío; Mayor, Federico; Salaices, Mercedes; Briones, Ana M; Murga, Cristina

    2014-02-01

    G protein-coupled receptor kinase 2 (GRK2) is a ubiquitous serine/threonine protein kinase able to phosphorylate and desensitize the active form of several G protein-coupled receptors. Given the lack of selective inhibitors for GRK2, we investigated the effects elicited by GRK2 inhibition in vascular responses using global adult hemizygous mice (GRK2(+/-)). The vasodilator responses to acetylcholine or isoproterenol were increased in aortas and mesenteric resistance arteries from GRK2(+/-) mice compared with wild-type (WT) littermates. After angiotensin II (AngII) infusion, GRK2(+/-) mice were partially protected against hypertension, vascular remodeling, and mechanical alterations, even when resting basal blood pressures were not significantly different. AngII infusion also (1) increased GRK2 levels in WT but not in GRK2(+/-) vessels; (2) increased vasoconstrictor responses to phenylephrine in WT but not in GRK2(+/-) mice; and (3) decreased vasodilator responses to acetylcholine and vascular pAkt and eNOS levels more in WT than in GRK2(+/-) animals. Vascular NO production and the modulation of vasoconstrictor responses by endothelial-derived NO remained enhanced in GRK2(+/-) mice infused with AngII. Thus, GRK2(+/-) mice are resistant to the development of vascular remodeling and mechanical alterations, endothelial dysfunction, increased vasoconstrictor responses, and hypertension induced by AngII at least partially through the preservation of NO bioavailability. In conclusion, our results describe an important role for GRK2 in systemic hypertension and further establish that an inhibition of GRK2 could be a beneficial treatment for this condition.

  7. Effect of insulin supplementation on in vitro maturation of pre-antral follicles from adult and pre-pubertal mice.

    PubMed

    Nath, Amar; Hakim, Bilal Ahmad; Rajender, Singh; Singh, Kavita; Sachdev, Monika; Konwar, Rituraj

    2016-05-01

    This study was aimed to determine the impact of insulin concentrations on in vitro pre-antral follicle growth, survival, antrum formation rate, and retrieval of mature oocytes in mice. Mice pre-antral follicle growth were recorded on days 2, 4, 6, 8, 10, and 12 in α-modified essential media (α-MEM) supplemented with insulin concentrations of 6, 8, and 10 μg/ml along with 10% FBS, 100 mIU/ml follicle stimulating hormone, 10 mIU/ml luteinizing hormone, 100 μg/ml penicillin, and 50 μg/ml streptomycin. After 12 d of growth in vitro, follicles were allowed to mature for 16-18 h in α-MEM supplemented with 1.5 IU/ml human chorionic gonadotrophin (hCG) and 5 ng/ml epidermal growth factor (EGF). The initial diameter (54.86 ± 2.5 μm) of mice oocyte progressively increased in all the three insulin concentration groups and attained a maximum size on day 12 (71.90 ± 2.8 μm). Supplementation with higher concentrations of insulin (both 8 and 10 μg/ml) significantly enhanced antrum formation without effecting the oocyte diameter and percent retrieval of mature oocyte in all the three concentration groups. Both in vitro cultured as well as in vivo collected follicles and oocytes showed similar localization and expression of oocyte maturation markers SAS1B and GDF9. Insulin concentration of 8 μg/ml was found to be optimal for in vitro follicle culture of adult mice (42-49 d). Optimized follicle culture conditions were also assessed successfully with pre-pubertal mice (12-14 d); however, adult mice showed higher follicle survival, antrum formation, and more mature oocytes production in comparison to pre-pubertal mice.

  8. Perinatal exposure of mice to the pesticide DDT impairs energy expenditure and metabolism in adult female offspring.

    PubMed

    La Merrill, Michele; Karey, Emma; Moshier, Erin; Lindtner, Claudia; La Frano, Michael R; Newman, John W; Buettner, Christoph

    2014-01-01

    Dichlorodiphenyltrichloroethane (DDT) has been used extensively to control malaria, typhus, body lice and bubonic plague worldwide, until countries began restricting its use in the 1970s. Its use in malaria control continues in some countries according to recommendation by the World Health Organization. Individuals exposed to elevated levels of DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) have an increased prevalence of diabetes and insulin resistance. Here we hypothesize that perinatal exposure to DDT disrupts metabolic programming leading to impaired metabolism in adult offspring. To test this, we administered DDT to C57BL/6J mice from gestational day 11.5 to postnatal day 5 and studied their metabolic phenotype at several ages up to nine months. Perinatal DDT exposure reduced core body temperature, impaired cold tolerance, decreased energy expenditure, and produced a transient early-life increase in body fat in female offspring. When challenged with a high fat diet for 12 weeks in adulthood, female offspring perinatally exposed to DDT developed glucose intolerance, hyperinsulinemia, dyslipidemia, and altered bile acid metabolism. Perinatal DDT exposure combined with high fat feeding in adulthood further impaired thermogenesis as evidenced by reductions in core temperature and in the expression of numerous RNA that promote thermogenesis and substrate utilization in the brown adipose tissue of adult female mice. These observations suggest that perinatal DDT exposure impairs thermogenesis and the metabolism of carbohydrates and lipids which may increase susceptibility to the metabolic syndrome in adult female offspring.

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

    PubMed Central

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

    2007-01-01

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

  10. Type 1 inositol trisphosphate receptor regulates cerebellar circuits by maintaining the spine morphology of purkinje cells in adult mice.

    PubMed

    Sugawara, Takeyuki; Hisatsune, Chihiro; Le, Tung Dinh; Hashikawa, Tsutomu; Hirono, Moritoshi; Hattori, Mitsuharu; Nagao, Soichi; Mikoshiba, Katsuhiko

    2013-07-24

    The structural maintenance of neural circuits is critical for higher brain functions in adulthood. Although several molecules have been identified as regulators for spine maintenance in hippocampal and cortical neurons, it is poorly understood how Purkinje cell (PC) spines are maintained in the mature cerebellum. Here we show that the calcium channel type 1 inositol trisphosphate receptor (IP3R1) in PCs plays a crucial role in controlling the maintenance of parallel fiber (PF)-PC synaptic circuits in the mature cerebellum in vivo. Significantly, adult mice lacking IP3R1 specifically in PCs (L7-Cre;Itpr1(flox/flox)) showed dramatic increase in spine density and spine length of PCs, despite having normal spines during development. In addition, the abnormally rearranged PF-PC synaptic circuits in mature cerebellum caused unexpectedly severe ataxia in adult L7-Cre;Itpr1(flox/flox) mice. Our findings reveal a specific role for IP3R1 in PCs not only as an intracellular mediator of cerebellar synaptic plasticity induction, but also as a critical regulator of PF-PC synaptic circuit maintenance in the mature cerebellum in vivo; this mechanism may underlie motor coordination and learning in adults.

  11. Chronic early postnatal scream sound stress induces learning deficits and NMDA receptor changes in the hippocampus of adult mice.

    PubMed

    Hu, Lili; Han, Bo; Zhao, Xiaoge; Mi, Lihua; Song, Qiang; Wang, Jue; Song, Tusheng; Huang, Chen

    2016-04-13

    Chronic scream sounds during adulthood affect spatial learning and memory, both of which are sexually dimorphic. The long-term effects of chronic early postnatal scream sound stress (SSS) during postnatal days 1-21 (P1-P21) on spatial learning and memory in adult mice as well as whether or not these effects are sexually dimorphic are unknown. Therefore, the present study examines the performance of adult male and female mice in the Morris water maze following exposure to chronic early postnatal SSS. Hippocampal NR2A and NR2B levels as well as NR2A/NR2B subunit ratios were tested using immunohistochemistry. In the Morris water maze, stress males showed greater impairment in spatial learning and memory than background males; by contrast, stress and background females performed equally well. NR2B levels in CA1 and CA3 were upregulated, whereas NR2A/NR2B ratios were downregulated in stressed males, but not in females. These data suggest that chronic early postnatal SSS influences spatial learning and memory ability, levels of hippocampal NR2B, and NR2A/NR2B ratios in adult males. Moreover, chronic early stress-induced alterations exert long-lasting effects and appear to affect performance in a sex-specific manner.

  12. Conditional Deletion of Fgfr3 in Chondrocytes leads to Osteoarthritis-like Defects in Temporomandibular Joint of Adult Mice

    PubMed Central

    Zhou, Siru; Xie, Yangli; Li, Wei; Huang, Junlan; Wang, Zuqiang; Tang, Junzhou; Xu, Wei; Sun, Xianding; Tan, Qiaoyan; Huang, Shuo; Luo, Fengtao; Xu, Meng; Wang, Jun; Wu, Tingting; chen, Liang; Chen, Hangang; Su, Nan; Du, Xiaolan; Shen, Yue; Chen, Lin

    2016-01-01

    Osteoarthritis (OA) in the temporomandibular joint (TMJ) is a common degenerative disease in adult, which is characterized by progressive destruction of the articular cartilage. To investigate the role of FGFR3 in the homeostasis of TMJ cartilage during adult stage, we generated Fgfr3f/f; Col2a1-CreERT2 (Fgfr3 cKO) mice, in which Fgfr3 was deleted in chondrocytes at 2 months of age. OA-like defects were observed in Fgfr3 cKO TMJ cartilage. Immunohistochemical staining and quantitative real-time PCR analyses revealed a significant increase in expressions of COL10, MMP13 and AMAMTS5. In addition, there was a sharp increase in chondrocyte apoptosis at the Fgfr3 cKO articular surface, which was accompanied by a down-regulation of lubricin expression. Importantly, the expressions of RUNX2 and Indian hedgehog (IHH) were up-regulated in Fgfr3 cKO TMJ. Primary Fgfr3 cKO chondrocytes were treated with IHH signaling inhibitor, which significantly reduced expressions of Runx2, Col10, Mmp13 and Adamts5. Furthermore, the IHH signaling inhibitor partially alleviated OA-like defects in the TMJ of Fgfr3 cKO mice, including restoration of lubricin expression and improvement of the integrity of the articular surface. In conclusion, our study proposes that FGFR3/IHH signaling pathway plays a critical role in maintaining the homeostasis of TMJ articular cartilage during adult stage. PMID:27041063

  13. Transient Treg-cell depletion in adult mice results in persistent self-reactive CD4(+) T-cell responses.

    PubMed

    Nyström, Sofia N; Bourges, Dorothée; Garry, Sarah; Ross, Ellen M; van Driel, Ian R; Gleeson, Paul A

    2014-12-01

    Depletion of Foxp3(+) CD4(+) regulatory T cells (Treg) in adults results in chronic inflammation and autoimmune disease. However, the impact of transient Treg-cell depletion on self-reactive responses is poorly defined. Here, we studied the effect of transient depletion of Treg cells on CD4(+) T-cell responses to endogenous self-antigens. Short-term ablation of Treg cells in mice resulted in rapid activation of CD4(+) T cells, increased percentage of IFN-γ(+) and Th17 cells in lymphoid organs, and development of autoimmune gastritis. To track self-reactive responses, we analyzed the activation of naïve gastric-specific CD4(+) T cells. There was a dramatic increase in proliferation and acquisition of effector function of gastric-specific T cells in the stomach draining LNs of Treg-cell-depleted mice, compared with untreated mice, either during Treg-cell depletion or after Treg-cell reconstitution. Moreover, the hyperproliferation of gastric-specific T cells in the Treg-cell-ablated mice was predominantly antigen-dependent. Transient depletion of Treg cells resulted in a shift in the ratio of peripheral:thymic Treg cells in the reemerged Treg-cell population, indicating an altered composition of Treg cells. These findings indicate that transient Treg-cell depletion results in ongoing antigen-driven self-reactive T-cell responses and emphasize the continual requirement for an intact Treg-cell population.

  14. Chronic social defeat stress increases dopamine D2 receptor dimerization in the prefrontal cortex of adult mice.

    PubMed

    Bagalkot, T R; Jin, H-M; Prabhu, V V; Muna, S S; Cui, Y; Yadav, B K; Chae, H-J; Chung, Y-C

    2015-12-17

    The present study aimed to examine the effects of chronic social defeat stress on the dopamine receptors and proteins involved in post-endocytic trafficking pathways. Adult mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. Western blot analysis was used to measure the protein expression levels of dopamine D2 receptors (D2Rs), a short (D2S) and a long form (D2L) and, D2R monomers and dimers, dopamine D1 receptors (D1Rs), neuronal calcium sensor-1 (NCS-1) and G protein-coupled receptor-associated sorting protein-1 (GASP-1), and reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression levels of D2S, D2L, D2R monomers and dimers, and D1Rs in different brain areas. We observed increased expression of D2S, D2L and D2Rs dimers in the prefrontal cortex (PFC) of susceptible and/or unsusceptible mice compared with controls. The only significant findings with regard to mRNA expression levels were lower expression of D2S mRNA in the amygdala (AMYG) of susceptible and unsusceptible mice compared with controls. The present study demonstrated that chronic social defeat stress induced increased expression of D2S, D2L, and D2R dimers in the PFC of susceptible and/or unsusceptible mice.

  15. Properties of Taurine Release in Glucose-Free Media in Hippocampal Slices from Developing and Adult Mice

    PubMed Central

    Oja, Simo S.; Saransaari, Pirjo

    2015-01-01

    The release of preloaded [3H]taurine from hippocampal slices from developing 7-day-old and young adult 3-month-old mice was studied in a superfusion system in the absence of glucose. These hypoglycemic conditions enhanced the release at both ages, the effect being markedly greater in developing mice. A depolarizing K+ concentration accentuated the release, which indicates that it was partially mediated by exocytosis. The anion channel blockers were inhibitory, witnessing the contribution of ion channels. NO-generating agents fomented the release as a sign of the participation of excitatory amino acid receptors. The other second messenger systems were apparently less efficient. The much greater taurine release could be a reason for the well-known greater tolerance of developing nervous tissue to lack of glucose. PMID:26347028

  16. Effects of spaced learning in the water maze on development of dentate granule cells generated in adult mice.

    PubMed

    Trinchero, Mariela F; Koehl, Muriel; Bechakra, Malik; Delage, Pauline; Charrier, Vanessa; Grosjean, Noelle; Ladeveze, Elodie; Schinder, Alejandro F; Abrous, D Nora

    2015-11-01

    New dentate granule cells (GCs) are generated in the hippocampus throughout life. These adult-born neurons are required for spatial learning in the Morris water maze (MWM). In rats, spatial learning shapes the network by regulating their number and dendritic development. Here, we explored whether such modulatory effects exist in mice. New GCs were tagged using thymidine analogs or a GFP-expressing retrovirus. Animals were exposed to a reference memory protocol for 10-14 days (spaced training) at different times after newborn cells labeling. Cell proliferation, cell survival, cell death, neuronal phenotype, and dendritic and spine development were examined using immunohistochemistry. Surprisingly, spatial learning did not modify any of the parameters under scrutiny including cell number and dendritic morphology. These results suggest that although new GCs are required in mice for spatial learning in the MWM, they are, at least for the developmental intervals analyzed here, refractory to behavioral stimuli generated in the course of learning in the MWM.

  17. Effects of neuron-specific estrogen receptor (ER) α and ERβ deletion on the acute estrogen negative feedback mechanism in adult female mice.

    PubMed

    Cheong, Rachel Y; Porteous, Robert; Chambon, Pierre; Abrahám, István; Herbison, Allan E

    2014-04-01

    The negative feedback mechanism through which 17β-estradiol (E2) acts to suppress the activity of the GnRH neurons remains unclear. Using inducible and cell-specific genetic mouse models, we examined the estrogen receptor (ER) isoforms expressed by neurons that mediate acute estrogen negative feedback. Adult female mutant mice in which ERα was deleted from all neurons in the neonatal period failed to exhibit estrous cycles or negative feedback. Adult mutant female mice with neonatal neuronal ERβ deletion exhibited normal estrous cycles, but a failure of E2 to suppress LH secretion was seen in ovariectomized mice. Mutant mice with a GnRH neuron-selective deletion of ERβ exhibited normal cycles and negative feedback, suggesting no critical role for ERβ in GnRH neurons in acute negative feedback. To examine the adult roles of neurons expressing ERα, an inducible tamoxifen-based Cre-LoxP approach was used to ablate ERα from neurons that express calmodulin kinase IIα in adults. This resulted in mice with no estrous cycles, a normal increase in LH after ovariectomy, but an inability of E2 to suppress LH secretion. Finally, acute administration of ERα- and ERβ-selective agonists to adult ovariectomized wild-type mice revealed that activation of ERα suppressed LH secretion, whereas ERβ agonists had no effect. This study highlights the differences in adult reproductive phenotypes that result from neonatal vs adult ablation of ERα in the brain. Together, these experiments expand previous global knockout studies by demonstrating that neurons expressing ERα are essential and probably sufficient for the acute estrogen negative feedback mechanism in female mice.

  18. The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice.

    PubMed

    Wen, Paul H; Hof, Patrick R; Chen, Xiaoping; Gluck, Karen; Austin, Gregory; Younkin, Steven G; Younkin, Linda H; DeGasperi, Rita; Gama Sosa, Miguel A; Robakis, Nikolaos K; Haroutunian, Vahram; Elder, Gregory A

    2004-08-01

    The functions of presenilin 1 (PS1) and how PS1 mutations cause familial Alzheimer's disease (FAD) are incompletely understood. PS1 expression is essential for neurogenesis during embryonic development and may also influence neurogenesis in adult brain. We examined how increasing PS1 expression or expressing an FAD mutant would affect neurogenesis in the adult hippocampus. A neuron-specific enolase (NSE) promoter was used to drive neuronal overexpression of either wild-type human PS1 or the FAD mutant P117L in transgenic mice, and the animals were studied under standard-housing conditions or after environmental enrichment. As judged by bromodeoxyuridine (BrdU) labeling, neural progenitor proliferation rate was mostly unaffected by increasing expression of either wild-type or FAD mutant PS1. However, in both housing conditions, the FAD mutant impaired the survival of BrdU-labeled neural progenitor cells leading to fewer new beta-III-tubulin-immunoreactive neurons being generated in FAD mutant animals during the 4-week postlabeling period. The effect was FAD mutant specific in that neural progenitor survival and differentiation in mice overexpressing wild-type human PS1 were similar to nontransgenic controls. Two additional lines of PS1 wild-type and FAD mutant transgenic mice showed similar changes indicating that the effects were not integration site-dependent. These studies demonstrate that a PS1 FAD mutant impairs new neuron production in adult hippocampus by decreasing neural progenitor survival. They also identify a new mechanism whereby PS1 FAD mutants may impair normal neuronal function and may have implications for the physiological functioning of the hippocampus in FAD.

  19. Impact of Sox9 Dosage and Hes1-mediated Notch Signaling in Controlling the Plasticity of Adult Pancreatic Duct Cells in Mice

    PubMed Central

    Hosokawa, Shinichi; Furuyama, Kenichiro; Horiguchi, Masashi; Aoyama, Yoshiki; Tsuboi, Kunihiko; Sakikubo, Morito; Goto, Toshihiko; Hirata, Koji; Tanabe, Wataru; Nakano, Yasuhiro; Akiyama, Haruhiko; Kageyama, Ryoichiro; Uemoto, Shinji; Kawaguchi, Yoshiya

    2015-01-01

    In the adult pancreas, there has been a long-standing dispute as to whether stem/precursor populations that retain plasticity to differentiate into endocrine or acinar cell types exist in ducts. We previously reported that adult Sox9-expressing duct cells are sufficiently plastic to supply new acinar cells in Sox9-IRES-CreERT2 knock-in mice. In the present study, using Sox9-IRES-CreERT2 knock-in mice as a model, we aimed to analyze how plasticity is controlled in adult ducts. Adult duct cells in these mice express less Sox9 than do wild-type mice but Hes1 equally. Acinar cell differentiation was accelerated by Hes1 inactivation, but suppressed by NICD induction in adult Sox9-expressing cells. Quantitative analyses showed that Sox9 expression increased with the induction of NICD but did not change with Hes1 inactivation, suggesting that Notch regulates Hes1 and Sox9 in parallel. Taken together, these findings suggest that Hes1-mediated Notch activity determines the plasticity of adult pancreatic duct cells and that there may exist a dosage requirement of Sox9 for keeping the duct cell identity in the adult pancreas. In contrast to the extended capability of acinar cell differentiation by Hes1 inactivation, we obtained no evidence of islet neogenesis from Hes1-depleted duct cells in physiological or PDL-induced injured conditions. PMID:25687338

  20. Clone-forming activity of embryonal stem hemopoietic cells after transplantation to newborn or adult sublethally irradiated mice.

    PubMed

    Drize, N I; Chertkov, I L

    2000-07-01

    Hemopoietic activity of stem hemopoietic cells from the liver of embryos was studied at different terms of intrauterine development. The fate of individual clones of hemopoietic cells marked by human adenosine deaminase gene was followed up in sublethally irradiated or newborn recipients. The efficiency of marker gene incorporation in primitive stem hemopoietic cells from the liver of 12-, 13-, and 17-day embryos was not high. Gene transfer was performed without cell prestimulation to division, and hence, these data show that primitive stem cells proliferate even in 17-day embryos. Cells from embryonal liver in all terms maintain hemopoiesis both in newborn and adult microenvironment, hemopoiesis being realized according to the clonal succession model, i. e. in the some way after transplantation of the bone marrow from adult mice.

  1. Identifying and structurally characterizing CD1b in Aotus nancymaae owl monkeys.

    PubMed

    Castillo, Fabio; Guerrero, Carlos; Trujillo, Esperanza; Delgado, Gabriela; Martinez, Pilar; Salazar, Luz M; Barato, Paola; Patarroyo, Manuel E; Parra-López, Carlos

    2004-10-01

    This study reports the molecular characterization and tissue expression of the non-human Aotus nancymaae primate CD1b isoform in the search for an experimental animal model to be used in evaluating the role of non-peptide antigen-presentation molecules in the immune response to infectious agents. CD1b expression on the surface of A. nancymaae peripheral blood monocyte-derived dendritic cells, shown by flow cytometry, was made possible by using human CD1b isoform antibodies. Studying the expression of CD1b-encoded transcripts revealed this molecule's broad distribution in several tissues. The A. nancymaae CD1b transcript-encoded amino-acid sequence showed 95.5% identity with the human sequence. Such high sequence homology was reflected in the identical structural conservation of how pockets A', C' and F' and tunnel T' conforming the antigen's binding site are organized, the similar arrangement of those amino-acids interacting with the T-cell receptor (TCR) during antigen presentation, and the conservation of YQNI-motif sequence in the cytoplasmatic tail (responsible for the molecule's intracellular trafficking in humans). Comparing the structure of human CD1a and CD1b and mouse CD1d proteins with CD1b structure in A. nancymaae obtained by minimization revealed that changes in the latter molecule's alpha1 and alpha2 domains imposed a narrowing of the antigen-binding groove in A. nancymaae CD1b. The high structural similarity between A. nancymaae CD1b and that from humans presented in this study leads to A. nancymaae being proposed as a suitable experimental animal model for analyzing CD1b in vivo, mainly in bacterial and parasite infections such as tuberculosis and malaria, respectively.

  2. Comparison of the deleterious effects of binge drinking-like alcohol exposure in adolescent and adult mice.

    PubMed

    Lacaille, Hélène; Duterte-Boucher, Dominique; Liot, Donovan; Vaudry, Hubert; Naassila, Mickael; Vaudry, David

    2015-03-01

    A major cause of alcohol toxicity is the production of reactive oxygen species generated during ethanol metabolism. The aim of this study was to compare the effect of binge drinking-like alcohol exposure on a panel of genes implicated in oxidative mechanisms in adolescent and adult mice. In adolescent animals, alcohol decreased the expression of genes involved in the repair and protection of oxidative DNA damage such as atr, gpx7, or nudt15 and increased the expression of proapoptotic genes such as casp3. In contrast, in the adult brain, genes activated by alcohol were mainly associated with protective mechanisms that prevent cells from oxidative damage. Whatever the age, iterative binge-like episodes provoked the same deleterious effects as those observed after a single binge episode. In adolescent mice, multiple binge ethanol exposure substantially reduced neurogenesis in the dentate gyrus and impaired short-term memory in the novel object and passive avoidance tests. Taken together, our results indicate that alcohol causes deleterious effects in the adolescent brain which are distinct from those observed in adults. These data contribute to explain the greater sensitivity of the adolescent brain to alcohol toxicity. The effects of alcohol exposure were investigated on genes involved in oxidative mechanisms. In adolescent animals, alcohol decreased the expression of genes involved in DNA repair, a potential cause of the observed decrease of neurogenesis. In contrast, in the adult brain, alcohol increased the expression of genes associated with antioxidant mechanisms. Apoptosis was increase in all groups and converged with other biochemical alterations to enhance short-term memory impairment in the adolescent brain. These data contribute to explain the greater sensitivity of the adolescent brain to alcohol toxicity.

  3. Young adult donor bone marrow infusions into female mice postpone age-related reproductive failure and improve offspring survival.

    PubMed

    Selesniemi, Kaisa; Lee, Ho-Joon; Niikura, Teruko; Tilly, Jonathan L

    2008-11-14

    The female reproductive axis is the first major organ system of the body to fail with advancing age. In addition to a permanent cessation of fertile potential, the loss of cyclic ovarian function in humans heralds the onset of menopause, which in turn underlies the emergence of a diverse spectrum of health issues in aging women. Recently, it was reported that bone marrow (BM) transplantation (BMT) into adult female mice conditioned a week earlier with highly cytotoxic drugs rescues ovarian function and fertility. Herein we show in mice receiving no prior conditioning regimen that once-monthly infusions of BM-derived cells retrieved from young adult female donors bearing an enhanced green fluorescent protein (EGFP) transgene sustain the fertile potential of aging wild-type females long past their time of normal reproductive senescence. The fertility-promoting effects of female donor BM are observed regardless whether the infusions are initiated in young adult or middle-aged females. Although the mechanism by which BM infusions benefit the reproductive performance of aging females remains to be elucidated, the absence of EGFP-expressing offspring suggests that it does not depend on development of mature eggs derived from germline-committed cells in the donor marrow. However, donor BM-derived somatic cells accumulate in the recipients, indicating efficient donor cell engraftment without prior conditioning. These findings provide a strong impetus to further explore development of adult stem cell-based technologies to safely extend function of the female reproductive axis into advanced age without the need for toxic pre-conditioning protocols routinely used in other models of stem cell delivery.

  4. Embryonic caffeine exposure acts via A1 adenosine receptors to alter adult cardiac function and DNA methylation in mice.

    PubMed

    Buscariollo, Daniela L; Fang, Xiefan; Greenwood, Victoria; Xue, Huiling; Rivkees, Scott A; Wendler, Christopher C

    2014-01-01

    Evidence indicates that disruption of normal prenatal development influences an individual's risk of developing obesity and cardiovascular disease as an adult. Thus, understanding how in utero exposure to chemical agents leads to increased susceptibility to adult diseases is a critical health related issue. Our aim was to determine whether adenosine A1 receptors (A1ARs) mediate the long-term effects of in utero caffeine exposure on cardiac function and whether these long-term effects are the result of changes in DNA methylation patterns in adult hearts. Pregnant A1AR knockout mice were treated with caffeine (20 mg/kg) or vehicle (0.09% NaCl) i.p. at embryonic day 8.5. This caffeine treatment results in serum levels equivalent to the consumption of 2-4 cups of coffee in humans. After dams gave birth, offspring were examined at 8-10 weeks of age. A1AR+/+ offspring treated in utero with caffeine were 10% heavier than vehicle controls. Using echocardiography, we observed altered cardiac function and morphology in adult mice exposed to caffeine in utero. Caffeine treatment decreased cardiac output by 11% and increased left ventricular wall thickness by 29% during diastole. Using DNA methylation arrays, we identified altered DNA methylation patterns in A1AR+/+ caffeine treated hearts, including 7719 differentially methylated regions (DMRs) within the genome and an overall decrease in DNA methylation of 26%. Analysis of genes associated with DMRs revealed that many are associated with cardiac hypertrophy. These data demonstrate that A1ARs mediate in utero caffeine effects on cardiac function and growth and that caffeine exposure leads to changes in DNA methylation.

  5. Exposure to N-Ethyl-N-Nitrosourea in Adult Mice Alters Structural and Functional Integrity of Neurogenic Sites

    PubMed Central

    Capilla-Gonzalez, Vivian; Gil-Perotin, Sara; Ferragud, Antonio; Bonet-Ponce, Luis; Canales, Juan Jose; Garcia-Verdugo, Jose Manuel

    2012-01-01

    Background Previous studies have shown that prenatal exposure to the mutagen N-ethyl-N-nitrosourea (ENU), a N-nitroso compound (NOC) found in the environment, disrupts developmental neurogenesis and alters memory formation. Previously, we showed that postnatal ENU treatment induced lasting deficits in proliferation of neural progenitors in the subventricular zone (SVZ), the main neurogenic region in the adult mouse brain. The present study is aimed to examine, in mice exposed to ENU, both the structural features of adult neurogenic sites, incorporating the dentate gyrus (DG), and the behavioral performance in tasks sensitive to manipulations of adult neurogenesis. Methodology/Principal Findings 2-month old mice received 5 doses of ENU and were sacrificed 45 days after treatment. Then, an ultrastructural analysis of the SVZ and DG was performed to determine cellular composition in these regions, confirming a significant alteration. After bromodeoxyuridine injections, an S-phase exogenous marker, the immunohistochemical analysis revealed a deficit in proliferation and a decreased recruitment of newly generated cells in neurogenic areas of ENU-treated animals. Behavioral effects were also detected after ENU-exposure, observing impairment in odor discrimination task (habituation-dishabituation test) and a deficit in spatial memory (Barnes maze performance), two functions primarily related to the SVZ and the DG regions, respectively. Conclusions/Significance The results demonstrate that postnatal exposure to ENU produces severe disruption of adult neurogenesis in the SVZ and DG, as well as strong behavioral impairments. These findings highlight the potential risk of environmental NOC-exposure for the development of neural and behavioral deficits. PMID:22238669

  6. Impact of fasting on the rhythmic expression of myogenic and metabolic factors in skeletal muscle of adult mice.

    PubMed

    Shavlakadze, T; Anwari, T; Soffe, Z; Cozens, G; Mark, P J; Gondro, C; Grounds, M D

    2013-07-01

    Circadian rhythms and metabolism are tightly integrated, and rhythmic expression of metabolic factors is common in homeostatic processes. We measured the temporal changes in the expression of myogenic regulatory factors and expression and activity level of molecules involved in protein metabolism in skeletal muscles and livers in mice and examined the impact of fasting. Tissues were collected over 24 h (at zeitgeber times ZT1, ZT5, ZT9, ZT13, ZT17, ZT21, and ZT1 the following day) from adult male C57Bl/6J mice that had been either freely fed or fasted for 24 h. In skeletal muscle, there was a robust rise in the mRNA expression of the myogenic regulatory factors MyoD and myogenin during dark hours which was strongly suppressed by fasting. Circadian pattern was observed for mRNA of MuRF1, Akt1, and ribosomal protein S6 in muscles in fed and fasted mice and for Fbxo32 in fed mice. Activity (phosphorylation) levels of Akt(Ser473) displayed temporal regulation in fasted (but not fed) mice and were high at ZT9. Fasting caused significant reductions in phosphorylation for both Akt and S6 in muscles, indicative of inactivation. Hepatic phosphorylated Akt(Ser473) and S6(Ser235/236) proteins did not exhibit daily rhythms. Fasting significantly reduced hepatic Akt(473) phosphorylation compared with fed levels, although (unlike in muscle) it did not affect S6(Ser235/236) phosphorylation. This in vivo circadian study addresses for the first time the signaling activities of key molecules related to protein turnover and their possible cross-regulation of expression of genes related to protein degradation.

  7. High-Yield Superovulation in Adult Mice by Anti-Inhibin Serum Treatment Combined with Estrous Cycle Synchronization.

    PubMed

    Hasegawa, Ayumi; Mochida, Keiji; Inoue, Hiroki; Noda, Yoshihiro; Endo, Tamao; Watanabe, Gen; Ogura, Atsuo

    2016-01-01

    Producing many mature oocytes is of great importance for assisted reproductive technologies. In mice, superovulation by consecutive injections of equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG) has been the gold standard for oocyte collection. However, the yield of mature oocytes by this regimen can fluctuate according to the stage of the estrous cycle, strain, and age. Therefore, our objective was to develop a high-yield superovulation protocol to collect higher numbers of oocytes from adult female mice of different strains and ages. First, we aimed to synchronize the estrous cycle using C57BL/6 (B6) female mice. Most (93%) were synchronized to metestrus after two daily injections of progesterone. Second, we found that with the injection of anti-inhibin serum (AIS) instead of eCG, the mean number of ovulated oocytes almost doubled (21 vs. 41 per mouse). Third, by combining estrous cycle synchronization with two AIS injections, we obtained 62 oocytes per mouse, about three times that with the eCG-hCG protocol. Importantly, this approach increased the proportion of mice that ovulated >25 oocytes from about 40% (eCG-hCG) to 90%. The same protocol was also effective in other inbred (BALB/cA), outbred (ICR), and hybrid (B6D2F1) strains. In addition, B6 female mice aged over 1 yr ovulated 1.8-fold more oocytes by this protocol. Thus, estrous cycle synchronization followed by AIS-hCG yielded a broadly applicable, highly efficient superovulation. This protocol should promote the effective use of invaluable female mouse strains and decrease the numbers of animals euthanized.

  8. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice.

    PubMed

    Han, Xiaoning; Chen, Michael; Wang, Fushun; Windrem, Martha; Wang, Su; Shanz, Steven; Xu, Qiwu; Oberheim, Nancy Ann; Bekar, Lane; Betstadt, Sarah; Silva, Alcino J; Takano, Takahiro; Goldman, Steven A; Nedergaard, Maiken

    2013-03-07

    Human astrocytes are larger and more complex than those of infraprimate mammals, suggesting that their role in neural processing has expanded with evolution. To assess the cell-autonomous and species-selective properties of human glia, we engrafted human glial progenitor cells (GPCs) into neonatal immunodeficient mice. Upon maturation, the recipient brains exhibited large numbers and high proportions of both human glial progenitors and astrocytes. The engrafted human glia were gap-junction-coupled to host astroglia, yet retained the size and pleomorphism of hominid astroglia, and propagated Ca2+ signals 3-fold faster than their hosts. Long-term potentiation (LTP) was sharply enhanced in the human glial chimeric mice, as was their learning, as assessed by Barnes maze navigation, object-location memory, and both contextual and tone fear conditioning. Mice allografted with murine GPCs showed no enhancement of either LTP or learning. These findings indicate that human glia differentially enhance both activity-dependent plasticity and learning in mice.

  9. High levels of gene expression in the hepatocytes of adult mice, neonatal mice and tree shrews via retro-orbital sinus hydrodynamic injections of naked plasmid DNA.

    PubMed

    Yan, Shaoduo; Fu, Qiuxia; Zhou, Yong; Wang, Jidong; Liu, Ying; Duan, Xiangguo; Jia, Shuaizheng; Peng, Jianchun; Gao, Bo; Du, Juan; Zhou, Qianqian; Li, Yuan; Wang, Xiaohui; Zhan, Linsheng

    2012-08-10

    Hydrodynamic-based gene delivery has emerged as an efficient and simple method for the intracellular transfection of naked plasmid DNA (pDNA) in vivo. In this system, a hydrodynamic injection via the tail vein is the most effective non-viral method of liver-targeted gene delivery. However, this injection is often technically challenging when used in animals whose tail veins are difficult to visualize or too small to operate on. To overcome this limitation, an alternative in vivo gene delivery method, the rapid injection of large volume of pDNA solution through retro-orbital sinus, was established. Using this technique, we successfully delivered pDNA to the tissue of adult mice, neonatal mice and tree shrews. The efficient expression of exogenous genes was specifically detected in the liver of test animals treated with this gene delivery method. This study demonstrates for the first time that the hydrodynamic gene delivery via the retro-orbital sinus can not only reach the same transgene efficiency as a tradition hydrodynamic-based intravascular injection but also be used in animals that are difficult to inject via the tail vein. This method could open up new areas in gene function studies and gene therapy disease treatment.

  10. Lysosomal-associated transmembrane protein 5 (LAPTM5) is a molecular partner of CD1e.

    PubMed

    Angénieux, Catherine; Waharte, François; Gidon, Alexandre; Signorino-Gelo, François; Wurtz, Virginie; Hojeij, Rim; Proamer, Fabienne; Gachet, Christian; Van Dorsselaer, Alain; Hanau, Daniel; Salamero, Jean; de la Salle, Henri

    2012-01-01

    The CD1e protein participates in the presentation of lipid antigens in dendritic cells. Its transmembrane precursor is transported to lysosomes where it is cleaved into an active soluble form. In the presence of bafilomycin, which inhibits vacuolar ATPase and consequently the acidification of endosomal compartments, CD1e associates with a 27 kD protein. In this work, we identified this molecular partner as LAPTM5. The latter protein and CD1e colocalize in trans-Golgi and late endosomal compartments. The quantity of LAPTM5/CD1e complexes increases when the cells are treated with bafilomycin, probably due to the protection of LAPTM5 from lysosomal proteases. Moreover, we could demonstrate that LAPTM5/CD1e association occurs under physiological conditions. Although LAPTM5 was previously shown to act as a platform recruiting ubiquitin ligases and facilitating the transport of receptors to lysosomes, we found no evidence that LATPM5 controls either CD1e ubiquitination or the generation of soluble lysosomal CD1e proteins. Notwithstanding these last observations, the interaction of LAPTM5 with CD1e and their colocalization in antigen processing compartments both suggest that LAPTM5 might influence the role of CD1e in the presentation of lipid antigens.

  11. Long-term voluntary running improves diet-induced adiposity in young adult mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study investigated the effects of long-term voluntary running on diet-induced adiposity in male C57BL/6 mice. Four-week old mice (n = 15 per group) were fed the AIN93G diet or a 45% high-fat diet (% kcal.) with or without access to in-cage activity wheels for 14 weeks. The high-fat die...

  12. Differential Recognition of CD1d-[alpha]-Galactosyl Ceramide by the V[beta]8.2 and V[beta]7 Semi-invariant NKT T Cell Receptors

    SciTech Connect

    Pellicci, Daniel G.; Patel, Onisha; Kjer-Nielsen, Lars; Pang, Siew Siew; Sullivan, Lucy C.; Kyparissoudis, Konstantinos; Brooks, Andrew G.; Reid, Hugh H.; Gras, Stephanie; Lucet, Isabelle S.; Koh, Ruide; Smyth, Mark J.; Mallevaey, Thierry; Matsuda, Jennifer L.; Gapin, Laurent; McCluskey, James; Godfrey, Dale I.; Rossjohn, Jamie; PMCI-A; Monash; UCHSC; Melbourne

    2009-09-02

    The semi-invariant natural killer T cell receptor (NKT TCR) recognizes CD1d-lipid antigens. Although the TCR{alpha} chain is typically invariant, the {beta} chain expression is more diverse, where three V{beta} chains are commonly expressed in mice. We report the structures of V{alpha}14-V{beta}8.2 and V{alpha}14-V{beta}7 NKT TCRs in complex with CD1d-{alpha}-galactosylceramide ({alpha}-GalCer) and the 2.5 {angstrom} structure of the human NKT TCR-CD1d-{alpha}-GalCer complex. Both V{beta}8.2 and V{beta}7 NKT TCRs and the human NKT TCR ligated CD1d-{alpha}-GalCer in a similar manner, highlighting the evolutionarily conserved interaction. However, differences within the V{beta} domains of the V{beta}8.2 and V{beta}7 NKT TCR-CD1d complexes resulted in altered TCR{beta}-CD1d-mediated contacts and modulated recognition mediated by the invariant {alpha} chain. Mutagenesis studies revealed the differing contributions of V{beta}8.2 and V{beta}7 residues within the CDR2{beta} loop in mediating contacts with CD1d. Collectively we provide a structural basis for the differential NKT TCR V{beta} usage in NKT cells.

  13. Protocol to Isolate a Large Amount of Functional Oligodendrocyte Precursor Cells from the Cerebral Cortex of Adult Mice and Humans

    PubMed Central

    Medina-Rodríguez, Eva María; Arenzana, Francisco Javier; Bribián, Ana; de Castro, Fernando

    2013-01-01

    During development, oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), a cell type that is a significant proportion of the total cells (3-8%) in the adult central nervous system (CNS) of both rodents and humans. Adult OPCs are responsible for the spontaneous remyelination that occurs in demyelinating diseases like Multiple Sclerosis (MS) and they constitute an interesting source of cells for regenerative therapy in such conditions. However, there is little data regarding the neurobiology of adult OPCs isolated from mice since an efficient method to isolate them has yet to be established. We have designed a protocol to obtain viable adult OPCs from the cerebral cortex of different mouse strains and we have compared its efficiency with other well-known methods. In addition, we show that this protocol is also useful to isolate functional OPCs from human brain biopsies. Using this method we can isolate primary cortical OPCs in sufficient quantities so as to be able to study their survival, maturation and function, and to facilitate an evaluation of their utility in myelin repair. PMID:24303061

  14. Properties of doublecortin-(DCX)-expressing cells in the piriform cortex compared to the neurogenic dentate gyrus of adult mice.

    PubMed

    Klempin, Friederike; Kronenberg, Golo; Cheung, Giselle; Kettenmann, Helmut; Kempermann, Gerd

    2011-01-01

    The piriform cortex receives input from the olfactory bulb and (via the entorhinal cortex) sends efferents to the hippocampus, thereby connecting the two canonical neurogenic regions of the adult rodent brain. Doublecortin (DCX) is a cytoskeleton-associated protein that is expressed transiently in the course of adult neurogenesis. Interestingly, the adult piriform cortex, which is usually considered non-neurogenic (even though some reports exist that state otherwise), also contains an abundant population of DCX-positive cells. We asked how similar these cells would be to DCX-positive cells in the course of adult hippocampal neurogenesis. Using BAC-generated transgenic mice that express GFP under the DCX promoter, we studied DCX-expression and electrophysiological properties of DCX-positive cells in the mouse piriform cortex in comparison with the dentate gyrus. While one class of cells in the piriform cortex indeed showed features similar to newly generated immature granule neurons, the majority of DCX cells in the piriform cortex was mature and revealed large Na+ currents and multiple action potentials. Furthermore, when proliferative activity was assessed, we found that all DCX-expressing cells in the piriform cortex were strictly postmitotic, suggesting that no DCX-positive "neuroblasts" exist here as they do in the dentate gyrus. We conclude that DCX in the piriform cortex marks a unique population of postmitotic neurons with a subpopulation that retains immature characteristics associated with synaptic plasticity. DCX is thus, per se, no marker of neurogenesis but might be associated more broadly with plasticity.

  15. ERK1/2 Activation in Preexisting Oligodendrocytes of Adult Mice Drives New Myelin Synthesis and Enhanced CNS Function

    PubMed Central

    Jeffries, Marisa A.; Urbanek, Kelly; Torres, Lester; Wendell, Stacy Gelhaus; Rubio, Maria E.

    2016-01-01

    Growing evidence shows that mechanisms controlling CNS plasticity extend beyond the synapse and that alterations in myelin can modify conduction velocity, leading to changes in neural circuitry. Although it is widely accepted that newly generated oligodendrocytes (OLs) produce myelin in the adult CNS, the contribution of preexisting OLs to functional myelin remodeling is not known. Here, we show that sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in preexisting OLs of adult mice is sufficient to drive increased myelin thickness, faster conduction speeds, and enhanced hippocampal-dependent emotional learning. Although preexisting OLs do not normally contribute to remyelination, we show that sustained activation of ERK1/2 renders them able to do so. These data suggest that strategies designed to push mature OLs to reinitiate myelination may be beneficial both for enhancing remyelination in demyelinating diseases and for increasing neural plasticity in the adult CNS. SIGNIFICANCE STATEMENT Myelin is a crucial regulator of CNS plasticity, function, and repair. Although it is generally accepted that new myelin production in the adult CNS is initiated by newly generated oligodendrocytes (OLs), great interest remains in additionally driving mature preexisting OLs to make myelin. The ability to induce myelination by the larger population of preexisting OLs carries the potential for enhanced remyelination in demyelinating diseases and increased neural plasticity in the adult CNS. Here, we show that sustained activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway is sufficient to drive mature OLs in the adult mouse CNS to reinitiate myelination, leading to new myelin wraps and functional changes. PMID:27581459

  16. Transplacental arsenic carcinogenesis in mice

    SciTech Connect

    Waalkes, Michael P. Liu, Jie; Diwan, Bhalchandra A.

    2007-08-01

    Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans

  17. Contractile properties of skinned muscle fibres from young and adult normal and dystrophic (mdx) mice.

    PubMed Central

    Williams, D A; Head, S I; Lynch, G S; Stephenson, D G

    1993-01-01

    1. Single muscle fibres were enzymatically isolated from the soleus and extensor digitorum longus (EDL) muscles of genetically dystrophic mdx and normal (C57BL/10) mice aged 3-6 or 17-23 weeks. 2. Fibres of both muscles were chemically skinned with the non-ionic detergent Triton X-100 (2% v/v). Ca(2+)- and Sr(2+)-activated contractile responses were recorded and comparisons were made between several contractile parameters of various fibre types of normal and dystrophic mice of similar age. 3. There were no significant differences in the following contractile parameters of skinned fibres of normal and mdx mice of the same age: sensitivity to activating Ca2+ (pCa50) or Sr2+ (pSr50) and differential sensitivity to the activating ions (pCa50-pSr50). However the maximum isometric tension (Po) and the frequency of myofibrillar force oscillations in EDL fast-twitch fibres of young mdx mice were significantly lower than those of soleus fast-twitch fibres of the same animals, or fast-twitch fibres (EDL or soleus) of normal mice. 4. Age-related differences were apparent in some contractile parameters of both normal and mdx mice. In particular the steepness of force-pCa and force-pSr curves increased with age in normal mice, yet decreased with age in fibres of mdx mice. 5. A fluorescent probe, ethidium bromide, which interchelates with DNA, was used with laser-scanning confocal microscopy to determine the distribution of myonuclei in fibres. Fibres isolated from either muscle type of normal animals displayed a characteristic peripheral spiral of myonuclei. Fibres from muscles of mdx mice displayed three major patterns of nuclear distribution; the normal peripheral spiral, long central strands of nuclei, and a mixture of these two patterns. 6. The contractile characteristics of mdx fibres were not markedly influenced by the nuclear distribution pattern in that there were no discernible differences in the major contractile parameters (the Hill coefficients nCa and nSr, which

  18. Opposite-sex attraction in male mice requires testosterone-dependent regulation of adult olfactory bulb neurogenesis

    PubMed Central

    Schellino, Roberta; Trova, Sara; Cimino, Irene; Farinetti, Alice; Jongbloets, Bart C.; Pasterkamp, R. Jeroen; Panzica, Giancarlo; Giacobini, Paolo; De Marchis, Silvia; Peretto, Paolo

    2016-01-01

    Opposite-sex attraction in most mammals depends on the fine-tuned integration of pheromonal stimuli with gonadal hormones in the brain circuits underlying sexual behaviour. Neural activity in these circuits is regulated by sensory processing in the accessory olfactory bulb (AOB), the first central station of the vomeronasal system. Recent evidence indicates adult neurogenesis in the AOB is involved in sex behaviour; however, the mechanisms underlying this function are unknown. By using Semaphorin 7A knockout (Sema7A ko) mice, which show a reduced number of gonadotropin-releasing-hormone neurons, small testicles and subfertility, and wild-type males castrated during adulthood, we demonstrate that the level of circulating testosterone regulates the sex-specific control of AOB neurogenesis and the vomeronasal system activation, which influences opposite-sex cue preference/attraction in mice. Overall, these data highlight adult neurogenesis as a hub for the integration of pheromonal and hormonal cues that control sex-specific responses in brain circuits. PMID:27782186

  19. Targeted Disruption of the Lama3 Gene in Adult Mice Is Sufficient to Induce Skin Inflammation and Fibrosis.

    PubMed

    Pesch, Monika; König, Sabrina; Aumailley, Monique

    2017-02-01

    Genetic, clinical, and biochemical studies have shown that integrity of the dermal-epidermal junction requires a particular subset of laminins, that is, those containing the α3 chain encoded by the Lama3 gene. Inherited mutations in the human gene or introduction of constitutive mutations in the mouse gene prevent expression of these laminins, causing junctional epidermolysis bullosa, a very severe, often lethal disorder characterized by detachment of the epidermis from the dermis. This has precluded in vivo functional analysis of α3 chain-containing laminins, and it is still unknown whether and how they contribute to adult skin homeostasis. To address this question, we have disrupted the Lama3 gene in basal keratinocytes of adult mice. This led to the gradual disappearance of α3 chain-containing laminins along the dermal-epidermal junction and formation of subepidermal blisters like in congenital junctional epidermis bullosa. The mice lose their nails and have bullae and erosions on the footpads. Because the blistering is restricted to the interfollicular epidermis, the animals do not lose the epidermis and are viable. There is abundant and scattered deposition of collagen VII on the dermal side of the blisters, inflammation, and development of skin fibrosis with extensive accumulation of interstitial and microfibrillar collagens.

  20. 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice

    PubMed Central

    Liu, Min-Tsai; Kuan, Yung-Hui; Wang, Jingwen; Hen, René; Gershon, Michael D.

    2009-01-01

    Although the mature enteric nervous system (ENS) has been shown to retain stem cells, enteric neurogenesis has not previously been demonstrated in adults. The relative number of enteric neurons in wild-type (WT) mice and those lacking 5-HT4 receptors (KO) was found to be similar at birth; however, the abundance of ENS neurons increased during the first 4 months after birth in WT but not KO littermates. Enteric neurons subsequently decreased in both WT and KO but at 12 months were significantly more numerous in WT. We tested the hypothesis that stimulation of the 5-HT4 receptor promotes enteric neuron survival and/or neurogenesis. In vitro, 5-HT4 agonists increased enteric neuronal development/survival, decreased apoptosis, and activated CREB. In vivo, in WT but not KO mice, 5-HT4 agonists induced bromodeoxyuridine (BrdU) incorporation into cells that expressed markers of neurons (HuC/D, doublecortin), neural precursors (Sox10, nestin, Phox2b), or stem cells (Musashi-1). This is the first demonstration of adult enteric neurogenesis; our results suggest that 5-HT4 receptors are required postnatally for ENS growth and maintenance. PMID:19657021

  1. Melatonin synergizes with citalopram to induce antidepressant-like behavior and to promote hippocampal neurogenesis in adult mice.

    PubMed

    Ramírez-Rodríguez, Gerardo; Vega-Rivera, Nelly Maritza; Oikawa-Sala, Julián; Gómez-Sánchez, Ariadna; Ortiz-López, Leonardo; Estrada-Camarena, Erika

    2014-05-01

    Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here, we found decreased immobility behavior in mice treated with melatonin (<14-33%) and citalopram (<17-30%). Additionally, the MLTCITAL combination also decreased immobility (<22-35%) in comparison with control mice, reflecting an antidepressant-like effect after 14 days of treatment. Moreover, MLTCITAL decreased plasma corticosterone levels (≤13%) and increased cell proliferation (>29%), survival (>39%), and the absolute number of -associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant-like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.

  2. Embryonic interneurons from the medial, but not the caudal ganglionic eminence trigger ocular dominance plasticity in adult mice.

    PubMed

    Isstas, Marcel; Teichert, Manuel; Bolz, Jürgen; Lehmann, Konrad

    2017-01-01

    The maturation of cortical inhibition provided by parvalbumin-containing basket cells derived from the medial ganglionic eminence (MGE) is a key event in starting the enhanced visual cortical plasticity during the critical period. Although it is generally assumed that a further increase in inhibition closes the critical period again, it was recently shown that embryonic interneurons derived from the MGE can induce an additional, artificial critical period when injected into the visual cortex of young mice. It has, however, remained open whether this effect was indeed specific for MGE-derived cells, and whether critical period-like plasticity could also be induced in fully adult animals. To clarify these issues, we injected explants from either the MGE or the caudal ganglionic eminence (CGE) into the visual cortices of fully adult mice, and performed monocular deprivation 33 days later for 4 days. Animals implanted with MGE cells, but not with CGE cells, showed marked ocular dominance plasticity. Immunohistochemistry confirmed that the injected cells from both sources migrated far in the host cortex, that most developed into neurons producing GABA, and that only cells from the MGE expressed parvalbumin. Thus, our results confirm that the plasticity-inducing effect of embryonic interneurons is specific for cells from the MGE, and is independent of the host animal's age.

  3. Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice.

    PubMed

    Nomura, J; Jaaro-Peled, H; Lewis, E; Nuñez-Abades, P; Huppe-Gourgues, F; Cash-Padgett, T; Emiliani, F; Kondo, M A; Furuya, A; Landek-Salgado, M A; Ayhan, Y; Kamiya, A; Takumi, T; Huganir, R; Pletnikov, M; O'Donnell, P; Sawa, A

    2016-03-01

    NMDA glutamate receptors have key roles in brain development, function and dysfunction. Regulatory roles of D-serine in NMDA receptor-mediated synaptic plasticity have been reported. Nonetheless, it is unclear whether and how neonatal deficits in NMDA-receptor-mediated neurotransmission affect adult brain functions and behavior. Likewise, the role of D-serine during development remains elusive. Here we report behavioral and electrophysiological deficits associated with the frontal cortex in Pick1 knockout mice, which show D-serine deficits in a neonatal- and forebrain-specific manner. The pathological manifestations observed in adult Pick1 mice are rescued by transient neonatal supplementation of D-serine, but not by a similar treatment in adulthood. These results indicate a role for D-serine in neurodevelopment and provide novel insights on how we interpret data of psychiatric genetics, indicating the involvement of genes associated with D-serine synthesis and degradation, as well as how we consider animal models with neonatal application of NMDA receptor antagonists.

  4. Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny

    SciTech Connect

    Haddad, Rami; Kasneci, Amanda; Mepham, Kathryn; Sebag, Igal A.; and others

    2013-01-01

    Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0 μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5–14.5. At 3 months, male progeny were left sedentary or were swim trained for 4 weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. -- Highlights: ► Gestational DES changes cardiac SERCA2a and CASQ2 expression. ► Echocardiography identified systolic dysfunction and increased diastolic relaxation. ► DES

  5. Identification of novel indicators of cyclosporine A nephrotoxicity in a CD-1 mouse model

    SciTech Connect

    O'Connell, Sein; Slattery, Craig; Ryan, Michael P.; McMorrow, Tara

    2011-04-15

    The calcineurin inhibitor cyclosporine A (CsA) is a widely used immunosuppressive agent. However, nephrotoxicity is a serious side effect observed in patients which limits clinical use of CsA. CsA nephrotoxicity is associated with tubulointerstitial injury progressing to nephropathy. This is typically diagnosed by invasive renal biopsy and is often only detected when the disease process is well advanced. Therefore identification of novel, early indicators of CsA nephrotoxicity could be clinically advantageous. This study aimed to establish a murine model of CsA nephrotoxicity and to identify urinary proteins that may indicate the onset of CsA-induced nephropathy using 2-D gel electrophoresis. CsA nephrotoxicity was induced in CD-1 mice by daily CsA administration for 4 weeks. By week 4, elevated serum creatinine and proteinuria were observed after CsA treatment indicating significant renal dysfunction. Decreased cadherin-1, increased {alpha}-smooth muscle actin and fibroblast specific protein 1 in kidney tissue indicated disruption of normal tubular architecture. Alterations in podocin and uromodulin were also observed which may indicate damage to other segments of the nephron. Proteomic analysis of urine identified a number of differentially regulated proteins that may be involved in early CsA nephropathy including cadherin 1, superoxide dismutase and vinculin. These findings suggest novel mechanisms of CsA nephrotoxicity and identify novel potential markers of the disease.

  6. Delivery of human EV71 receptors by adeno-associated virus increases EV71 infection-induced local inflammation in adult mice.

    PubMed

    Hsiao, Hung-Bo; Chou, Ai-Hsiang; Lin, Su-I; Lien, Shu-Pei; Liu, Chia-Chyi; Chong, Pele; Chen, Chih-Yeh; Tao, Mi-Hua; Liu, Shih-Jen

    2014-01-01

    Enterovirus71 (EV71) is now recognized as an emerging neurotropic virus in Asia and one major causative agent of hand-foot-mouth diseases (HFMD). However potential animal models for vaccine development are limited to young mice. In this study, we used an adeno-associated virus (AAV) vector to introduce the human EV71 receptors P-selectin glycoprotein ligand-1 (hPSGL1) or a scavenger receptor class-B member-2 (hSCARB2) into adult ICR mice to change their susceptibility to EV71 infection. Mice were administered AAV-hSCARB2 or AAV-hPSGL1 through intravenous and oral routes. After three weeks, expression of human SCARB2 and PSGL1 was detected in various organs. After infection with EV71, we found that the EV71 viral load in AAV-hSCARB2- or AAV-hPSGL1-transduced mice was higher than that of the control mice in both the brain and intestines. The presence of EV71 viral particles in tissues was confirmed using immunohistochemistry analysis. Moreover, inflammatory cytokines were induced in the brain and intestines of AAV-hSCARB2- or AAV-hPSGL1-transduced mice after EV71 infection but not in wild-type mice. However, neurological disease was not observed in these animals. Taken together, we successfully infected adult mice with live EV71 and induced local inflammation using an AAV delivery system.

  7. Therapeutic implications of CD1d expression and tumor-infiltrating macrophages in pediatric medulloblastomas.

    PubMed

    Teo, Wan-Yee; Elghetany, M Tarek; Shen, Jianhe; Man, Tsz-Kwong; Li, Xiaonan; Chintagumpala, Murali; Su, Jack Meng Fen; Dauser, Robert; Whitehead, William; Adesina, Adekunle M; Lau, Ching C

    2014-11-01

    Immunobiology of medulloblastoma (MB), the most common malignant brain tumor in children, is poorly understood. Although tumor cells in some MBs were recently shown to express CD1d and be susceptible to Vα24-invariant natural killer T (NKT)-cell cytotoxicity, the clinical relevance of CD1d expression in MB patients remains unknown. We investigated the expression of CD1d in pediatric MBs and correlated with molecular and clinical characteristics. Specifically, we explored if NKT cell therapy can be targeted at a subset of pediatric MBs with poorer prognosis. Particularly, infantile MBs have a worse outcome because radiotherapy is delayed to avoid neurocognitive sequelae. Immunohistochemistry for CD1d was performed on a screening set of 38 primary pediatric MBs. Gene expression of the membrane form of M2 macrophage marker, CD163, was studied in an expanded cohort of 60 tumors. Outcome data was collected prospectively. Thirteen of 38 MBs (34.2 %) expressed CD1d on immunohistochemistry. CD1d was expressed mainly on MB tumor cells, and on some tumor-associated macrophages. Majority (18/22, 82 %) of non sonic-hedgehog/Wingless-activated MBs (group 3 and 4) were CD1d-negative (p = 0.05). A subset of infantile MBs (4/9, 44.4 %) expressed CD1d. Macrophages infiltrating MB expressed CD163 apart from CD1d. Molecular subtypes demonstrated statistical differences in CD163 expression, SHH-tumors were the most enriched (p = 0.006). Molecular and clinical subtypes of pediatric MB exhibit distinct differences in CD1d expression, which have important therapeutic implications. High CD1d expression in infantile MBs offers potential new immunotherapeutic treatment with NKT cell therapy in infants, where treatment is suboptimal due delayed radiotherapy.

  8. Potent neutralizing anti-CD1d antibody reduces lung cytokine release in primate asthma model

    PubMed Central

    Nambiar, Jonathan; Clarke, Adam W; Shim, Doris; Mabon, David; Tian, Chen; Windloch, Karolina; Buhmann, Chris; Corazon, Beau; Lindgren, Matilda; Pollard, Matthew; Domagala, Teresa; Poulton, Lynn; Doyle, Anthony G

    2015-01-01

    CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically <100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical. PMID:25751125

  9. Potent neutralizing anti-CD1d antibody reduces lung cytokine release in primate asthma model.

    PubMed

    Nambiar, Jonathan; Clarke, Adam W; Shim, Doris; Mabon, David; Tian, Chen; Windloch, Karolina; Buhmann, Chris; Corazon, Beau; Lindgren, Matilda; Pollard, Matthew; Domagala, Teresa; Poulton, Lynn; Doyle, Anthony G

    2015-01-01

    CD1d is a receptor on antigen-presenting cells involved in triggering cell populations, particularly natural killer T (NKT) cells, to release high levels of cytokines. NKT cells are implicated in asthma pathology and blockade of the CD1d/NKT cell pathway may have therapeutic potential. We developed a potent anti-human CD1d antibody (NIB.2) that possesses high affinity for human and cynomolgus macaque CD1d (KD ∼100 pM) and strong neutralizing activity in human primary cell-based assays (IC50 typically <100 pM). By epitope mapping experiments, we showed that NIB.2 binds to CD1d in close proximity to the interface of CD1d and the Type 1 NKT cell receptor β-chain. Together with data showing that NIB.2 inhibited stimulation via CD1d loaded with different glycolipids, this supports a mechanism whereby NIB.2 inhibits NKT cell activation by inhibiting Type 1 NKT cell receptor β-chain interactions with CD1d, independent of the lipid antigen in the CD1d antigen-binding cleft. The strong in vitro potency of NIB.2 was reflected in vivo in an Ascaris suum cynomolgus macaque asthma model. Compared with vehicle control, NIB.2 treatment significantly reduced bronchoalveolar lavage (BAL) levels of Ascaris-induced cytokines IL-5, IL-8 and IL-1 receptor antagonist, and significantly reduced baseline levels of GM-CSF, IL-6, IL-15, IL-12/23p40, MIP-1α, MIP-1β, and VEGF. At a cellular population level NIB.2 also reduced numbers of BAL lymphocytes and macrophages, and blood eosinophils and basophils. We demonstrate that anti-CD1d antibody blockade of the CD1d/NKT pathway modulates inflammatory parameters in vivo in a primate inflammation model, with therapeutic potential for diseases where the local cytokine milieu is critical.

  10. A Foxp2 Mutation Implicated in Human Speech Deficits Alters Sequencing of Ultrasonic Vocalizations in Adult Male Mice

    PubMed Central

    Chabout, Jonathan; Sarkar, Abhra; Patel, Sheel R.; Radden, Taylor; Dunson, David B.; Fisher, Simon E.; Jarvis, Erich D.

    2016-01-01

    Development of proficient spoken language skills is disrupted by mutations of the FOXP2 transcription factor. A heterozygous missense mutation in the KE family causes speech apraxia, involving difficulty producing words with complex learned sequences of syllables. Manipulations in songbirds have helped to elucidate the role of this gene in vocal learning, but findings in non-human mammals have been limited or inconclusive. Here, we performed a systematic study of ultrasonic vocalizations (USVs) of adult male mice carrying the KE family mutation. Using novel statistical tools, we found that Foxp2 heterozygous mice did not have detectable changes in USV syllable acoustic structure, but produced shorter sequences and did not shift to more complex syntax in social contexts where wildtype animals did. Heterozygous mice also displayed a shift in the position of their rudimentary laryngeal motor cortex (LMC) layer-5 neurons. Our findings indicate that although mouse USVs are mostly innate, the underlying contributions of FoxP2 to sequencing of vocalizations are conserved with humans. PMID:27812326

  11. Investigating the neurobiology of music: brain-derived neurotrophic factor modulation in the hippocampus of young adult mice.

    PubMed

    Angelucci, Francesco; Fiore, Marco; Ricci, Enzo; Padua, Luca; Sabino, Andrea; Tonali, Pietro Attilio

    2007-09-01

    It has been shown that music might be able to improve mood state in people affected by psychiatric disorders, ameliorate cognitive deficits in people with dementia and increase motor coordination in Parkinson patients. Robust experimental evidence explaining the central effects of music, however, is missing. This study was designed to investigate the effect of music on brain neurotrophin production and behavior in the mouse. We exposed young adult mice to music with a slow rhythm (6 h/day; mild sound pressure levels, between 50 and 60 db) for 21 consecutive days. At the end of the treatment, mice were tested for passive avoidance learning and then killed for analysis of brain-derived neurotrophic factor (BDNF) and nerve growth factor with enzyme-linked immunosorbent assay (ELISA) in selected brain regions. We found that music-exposed mice showed increased BDNF, but not nerve growth factor in the hippocampus. Furthermore, we observed that music exposure significantly enhanced learning performance, as measured by the passive avoidance test. Our results demonstrate that exposure to music can modulate the activity of the hippocampus by influencing BDNF production. Our findings also suggest that music exposure might be of help in several central nervous system pathologies.

  12. THE ANABOLIC STEROIDS TESTOSTERONE PROPIONATE AND NANDROLONE, BUT NOT 17α-METHYLTESTOSTERONE, INDUCE CONDITIONED PLACE PREFERENCE IN ADULT MICE

    PubMed Central

    Parrilla-Carrero, Jeffrey; Figueroa, Orialis; Lugo, Alejandro; García-Sosa, Rebecca; Brito-Vargas, Paul; Cruz, Beatriz; Rivera, Melanis; Barreto-Estrada, Jennifer L.

    2009-01-01

    Anabolic androgenic steroids (AAS) are often misused by adolescents and athletes. Their effects vary according to chemical structure and metabolism, route of administration, and AAS regimen. In this study, adult C57Bl/6 male mice were systemically exposed to testosterone propionate (TP), nandrolone or 17α-methyltestosterone (17α-meT), type I, type II and type III AAS, respectively, in order to determine the hedonic or aversive properties of each drug. For this purpose, the conditioned place preference (CPP) test was employed at three different AAS doses (0.075, 0.75 and 7.5 mg/kg). Other behavioral domains monitored were light-dark transitions (side changes) and general activity. TP shifted place preference at all doses tested, and nandrolone shifted place preference at 0.75 and 7.5mg/kg, but not at 0.075 mg/kg, the lower dose tested. Conversely, mice receiving 17α-meT did not show alteration in the preference score. The lower dose of nandrolone did modify exploratory based-anxiety showing a decrease in light-dark transitions if compared to vehicle-treated animals, while mice treated with TP or 17α-meT were not affected. Our data suggest that when studying hedonic and rewarding properties of synthetic androgens, distinction has to be made based on type of AAS and metabolism. PMID:19028026

  13. The anabolic steroids testosterone propionate and nandrolone, but not 17alpha-methyltestosterone, induce conditioned place preference in adult mice.

    PubMed

    Parrilla-Carrero, Jeffrey; Figueroa, Orialis; Lugo, Alejandro; García-Sosa, Rebecca; Brito-Vargas, Paul; Cruz, Beatriz; Rivera, Mélanis; Barreto-Estrada, Jennifer L

    2009-02-01

    Anabolic androgenic steroids (AAS) are often misused by adolescents and athletes. Their effects vary according to chemical structure and metabolism, route of administration, and AAS regimen. In this study, adult C57Bl/6 male mice were systemically exposed to testosterone propionate (TP), nandrolone or 17alpha-methyltestosterone (17alpha-meT), type I, type II and type III AAS, respectively, in order to determine the hedonic or aversive properties of each drug. For this purpose, the conditioned place preference (CPP) test was employed at three different AAS doses (0.075, 0.75 and 7.5 mg/kg). Other behavioral domains monitored were light-dark transitions (side changes) and general activity. TP shifted place preference at all doses tested, and nandrolone shifted place preference at 0.75 and 7.5 mg/kg, but not at 0.075 mg/kg, the lower dose tested. Conversely, mice receiving 17alpha-meT did not show alteration in the preference score. The lower dose of nandrolone did modify exploratory-based anxiety showing a decrease in light-dark transitions if compared to vehicle-treated animals, while mice treated with TP or 17alpha-meT were not affected. Our data suggest that when studying hedonic and rewarding properties of synthetic androgens, distinction has to be made based on type of AAS and metabolism.

  14. Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test.

    PubMed

    Hagio, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Ogawa, Izumi

    2014-06-01

    Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other.

  15. Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1G93A Mice and Nonhuman Primates

    PubMed Central

    Borel, Florie; Gernoux, Gwladys; Cardozo, Brynn; Metterville, Jake P.; Toro Cabreja, Gabriela C.; Song, Lina; Su, Qin; Gao, Guang Ping; Elmallah, Mai K.; Brown, Robert H.; Mueller, Christian

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3–5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1–3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1G93A protein, silencing the SOD1 gene prolongs survival. One study reports a therapeutic effect of silencing the SOD1 gene in systemically treated adult ALS mice; this was achieved with a short hairpin RNA, a silencing molecule that has raised multiple safety concerns, and recombinant adeno-associated virus (rAAV) 9. We report here a silencing method based on an artificial microRNA termed miR-SOD1 systemically delivered using adeno-associated virus rAAVrh10, a serotype with a demonstrated safety profile in CNS clinical trials. Silencing of SOD1 in adult SOD1G93A transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1G93A mice, and significantly preserved muscle strength and motor and respiratory functions. We also document that intrathecal delivery of the same rAAVrh10-miR-SOD1 in nonhuman primates significantly and safely silences SOD1 in lower motor neurons. This study supports the view that rAAVrh10-miR-SOD1 merits further development for the treatment of SOD1-linked ALS in humans. PMID:26710998

  16. Spectrographic analysis of the ultrasonic vocalisations of