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Sample records for adult mice leads

  1. Antidepressant-like effect of lead in adult mice

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    Mantovani M.

    1999-01-01

    Full Text Available It has been reported that lead can cause behavioral impairment by inhibiting the N-methyl-D-aspartate (NMDA receptor complex. MK-801, a noncompetitive NMDA receptor antagonist, exhibits an antidepressant-like action in the forced swimming test. The purpose of the present study was to determine whether subacute lead exposure in adult male Swiss mice weighing 30-35 g causes an antidepressant-like action in a forced swimming test. Mice were injected intraperitoneally (ip with 10 mg/kg lead acetate or saline daily for 7 consecutive days. Twenty-four hours after the last treatment, the saline and lead-treated mice received an injection of MK-801 (0.01 mg/kg, ip or saline and were tested in forced swimming and in open-field tests. Immobility time was similarly reduced in the saline-MK-801, Pb-saline and Pb-MK-801 groups compared to the saline-saline group (mean ± SEM; 197.3 ± 18.5, 193.5 ± 15.8, 191.3 ± 12.3 and 264.0 ± 14.4 s, respectively; N = 9. These data indicate that lead may exert its effect on the forced swimming test by directly or indirectly inhibiting the NMDA receptor complex. Lead treatment caused no deficit in memory of habituation and did not affect locomotor activity in an open-field (N = 14. However, mice that received MK-801 after lead exhibited a deficit in habituation (22% reduction in rearing responses between session 3 and 1; N = 14 as compared to control (41% reduction in rearing responses; N = 15, further suggesting that lead may have affected the NMDA receptor activity. Forced-swim immobility in a basin in two daily consecutive sessions was also significantly decreased by lead exposure (mean ± SEM; day 1 = 10.6 ± 3.2, day 2 = 19.6 ± 3.6; N = 16 as compared to control (day 1 = 18.4 ± 3.8, day 2 = 34.0 ± 3.7; N = 17, whereas the number of crossings was not affected by lead treatment, further indicating a specific antidepressant-like action of lead.

  2. Gestational lead exposure selectively decreases retinal dopamine amacrine cells and dopamine content in adult mice

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    Fox, Donald A., E-mail: dafox@uh.edu [College of Optometry, University of Houston, Houston, TX (United States); Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Department of Pharmacology and Pharmaceutical Sciences, University of Houston, Houston, TX (United States); Hamilton, W. Ryan [Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Johnson, Jerry E. [Department of Natural Sciences, University of Houston-Downtown, Houston, TX (United States); Xiao, Weimin [College of Optometry, University of Houston, Houston, TX (United States); Chaney, Shawntay; Mukherjee, Shradha [Department of Biology and Biochemistry, University of Houston, Houston, TX (United States); Miller, Diane B.; O' Callaghan, James P. [Toxicology and Molecular Biology Branch, Health Effects Research Laboratory, Centers for Disease Control and Prevention-NIOSH, Morgantown, WV USA (United States)

    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

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

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    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

  4. Dll1 haploinsufficiency in adult mice leads to a complex phenotype affecting metabolic and immunological processes.

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    Isabel Rubio-Aliaga

    Full Text Available BACKGROUND: The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1 is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage. METHODOLOGY/PRINCIPAL FINDINGS: Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1(C413Y. Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized. CONCLUSIONS/SIGNIFICANCE: In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes.

  5. Maternal preconceptional nutrition leads to variable fat deposition and gut dimensions of adult offspring mice (C57BL/6JBom)

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    Mortensen, Elna Louise Krogh; Wang, Tobias; Malte, H.;

    2010-01-01

    of the diet consumed before pregnancy affects fat deposition and gut dimensions of offspring mice. Methods:   Eight-week-old female mice (C57BL/6JBom) were fed isocaloric low protein (8.4% protein; LP), standard protein (21.5% protein; ST) or high protein (44.2% protein; HP) diets. After 8 weeks of feeding......Background:   Maternal nutrition during pregnancy or lactation may affect the chance of offspring becoming obese as adults, but little is known regarding the possible role of maternal nutrition before conception. In this study, we investigate how variable protein and carbohydrate content......, females were mated and fed a standard laboratory chow diet (22.5% protein) throughout periods of mating, gestation, lactation and weaning. Offspring mice were fed the same standard diet up to 46 days of age. Then offspring were killed and measures of dissected fat deposits and of the digestive system were...

  6. Lead induces similar gene expression changes in brains of gestationally exposed adult mice and in neurons differentiated from mouse embryonic stem cells.

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    Francisco Javier Sánchez-Martín

    Full Text Available Exposure to environmental toxicants during embryonic life causes changes in the expression of developmental genes that may last for a lifetime and adversely affect the exposed individual. Developmental exposure to lead (Pb, an ubiquitous environmental contaminant, causes deficits in cognitive functions and IQ, behavioral effects, and attention deficit hyperactivity disorder (ADHD. Long-term effects observed after early life exposure to Pb include reduction of gray matter, alteration of myelin structure, and increment of criminal behavior in adults. Despite growing research interest, the molecular mechanisms responsible for the effects of lead in the central nervous system are still largely unknown. To study the molecular changes due to Pb exposure during neurodevelopment, we exposed mice to Pb in utero and examined the expression of neural markers, neurotrophins, transcription factors and glutamate-related genes in hippocampus, cortex, and thalamus at postnatal day 60. We found that hippocampus was the area where gene expression changes due to Pb exposure were more pronounced. To recapitulate gestational Pb exposure in vitro, we differentiated mouse embryonic stem cells (ESC into neurons and treated ESC-derived neurons with Pb for the length of the differentiation process. These neurons expressed the characteristic neuronal markers Tubb3, Syp, Gap43, Hud, Ngn1, Vglut1 (a marker of glutamatergic neurons, and all the glutamate receptor subunits, but not the glial marker Gafp. Importantly, several of the changes observed in Pb-exposed mouse brains in vivo were also observed in Pb-treated ESC-derived neurons, including those affecting expression of Ngn1, Bdnf exon IV, Grin1, Grin2D, Grik5, Gria4, and Grm6. We conclude that our ESC-derived model of toxicant exposure during neural differentiation promises to be a useful model to analyze mechanisms of neurotoxicity induced by Pb and other environmental agents.

  7. Chrysophanol attenuates lead exposure-induced injury to hippocampal neurons in neonatal mice

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    Ji Zhang; Chunlin Yan; Shu Wang; Yong Hou; Guiping Xue; Li Zhang

    2014-01-01

    Previous studies have shown that chrysophanol protects against learning and memory impairments in lead-exposed adult mice. In the present study, we investigated whether chrys-ophanol can alleviate learning and memory dysfunction and hippocampal neuronal injury in lead-exposed neonatal mice. At the end of lactation, chrysophanol (0.1, 1.0, 10.0 mg/kg) was administered to the neonatal mice by intraperitoneal injection for 15 days. Chrysophanol signifi-cantly alleviated injury to hippocampal neurons and improved learning and memory abilities in the lead-poisoned neonatal mice. Chrysophanol also significantly decreased lead content in blood, brain, heart, spleen, liver and kidney in the lead-exposed neonatal mice. The levels of malondialdehyde in the brain, liver and kidney were significantly reduced, and superoxide dismutase and glutathione peroxidase activities were significantly increased after chrysophanol treatment. Collectively, these findings indicate that chrysophanol can significantly reduce damage to hippocampal neurons in lead-exposed neonatal mice.

  8. Effect of Chronic Lead Intoxication on Risky Behavior in Mice

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    L Mohammadyar

    2010-08-01

    Full Text Available Introduction: With industrialization of human societies, pollutants like lead have entered in the life cycle, causing harmful effects on body organs. No sufficient studies have been done on the effects of pollutants on behavior. The aim of this study was to investigate possible effects of lead on some measurable behaviors of an animal model. Methods: Forty eight male adult mice were divided into 4 groups of 12 each. Lead acetate was added at concentrations of 0, 5, 50, or 500 ppm to the drinking water of the animals for 4 weeks (28 days. On day 29, animals were placed on an Elevated Plus maze (EPM for 5 min and the time in sec spent was measured on closed arms, open arms and the end 1/3rd of the open arms. Increased time on open arms, particularly the end 1/3rd was considered to reflect an enhanced risk-accepting behavior. Results: In this study, it was shown that lead exposure caused an increased number of entrance (P=0.006 and time spent (P=0.034 by mice on open arms of the EPM. There was a positive correlation between the concentration of lead acetate and those two effects. Conclusion: The present study demonstrated that lead poisoning may decrease normal anxiety in mice and increase risky behavior in this species. Clinical studies on human subjects with risky behavior are strongly suggested in order to find a possible relation between chronic exposures to lead as well as plasma concentration of lead with the extent of this kind of behavior.

  9. Adult neurogenesis in the four-striped mice (Rhabdomys pumilio)

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    Olatunbosun O Olaleye; Amadi O Ihunwo

    2014-01-01

    In this study, we investigated non-captive four-striped mice (Rhabdomys pumilio) for evidence that adult neurogenesis occurs in the adult brain of animal models in natural environment. Ki-67 (a marker for cell proliferation) and doublecortin (a marker for immature neurons) immunos-taining conifrmed that adult neurogenesis occurs in the active sites of subventricular zone of the lateral ventricle with the migratory stream to the olfactory bulb, and the subgranular zone of the dentate gyrus of the hippocampus. No Ki-67 proliferating cells were observed in the striatum substantia nigra, amygdala, cerebral cortex or dorsal vagal complex. Doublecortin-immunore-active cells were observed in the striatum, third ventricle, cerebral cortex, amygdala, olfactory bulb and along the rostral migratory stream but absent in the substantia nigra and dorsal vagal complex. The potential neurogenic sites in the four-striped mouse species could invariably lead to increased neural plasticity.

  10. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

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    Kesby, James P; Kim, Jane J; Scadeng, Miriam; Woods, Gina; Kado, Deborah M; Olefsky, Jerrold M; Jeste, Dilip V; Achim, Cristian L; Semenova, Svetlana

    2015-01-01

    Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD) exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old) and aged (15 months old) mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.

  11. Spatial Cognition in Adult and Aged Mice Exposed to High-Fat Diet.

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    James P Kesby

    Full Text Available Aging is associated with a decline in multiple aspects of cognitive function, with spatial cognition being particularly sensitive to age-related decline. Environmental stressors, such as high-fat diet (HFD exposure, that produce a diabetic phenotype and metabolic dysfunction may indirectly lead to exacerbated brain aging and promote the development of cognitive deficits. The present work investigated whether exposure to HFD exacerbates age-related cognitive deficits in adult versus aged mice. Adult (5 months old and aged (15 months old mice were exposed to control diet or HFD for three months prior to, and throughout, behavioral testing. Anxiety-like behavior in the light-dark box test, discrimination learning and memory in the novel object/place recognition tests, and spatial learning and memory in the Barnes maze test were assessed. HFD resulted in significant gains in body weight and fat mass content with adult mice gaining significantly more weight and adipose tissue due to HFD than aged mice. Weight gain was attributed to food calories sourced from fat, but not total calorie intake. HFD increased fasting insulin levels in all mice, but adult mice showed a greater increase relative to aged mice. Behaviorally, HFD increased anxiety-like behavior in adult but not aged mice without significantly affecting spatial cognition. In contrast, aged mice fed either control or HFD diet displayed deficits in novel place discrimination and spatial learning. Our results suggest that adult mice are more susceptible to the physiological and anxiety-like effects of HFD consumption than aged mice, while aged mice displayed deficits in spatial cognition regardless of dietary influence. We conclude that although HFD induces systemic metabolic dysfunction in both adult and aged mice, overall cognitive function was not adversely affected under the current experimental conditions.

  12. Biological index of environmental lead pollution: accumulation of lead in liver and kidney in mice.

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    Takano, T; Okutomi, Y; Mochizuki, M; Ochiai, Y; Yamada, F; Mori, M; Ueda, F

    2015-12-01

    Lead (Pb) is known to be highly poisonous, and the acute poisoning of Cd causes the abdominal pains, vomiting, and shock. The digestive and nervous symptom is observed in the chronic lead poisoning. It was also known that the defect in hemoglobin synthesis by Pb produce anemia. The release of Pb into the environment presents a source of exposure for wild animals. In this study, we examined the utility of a new Pb-monitoring index in mice administered Pb. A solution containing 0.02, 0.2, 2, or 4 ppm lead chloride (PbCl2) was administered intraperitoneally to mice, and the Pb contents of the kidney and liver were determined at designated time points. The mean Pb content of both organs increased depending on the administered Pb dosage. Although the results of control was near the detection limits, the administration of 4 ppm in 4 weeks resulted in Pb levels of 260 mg ppm/wet weight and 110 ppm wet weight in the kidney and liver, respectively. However, there were no significant relationships among administered dose, duration of Pb treatment, and liver or kidney Pb content. Then, values in all mice administered control or 0.02 mg Pb were located inside the ellipse, representing the confidence area of the new index, and values in all mice administered more than 2 mg Pb were located outside the ellipse. These results confirm that animals exposed to high concentrations of Pb would be detected by this new index.

  13. Effect of caprine testicular extract on acrosome formation of spermatids of lead-injured mice

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    Hong-yan TIAN

    2012-11-01

    Full Text Available Objective  To investigate the effect of caprine testicular extract on the acrosomal formation of spermatids of lead-treated mice, and find a theoretical and experimental basis for further research on the effects of caprine testicular extract on the reproductive system. Methods The study was carried out on thirty male adult ICR mice, which were randomly assigned into control group, model group and treatment group (10 each. The testis-injury model was reproduced by intragastric administration of lead acetate (30mg/kg, 0.1ml/10g. Animals in treatment group received intragastric administration of lead acetate and intraabdominal injection of 0.5ml caprine testicular extract at the same time for 21days, and the mice in control group received the same amount of distilled water by intragastric administration and 0.5ml distilled water by intraabdominal injection. By the end of the experimental period, the mice were sacrificed. The testes were fixed by cardiac perfusion and processed for light microscopic examination. The acrosomal formation in round spermatids was observed by PAS staining. Results  Compared with the control group, the acrosomal formation in model group was blocked. Acrosomal vesicle was incomplete, the membrane was shrunken, rough and fuzzy. The acrosomal formation in treatment group was similar to that of the control group. The structure of the acrosomal vesicle was complete and the membrane was smooth. Conclusion  Administration of caprine testicular extract may protect the acrosomal formation of spermatids from lead poisoning, and the normal structure and function of the acrosome are preserved. Thus, indepth study of the effects of caprine testicular extract may contribute to the treatment of male infertility caused by heavy metal-induced testicular damage, and offer an effective protective measure for the lead-exposed males.

  14. Spermatogenesis arrest caused by conditional deletion of Hsp90α in adult mice

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    Chiaki Kajiwara

    2012-08-01

    It is controversial whether a functional androgen receptor (AR on germ cells, including spermatogonia, is essential for their development into sperm and, thus, initiation and maintenance of spermatogenesis. It was recently shown that many spermatocytes underwent apoptosis in the testes of Hsp90α KO mice. We had generated Hsp90α KO mice independently and confirmed this phenotype. However, the important question of whether Hsp90α is required to maintain spermatogenesis in adult mice in which testicular maturation is already completed could not be addressed using these conventional KO mice. To answer this question, we generated a tamoxifen-inducible deletion mutant of Hsp90α and found that conditional deletion of Hsp90α in adult mice caused even more severe apoptosis in germ cells beyond the pachytene stage, leading to complete arrest of spermatogenesis and testicular atrophy. Importantly, immunohistochemical analysis revealed that AR expression in WT testis was more evident in spermatogonia than in spermatocytes, whereas its expression was aberrant and ectopic in Hsp90α KO testis, raising the possibility that an AR abnormality in primordial germ cells is involved in spermatogenesis arrest in the Hsp90α KO mice. Our results suggest that the AR, specifically chaperoned by Hsp90α in spermatogonia, is critical for maintenance of established spermatogenesis and for survival of spermatocytes in adult testis, in addition to setting the first wave of spermatogenesis before puberty.

  15. Heart regeneration in adult MRL mice

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    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.

  16. Non-occupational lead exposure and hypertension in Pakistani adults

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    RAHMAN Sohaila; KHALID Nasir; ZAIDI Jamshed Hussain; AHMAD Shujaat; IQBAL Mohammad Zafar

    2006-01-01

    Hypertension is one of the most prevalent diseases in the developed and developing countries. Based on the long historical association and the provocative findings of blood pressure effects at low level of lead exposure a study was carried out to determine if an association existed between low blood lead concentration and hypertension. In this study the effects of low-level exposure to lead on blood pressure were examined among 244 adults using atomic absorption spectrometer. For quality assurance purpose certified reference materials i.e., Animal blood A-13, Bovine liver 1577 and cotton cellulose V-9 from IAEA (International Atomic Energy Agency) and NIST (National Institute of Standard Technology) were analyzed under identical experimental conditions. The mean age of hypertensive adults was 52 years (range 43~66). The mean values of systolic and diastolic blood pressure were (209±11.7) (range 170~250) and (117±3.9) (range 105~140) mmHg respectively. Blood lead concentration ranged from 78~201μg/L with a mean of 139 μg/L and 165~497μg/L with a mean of 255 μg/L in normal and hypertensive adults respectively. Increase in systolic blood pressure was significantly predictive with increase in blood lead levels. Body mass index (BMI) and lipid profile including total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride correlated with blood pressure.

  17. Reduced white fat mass in adult mice bearing a truncated Patched 1

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    Zili Li, Heng Zhang, Leslie A. Denhard, Lan-Hsin Liu, Huaxin Zhou, Zi-Jian Lan

    2008-01-01

    Full Text Available Hedgehog (Hh signaling emerges as a potential pathway contributing to fat formation during postnatal development. In this report, we found that Patched 1 (Ptc1, a negative regulator of Hh signaling, was expressed in the epididymal fat pad of adult mice. Reduced total white fat mass and epididymal adipocyte cell size were observed in naturally occurring spontaneous mesenchymal dysplasia (mes adult mice (Ptc1mes/mes, which carry a deletion of Ptc1 at the carboxyl-terminal cytoplasmic region. Increased expression of truncated Ptc1, Ptc2 and Gli1, the indicators of ectopic activation of Hh signaling, was observed in epididymal fat pads of adult Ptc1mes/mes mice. In contrast, expression of peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, adipocyte P2 and adipsin were reduced in epididymal fat pads of adult Ptc1mes/mes mice. Taken together, our results indicate that deletion of carboxyl-terminal tail of Ptc1 can lead to the reduction of white fat mass during postnatal development.

  18. Toluene Induces Depression-Like Behaviors in Adult Mice

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    Yang, Miyoung; Kim, Sung-Ho; Kim, Jong-Choon; Shin, Taekyun; Moon, Changjong

    2010-01-01

    It has been clinically reported that toluene causes mental depression in humans. However, the detrimental effects of toluene exposure on brain function and the relation between features of mental depression and toluene exposure are poorly understood. This study evaluated depression-like behaviors in adult C57BL/6 mice after administration of toluene, and elucidated the effects of classical antidepressants on the depression-like behaviors. For the estimation of depression-like behaviors, tail ...

  19. Adaptation of enterovirus 71 to adult interferon deficient mice.

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    Elizabeth A Caine

    Full Text Available Non-polio enteroviruses, including enterovirus 71 (EV71, have caused severe and fatal cases of hand, foot and mouth disease (HFMD in the Asia-Pacific region. The development of a vaccine or antiviral against these pathogens has been hampered by the lack of a reliable small animal model. In this study, a mouse adapted EV71 strain was produced by conducting serial passages through A129 (α/β interferon (IFN receptor deficient and AG129 (α/β, γ IFN receptor deficient mice. A B2 sub genotype of EV71 was inoculated intraperitoneally (i.p. into neonatal AG129 mice and brain-harvested virus was subsequently passaged through 12 and 15 day-old A129 mice. When tested in 10 week-old AG129 mice, this adapted strain produced 100% lethality with clinical signs including limb paralysis, eye irritation, loss of balance, and death. This virus caused only 17% mortality in same age A129 mice, confirming that in the absence of a functional IFN response, adult AG129 mice are susceptible to infection by adapted EV71 isolates. Subsequent studies in adult AG129 and young A129 mice with the adapted EV71 virus examined the efficacy of an inactivated EV71 candidate vaccine and determined the role of humoral immunity in protection. Passive transfer of rabbit immune sera raised against the EV71 vaccine provided protection in a dose dependent manner in 15 day-old A129 mice. Intramuscular injections (i.m. in five week-old AG129 mice with the alum adjuvanted vaccine also provided protection against the mouse adapted homologous strain. No clinical signs of disease or mortality were observed in vaccinated animals, which received a prime-and-boost, whereas 71% of control animals were euthanized after exhibiting systemic clinical signs (P<0.05. The development of this animal model will facilitate studies on EV71 pathogenesis, antiviral testing, the evaluation of immunogenicity and efficacy of vaccine candidates, and has the potential to establish correlates of protection

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

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    Kerstin Wernike

    Full Text Available 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.

  1. Discovery of nigral dopaminergic neurogenesis in adult mice

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    Brad E Morrison

    2016-01-01

    Full Text Available Parkinson′s disease is characterized by the loss of dopaminergic neurons in the substantia nigra. As a result, intensive efforts have focused upon mechanisms that facilitate the death of mature dopaminergic neurons. Unfortunately, these efforts have been unsuccessful in providing an effective treatment to address neurodegeneration in this disease. Therefore, alternative theories of pathogenesis are being explored. Adult neurogenesis of dopaminergic neurons is an attractive concept that would provide a possible mechanism of neurodegeneration as well as offer an endogenous means to replenish affected neurons. To determine whether dopaminergic neurons experience neurogenesis in adult mice we developed a novel cell lineage tracing model that permitted detection of neurogenesis without many of the issues associated with popular techniques. Remarkably, we discovered that dopaminergic neurons are replenished in adult mice by Nestin+/Sox2- progenitor cells. What′s more, the rate of neurogenesis is similar to the rate of dopaminergic neuron loss reported using a chronic, systemic inflammatory response mouse model. This observation may indicate that neuron loss in Parkinson′s disease results from inhibition of neurogenesis.

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

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

    2015-09-01

    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

  3. Prenatal retinoid deficiency leads to airway hyperresponsiveness in adult mice

    OpenAIRE

    Chen, Felicia; Marquez, Hector; Kim, Youn-Kyung; Qian, Jun; Shao, Fengzhi; Fine, Alan; Cruikshank, William W.; Quadro, Loredana; Wellington V. Cardoso

    2014-01-01

    There is increasing evidence that vitamin A deficiency in utero correlates with abnormal airway smooth muscle (SM) function in postnatal life. The bioactive vitamin A metabolite retinoic acid (RA) is essential for formation of the lung primordium; however, little is known about the impact of early fetal RA deficiency on postnatal lung structure and function. Here, we provide evidence that during murine lung development, endogenous RA has a key role in restricting the airway SM differentiation...

  4. Exacerbation of Soft Tissue Lesions in Lead Exposed Virus Infected Mice

    Institute of Scientific and Technical Information of China (English)

    PRATIBHA GUPTA; M. M. HUSAIN; RAVI SHANKER; R. K. S. DOGRA; P. K. SETH; R. K. MAHESHWARI

    2003-01-01

    Objective To investigate the effect of Lead (Pb) acetate exposure on Semliki forest virus (SFV)pathogenesis in mice. Methods Different doses (62.5, 125, 250 and 500 mg/Kg body weight) of Pb dissolved in normal saline were given to mice by oral intubation in a sub-acute (28 days) and sub-chronic (90 days) regimen followed by SFV infection. Morbidity, mortality, clinical symptoms,mean survival time (MST), changes in body and organ weight, accumulation of lead in soft tissues,virus titre in brain and histopathological alterations were compared between lead exposed and infected groups. Results Early appearance of virus symptoms, increased mortality, decreased MST, enhanced SFV titre and greater tissue damage were observed in lead exposed-SFV-infected mice. Conclusion Pre-exposure to lead increases the susceptibility of mice towards SFV infection. Further studies are suggested in view of the persistence of lead in the environment and the possibility of infection bymicrobial pathogens.

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

    Directory of Open Access Journals (Sweden)

    Barnum Christopher J

    2012-01-01

    Full Text Available Abstract 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

  6. Effect of lead chloride on spermatogenesis and sperm parameters in mice

    Institute of Scientific and Technical Information of China (English)

    AntdnioGraca; JoaoRamalho-Santos; MariadeLourdesPereira

    2004-01-01

    Aim: To evaluate the effect of acute lead chloride exposure on testis and sperm parameters in mice.Methods: PbC12, 74 mg/kg, was daily administered to sexually mature male mice for 3 days and the effects on the testicular histology and ultrastructure as well as the motility and density of spermatozoa in cauda epididymis were observed. An additional group of mice were treated for 1-3 days and were allowed to recover for 32 days to determine the reversibility of lead-induced changes. Results: The testicular weight, seminiferous tubular diameter and sperm counts were significantly decreased following 3 days of PbCl2 treatment, but were unaffected by shorterterm exposures. The changes caused by lead are mostly reversible. Conclusion: Acute lead chloride exposure injures the fertility parameters of male mice and the effects are partially reversible. (Asian JAndrol 2004 Sep; 6: 237-241)

  7. Evaluation of Oogenesis Aspects in Neonatal and Adult Mice after Toloaldoxime Treatment

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    Mohammad Fazeltabar Malekshah

    2015-10-01

    Full Text Available Objective: Oximes are important materials in organic chemistry. Synparamethyl benzaldehyde oxime (toloaldoxime is structurally similar to other oximes, hence we have studied its effects on the neonatal and adult female Balb/c mice reproductive systems in order to provide a platform for future studies on the production of female contraceptive drugs. Materials and Methods: In experimental study, we studied the effects of toloaldoxime on ovary growth and gonadal hormones of neonatal and adult Balb/c mice. A regression model for prediction was presented. Results: The effects of toloaldoxime on neonatal mice were more than adult mice. The greatest effect was on the number of Graafian follicles (59.6% in adult mice and 31.83% in neonatal mice. The least effect was on ovary weight, and blood serum levels of follicle stimulating hormone (FSH and luteinizing hormone (LH. Conclusion: According to the data obtained, toloaldoxime can be considered an antipregnancy substance.

  8. Delayed expulsion of adult Trichinella spiralis by mast cell-deficient W/Wv mice.

    OpenAIRE

    Ha, T. Y.; Reed, N D; Crowle, P K

    1983-01-01

    Mast cell-deficient W/Wv mice and their mast cell-sufficient littermates were given infections of Trichinella spiralis. W/Wv mice were slower than their littermates to expel adult T. spiralis. Repair of the mast cell deficiency of W/Wv mice by bone marrow grafting was accompanied by accelerated expulsion of T. spiralis.

  9. Neurotoxicity of perfluorooctane sulfonate to hippocampal cells in adult mice.

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    Yan Long

    Full Text Available Perfluorooctane sulfonate (PFOS is a ubiquitous pollutant and found in the environment and in biota. The neurotoxicity of PFOS has received much concern among its various toxic effects when given during developing period of brain. However, little is known about the neurotoxic effects and potential mechanisms of PFOS in the mature brain. Our study demonstrated the neurotoxicity and the potential mechanisms of PFOS in the hippocampus of adult mice for the first time. The impairments of spatial learning and memory were observed by water maze studies after exposure to PFOS for three months. Significant apoptosis was found in hippocampal cells after PFOS exposure, accompanied with a increase of glutamate in the hippocampus and decreases of dopamine (DA and 3,4-dihydrophenylacetic acid (DOPAC in Caudate Putamen in the 10.75 mg/kg PFOS group. By two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE analysis, seven related proteins in the hippocampus that responded to PFOS exposure were identified, among which, Mib1 protein (an E3 ubiquitin-protein ligase, Herc5 (hect domain and RLD 5 isoform 2 and Tyro3 (TYRO3 protein tyrosine kinase 3 were found down-regulated, while Sdha (Succinate dehydrogenase flavoprotein subunit, Gzma (Isoform HF1 of Granzyme A precursor, Plau (Urokinase-type plasminogen activator precursor and Lig4 (DNA ligase 4 were found up-regulated in the 10.75 mg/kg PFOS-treated group compare with control group. Furthermore, we also found that (i increased expression of caspase-3 protein and decreased expression of Bcl-2, Bcl-XL and survivin proteins, (ii the increased glutamate release in the hippocampus. All these might contribute to the dysfunction of hippocampus which finally account for the impairments of spatial learning and memory in adult mice.

  10. Impaired Memory in OT-II Transgenic Mice Is Associated with Decreased Adult Hippocampal Neurogenesis Possibly Induced by Alteration in Th2 Cytokine Levels.

    Science.gov (United States)

    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. PMID:27432189

  11. Maternal MDMA administration in mice leads to neonatal growth delay.

    Science.gov (United States)

    Kaizaki, Asuka; Tanaka, Sachiko; Yoshida, Takemi; Numazawa, Satoshi

    2014-02-01

    The psychoactive recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is widely abused. The fact that MDMA induces neurotoxic damage in serotonergic nerve endings is well known. However, the effects of MDMA on pregnant and neonatal animals remain unknown. Therefore, we studied the effects of gestational exposure to MDMA on birth, growth, and behavior of pups. Female BALB/c mice were orally administered either water (10 ml/kg) or MDMA (20 mg/10 ml/kg) from gestational day 1 to postnatal day (P) 21. MDMA did not affect the birth rate, but the survival rate of the pups significantly decreased. A significant reduction in body weight gain was observed in pups from MDMA-administered dams during P3-P21. Maternal MDMA treatment caused an attenuated cliff avoidance reaction and decreased motor function in the pups, as determined by the wire hanging test. These results suggest that MDMA treatment during pregnancy and lactation causes growth retardation and dysfunction of motor neurons in mouse pups. PMID:24418707

  12. Olfactory Bulbectomy Leads to the Development of Epilepsy in Mice.

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    Yifei Jiang

    Full Text Available There is a clear link between epilepsy and depression. Clinical data demonstrate a 30-35% lifetime prevalence of depression in patients with epilepsy, and patients diagnosed with depression have a three to sevenfold higher risk of developing epilepsy. Traditional epilepsy models partially replicate the clinical observations, with the demonstration of depressive traits in epileptic animals. Studies assessing pro-epileptogenic changes in models of depression, however, are more limited. Here, we examined whether a traditional rodent depression model--bilateral olfactory bulbectomy--predisposes the animals towards the development of epilepsy. Past studies have demonstrated increased neuronal excitability after bulbectomy, but continuous seizure monitoring had not been conducted. For the present study, we monitored control and bulbectomized animals by video-EEG 24/7 for approximately two weeks following the surgery to determine whether they develop spontaneous seizures. All seven bulbectomized mice exhibited seizures during the monitoring period. Seizures began about one week after surgery, and occurred in clusters with severity increasing over the monitoring period. These results suggest that olfactory bulbectomy could be a useful model of TBI-induced epilepsy, with advantages of relatively rapid seizure onset and a high number of individuals developing the disease. The model may also be useful for investigating the mechanisms underlying the bidirectional relationship between epilepsy and depression.

  13. Myogenin regulates exercise capacity but is dispensable for skeletal muscle regeneration in adult mdx mice.

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    Eric Meadows

    Full Text Available Duchenne muscular dystrophy (DMD is the most prevalent inherited childhood muscle disorder in humans. mdx mice exhibit a similar pathophysiology to the human disorder allowing for an in-depth investigation of DMD. Myogenin, a myogenic regulatory factor, is best known for its role in embryonic myogenesis, but its role in adult muscle maintenance and regeneration is still poorly understood. Here, we generated an mdx:Myog(flox/flox mouse harboring a tamoxifen-inducible Cre recombinase transgene, which was used to conditionally delete Myog during adult life. After tamoxifen treatment, three groups of mice were created to study the effects of Myog deletion: mdx:Myog(flox/flox mice (mdx, Myog(flox/flox mice (wild-type, and mdx:Myog(floxΔ/floxΔ:Cre-ER mice (mdx:Myog-deleted. mdx:Myog-deleted mice exhibited no adverse phenotype and behaved normally. When run to exhaustion, mdx:Myog-deleted mice demonstrated an enhanced capacity for exercise compared to mdx mice, running nearly as far as wild-type mice. Moreover, these mice showed the same signature characteristics of muscle regeneration as mdx mice. Unexpectedly, we found that myogenin was dispensable for muscle regeneration. Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity. Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function.

  14. Selection of micronutrients used along with DMSA in the treatment of moderately lead intoxicated mice

    Energy Technology Data Exchange (ETDEWEB)

    Liao, Yingjun [China Medical University, Department of Physiology, School of Basic Medicine, Shenyang, Liaoning (China); Yu, Fei; Zhi, Xuping; An, Li; Yang, Jun [China Medical University, Department of Nutrition and Food Hygiene, School of Public Health, Shenyang, Liaoning (China); Jin, Yaping; Lu, Chunwei; Li, Gexin [China Medical University, Department of Environmental and Occupational Health, School of Public Health, Shenyang, Liaoning (China)

    2008-01-15

    The objective of this study was to explore the optimum combination of micronutrients used with 2,3-dimercaptosuccinic acid (DMSA) in the treatment of moderately lead-intoxicated mice. Experiment was carried out based on the orthogonal design L{sub 8}(2{sup 7}) setting six factors with two different levels of each, and eight groups of mice were needed. Mice were exposed to lead by drinking water contaminated with 0.1% lead acetate for four consecutive weeks, and then supplemented by gavage with different combinations of micronutrients with and without DMSA as designed in the orthogonal table. Lead levels in blood, liver, kidney, brain and bone and activities of blood {delta}-aminolevulinic acid dehydratase (ALAD) were analyzed after cessation of supplementation. The results suggested that DMSA was the only factor which could decrease significantly lead levels in blood, liver, kidney and bone; calcium and ascorbic acid were the notable factors decreasing lead levels in blood, liver, kidney, bone and brain; zinc and calcium were the notable factors reversing the lead-inhibited activities of blood ALAD; taurine was the notable factor decreasing lead levels in kidney and brain; and thiamine was the notable factor decreasing lead levels in brain. The lowest lead level in blood, liver, kidney and bone was shown in the mice supplemented with combination of calcium and ascorbic acid along with DMSA. In conclusion, the optimum combination of micronutrients used with DMSA suggested in present study was calcium and ascorbic acid, which seemed to potentiate the chelating efficacy of DMSA in the treatment of moderately lead intoxicated mice. (orig.)

  15. The study of lead content distribution in Chinese seafood and its oral bioavailability in mice.

    Science.gov (United States)

    Tong, Yongpeng; Zhu, Zhipeng; Hao, Xin; He, Long; He, Weibiao; Chen, Jianmin

    2016-01-01

    Using inductively coupled plasma mass spectrometry (ICP-MS), the lead concentrations and isotope ratios of 32 kinds of seafood collected from local markets of China were measured. Among these seafoods, the highest concentrations of lead were found in Patinopecten yessoensis and Mugil cephalus, which were 2.94 ± 0.40 and 2.02 ± 0.26 μg g(-1) of dry weight, respectively. Pb concentration was found to be higher in benthic fish than in other fish. The result indicated that lead concentrations in some seafood exceeded the maximum levels of Pb in foods proposed by European Commission (EC). Nine species of cooked seafood were chosen to feed mice (35-38 g). The result showed that Pb oral bioavailability of cooked seafood in vivo was below 10%. Furthermore, oral bioavailability of the same lead-containing seafood increased greatly in pregnant mice compared with non-pregnant mice.

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

    Science.gov (United States)

    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.

  17. Systemic Immune Activation Leads to Neuroinflammation and Sickness Behavior in Mice

    OpenAIRE

    Steven Biesmans; Meert, Theo F.; Jan A. Bouwknecht; Acton, Paul D.; Nima Davoodi; Patrick De Haes; Jacobine Kuijlaars; Xavier Langlois; Liam J. R. Matthews; Luc Ver Donck; Niels Hellings; Rony Nuydens

    2013-01-01

    Substantial evidence indicates an association between clinical depression and altered immune function. Systemic administration of bacterial lipopolysaccharide (LPS) is commonly used to study inflammation-associated behavioral changes in rodents. In these experiments, we tested the hypothesis that peripheral immune activation leads to neuroinflammation and depressive-like behavior in mice. We report that systemic administration of LPS induced astrocyte activation in transgenic GFAP-luc mice an...

  18. Hemopoietic precursor-cells in radiation chimeras restored by bone marrow of adult thymectomized mice

    International Nuclear Information System (INIS)

    Radioprotective capacity of bone marrow CFUs of adult thymectomized mice was studied. Lethaly irradiated mice were inoculated with bone marrow of mice thymectomized 8-11 months before. The colony forming capacity and proliferative rate of CFUs were studied 1-7.5 months after obtaining the radiation chimeras. It has been shown that proliferative capacity of bone marrow of adult thymectomized mice was reduced in comparison with that of normal animals. We also found that the content of CFUs in bone of those chimeras was reduced later - after 7.5 months. In this period (1-7.5 months) the cellularity of bone marrow did not change

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

    Science.gov (United States)

    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.

  20. Hyperprolactinemia induced by hCG leads to metabolic disturbances in female mice.

    Science.gov (United States)

    Ratner, Laura D; Stevens, Guillermina; Bonaventura, Maria Marta; Lux-Lantos, Victoria A; Poutanen, Matti; Calandra, Ricardo S; Huhtaniemi, Ilpo T; Rulli, Susana B

    2016-07-01

    The metabolic syndrome is a growing epidemic; it increases the risk for diabetes, cardiovascular disease, fatty liver, and several cancers. Several reports have indicated a link between hormonal imbalances and insulin resistance or obesity. Transgenic (TG) female mice overexpressing the human chorionic gonadotropin β-subunit (hCGβ+ mice) exhibit constitutively elevated levels of hCG, increased production of testosterone, progesterone and prolactin, and obesity. The objective of this study was to investigate the influence of hCG hypersecretion on possible alterations in the glucose and lipid metabolism of adult TG females. We evaluated fasting serum insulin, glucose, and triglyceride levels in adult hCGβ+ females and conducted intraperitoneal glucose and insulin tolerance tests at different ages. TG female mice showed hyperinsulinemia, hypertriglyceridemia, and dyslipidemia, as well as glucose intolerance and insulin resistance at 6 months of age. A 1-week treatment with the dopamine agonist cabergoline applied on 5-week-old hCGβ+ mice, which corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, effectively prevented the metabolic alterations. These data indicate a key role of the hyperprolactinemia-induced gonadal dysfunction in the metabolic disturbances of hCGβ+ female mice. The findings prompt further studies on the involvement of gonadotropins and prolactin on metabolic disorders and might pave the way for the development of new therapeutic strategies. PMID:27154336

  1. Vaccination of mice with liposome-entrapped adult antigens of Nippostrongylus brasiliensis.

    Science.gov (United States)

    Rhalem, A; Bourdieu, C; Luffau, G; Pery, P

    1988-01-01

    An immunization procedure was developed to induce protection of mice against the gastrointestinal helminth Nippostrongylus brasiliensis. Mice immunized by the oral route with antigens which were released by adult worms during their in vitro survival in a detergent-containing medium and which were entrapped in liposomes were protected against a challenge infection.

  2. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice.

    Science.gov (United States)

    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

    2015-09-01

    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

  3. Auto-mobilized adult hematopoietic stem cells advance neovasculature in diabetic retinopathy of mice

    Institute of Scientific and Technical Information of China (English)

    TIAN Bei; LI Xiao-xin; SHEN Li; ZHAO Min; YU Wen-zhen

    2010-01-01

    Background Hematopoietic stem cells (HSCs) can be used to deliver functionally active angiostatic molecules to the retinal vasculature by targeting active astrocytes and may be useful in targeting pre-angiogenic retinal lesions. We sought to determine whether HSC mobilization can ameliorate early diabetic retinopathy in mice.Methods Mice were devided into four groups: normal mice control group, normal mice HSC-mobilized group, diabetic mice control group and diabetic mice HSC mobilized group. Murine stem cell growth factor (murine SCF) and recombined human granulocyte colony stimulating factor (rhG-csf) were administered to the mice with diabetes and without diabetes for continuous 5 days to induce autologous HSCs mobilization, and subcutaneous injection of physiological saline was used as control. Immunohistochemical double staining was conducted with anti-mouse rat CD31 monoclonal antibody and anti-BrdU rat antibody.Results Marked HSCs clearly increased after SCF plus G-csf-mobilization. Non-mobilized diabetic mice showed more HSCs than normal mice (P=0.032), and peripheral blood significantly increased in both diabetic and normal mice (P=0.000).Diabetic mice showed more CD31 positive capillary vessels (P=0.000) and accelerated endothelial cell regeneration. Only diabetic HSC-mobilized mice expressed both BrdU and CD31 antigens in the endothelial cells of new capillaries.Conclusion Auto-mobilized adult hematopoietic stem cells advance neovasculature in diabetic retinopathy of mice.

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

    Science.gov (United States)

    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. PMID:27228897

  5. Consumption of lead-shot cervid meat and blood lead concentrations in a group of adult Norwegians.

    Science.gov (United States)

    Meltzer, H M; Dahl, H; Brantsæter, A L; Birgisdottir, B E; Knutsen, H K; Bernhoft, A; Oftedal, B; Lande, U S; Alexander, J; Haugen, M; Ydersbond, T A

    2013-11-01

    Several recent investigations have reported high concentrations of lead in samples of minced cervid meat. This paper describes findings from a Norwegian study performed in 2012 among 147 adults with a wide range of cervid game consumption. The main aim was to assess whether high consumption of lead-shot cervid meat is associated with increased concentration of lead in blood. A second aim was to investigate to what extent factors apart from game consumption explain observed variability in blood lead levels. Median (5 and 95 percentile) blood concentration of lead was 16.6 µg/L (7.5 and 39 µg/L). An optimal multivariate linear regression model for log-transformed blood lead indicated that cervid game meat consumption once a month or more was associated with approximately 31% increase in blood lead concentrations. The increase seemed to be mostly associated with consumption of minced cervid meat, particularly purchased minced meat. However, many participants with high and long-lasting game meat intake had low blood lead concentrations. Cervid meat together with number of bullet shots per year, years with game consumption, self-assembly of bullets, wine consumption and smoking jointly accounted for approximately 25% of the variation in blood lead concentrations, while age and sex accounted for 27% of the variance. Blood lead concentrations increased approximately 18% per decade of age, and men had on average 30% higher blood lead concentrations than women. Hunters who assembled their own ammunition had 52% higher blood lead concentrations than persons not making ammunition. In conjunction with minced cervid meat, wine intake was significantly associated with increased blood lead. Our results indicate that hunting practices such as use of lead-based ammunition, self-assembling of lead containing bullets and inclusion of lead-contaminated meat for mincing to a large extent determine the exposure to lead from cervid game consumption. PMID:24119336

  6. Estrogen Deficiency Leads to Further Bone Loss in the Mandible of CKD Mice.

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    Yuchen Guo

    Full Text Available Chronic kidney disease (CKD has been regarded as a grave public health problem. Estrogen is a critical factor for both renal protection and bone remodeling. Our previous study demonstrated that CKD impairs the healing of titanium implants. The aim of this study was to investigate the effects of estrogen deficiency on the mandibular bone in CKD mice.Forty eleven-week-old female C57BL mice were used in this study. Uremia and estrogen deficiency were induced by 5/6 nephrectomy and ovariectomy (OVX, respectively. After 8 weeks, the mice were sacrificed, and their mandibles were collected for micro-CT analysis and histological examination.All the mice survived the experimental period. Serum measurements confirmed a significant increase in BUN in the CKD group that was further increased by OVX. OVX led to significant decreases in both the BV/TV and cortical thickness of the mandibular bone in CKD mice.In summary, our findings indicate that estrogen deficiency leads to further mandibular bone loss in CKD mice.

  7. Lead poisoning following ingestion of pieces of lead roofing plates: pica-like behavior in an adult.

    Science.gov (United States)

    Sabouraud, Sabine; Testud, François; Descotes, Jacques; Benevent, Monique; Soglu, Gilbert

    2008-03-01

    A 37-year-old man was admitted to hospital after complaining of abdominal pain for the past two weeks. On admission the abdominal radiograph showed multiple radio-opaque flecks dispersed throughout the gastrointestinal tract. Blood testing showed hemoglobin level 8.7 g/dL and a blood lead level of 112.4 microg/dL. The family interview revealed that the patient had pica-like behavior since childhood. He was a site foreman and had been ingesting pieces of roofing plates for a few weeks. The patient was treated with laxatives and CaNa(2)EDTA therapy was initiated. The blood lead level then dropped to 69.9 microg/dL. The patient received two subsequent courses of oral succimer and the blood lead level decreased to 59 microg/dL 21 days after the first course. The follow-up abdominal X-ray 20 days after the first examination was normal. Four months later, an outpatient follow-up visit showed a blood lead level within normal limits (14.5 microg/dL) and a psychiatric follow-up was initiated. Lead poisoning following the ingestion of lead-containing foreign bodies is particularly rare in adults, while it is sometimes observed in children. Pica behavior is a well-identified risk factor of lead intoxication in children but is quite exceptional in adults, where it is usually considered to be a psychiatric condition. Other unusual sources of lead poisoning include the ingestion of lead bullets, ceramic lead glaze or glazed earthenware, lead-contaminated candies, ethnic or herbal remedies. PMID:17906991

  8. Amelioration of lead induced hepatotoxicity by Allium sativum extracts in Swiss albino mice

    OpenAIRE

    Sharma, Arti; Sharma, Veena; Kansal, Leena

    2010-01-01

    Lead is a blue-gray and highly toxic divalent metal that occurs naturally in the earth’s crust and is spread throughout the environment by various human activities. The efficacy of garlic (Allium sativum) to reduce hepatotoxicity induced by lead nitrate was evaluated experimentally in male mice. Oral treatment with lead nitrate at a dose of 50 mg/kg body weight daily for 40 days (1/45 of LD50) induced a significant increase in the levels of hepatic aspartate aminotransferase, alanine am...

  9. Does visual impairment lead to additional disability in adults with intellectual disabilities?

    NARCIS (Netherlands)

    Sjoukes, L.; Koot, H. M.; Kooijman, A. C.; Evenhuis, H.

    2009-01-01

    This study addresses the question to what extent visual impairment leads to additional disability in adults with intellectual disabilities (ID). In a multi-centre cross-sectional study of 269 adults with mild to profound ID, social and behavioural functioning was assessed with observant-based questi

  10. Does Visual Impairment Lead to Additional Disability in Adults with Intellectual Disabilities?

    Science.gov (United States)

    Evenhuis, Heleen M.; Sjoukes, L.; Koot, H. M.; Kooijman, A. C.

    2009-01-01

    Background: This study addresses the question to what extent visual impairment leads to additional disability in adults with intellectual disabilities (ID). Method: In a multi-centre cross-sectional study of 269 adults with mild to profound ID, social and behavioural functioning was assessed with observant-based questionnaires, prior to expert…

  11. Validation of K-XRF bone lead measurement in young adults.

    OpenAIRE

    Hoppin, J.A.; Aro, A C; Williams, P L; Hu, H; Ryan, P B

    1995-01-01

    K-X-ray fluorescence (K-XRF) is a useful tool for assessing environmental exposure to lead in occupationally exposed individuals and older adults. This study explores the possibility of using this technique on young adults with low environmental lead exposure. Twenty-three college students, aged 18-21 years, were recruited for 2 hr of bone lead measurement. Bone lead measurements were taken from the mid-shaft tibia for periods of 30 or 60 min. In the analysis, 30-min measurements were combine...

  12. Histomorphological evaluation of mice testis after co-exposure to lead and cadmium

    Institute of Scientific and Technical Information of China (English)

    Maria de Lourdes Pereira; Neidy Varela Rodrigues; Fernando Garcia e Costa

    2012-01-01

    Objective:The present study investigates the effects of co-exposure to lead and cadmium on mice testis using histomorphological approach.Methods:Male mice were subcutaneously injected with lead chloride on day1 and cadmium chloride on day2(74 and1 mg/kg body weight, respectively), and kept for24 h.Vehicle control group was also considered.Mice were then sacrificed and testis were collected and weighed.Samples were fixed onBouin´s solution and processed for histology.The diameter of seminiferous tubules in both groups was calculated using software based on deformable models(SNAKE).Results:The combined exposure of lead and cadmium induced degenerative changes in testis, namely, wavy contour of seminiferous tulules, germ cell loss, and release of immature cells into the lumen.Atrophy of seminiferous tubules was seen in this group, confirmed by a significant(P<0.001) decrease in the diameter.Conclusions:Cumulative effects of lead and cadmium may have disrupted the blood-testis barrier, then causing the histopathological lesions within testis.

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

    Science.gov (United States)

    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.

  14. CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice.

    Science.gov (United States)

    Ramirez, Alejandro; Co, Mary; Mathew, Anuja

    2016-01-01

    Several studies have shown a reduced efficacy of influenza vaccines in the elderly compared to young adults. In this study, we evaluated the immunogenicity and protective efficacy of a commercially available inactivated influenza vaccine (Fluzone®) in young adult and aged mice. C57/BL6 mice were administered a single or double immunization of Fluzone® with or without CpG and challenged intranasally with H1N1 A/California/09 virus. A double immunization of Fluzone® adjuvanted with CpG elicited the highest level of protection in young adult mice which was associated with increases in influenza specific IgG, elevated HAI titres, reduced viral titres and lung inflammation. In contrast, the vaccine schedule which provided fully protective immunity in young adult mice conferred limited protection in aged mice. Antigen presenting cells from aged mice were found to be less responsive to in vitro stimulation by Fluzone and CpG which may partially explain this result. Our data are supportive of studies that have shown limited effectiveness of influenza vaccines in the elderly and provide important information relevant to the design of more immunogenic vaccines in this age group. PMID:26934728

  15. Increased hippocampal Disrupted-In-Schizophrenia 1 expression in mice exposed prenatally to lead

    Institute of Scientific and Technical Information of China (English)

    Yuanyuan You; Liguang Sun; Bo Peng; Yan Li; Songbin Ben; Shuang Gao

    2012-01-01

    Disrupted-In-Schizophrenia 1 is a susceptibility gene for schizophrenia and other psychiatric disorders.Developmental lead exposure can cause neurological disorders similar to hyperactivity disorder,dyslexia and schizophrenia. In the present study, we examined the impact of developmental lead exposure, administered in vitro and in vivo, on hippocampal Disrupted-In- Schizophrenia 1 expression. Our results show that in cultured hippocampal neurons, in vitro exposure to 0.1-10 μM lead, inhibited neurite growth and increased Disrupted-In-Schizophrenia 1 mRNA and protein expression dose-dependently. In addition, blood lead levels in mice were increased with increasing mouse maternal lead (0.01-1 mM) exposure. Hippocampal neurons from these mice showed a concomitant increase in Disrupted-In-Schizophrenia 1 mRNA and protein expression. Overall our findings suggest that in vivo and in vitro lead exposure increases Disrupted-In-Schizophrenia 1 expression in hippocampal neurons dose-dependently, and consequently may influence synapse formation in newborn neurons.

  16. Adult hematopoietic progenitors are pluripotent in chimeric mice

    OpenAIRE

    Pessac, Bernard; K. Nimmagadda, Vamshi; Makar, Tapas; S. Fishman, Paul; T. Bever Jr., Christopher; Trisler, David

    2012-01-01

    18 pages, 7 figures. Embryonic stem cells (ESCs) and adult somatic cells, induced to pluripotency (iPSCs) by genetic manipulation, display high self-­‐renewal potential and the capacity to differentiate into multiple cell lineages. We asked whether there are in adult mammals natural stem cells that are pluripotent. We previously reported that normal adult mammalian bone marrow contains a sub-­‐population of CD34+ cells, that naturally expresses genes characteristic of ESCs and those requir...

  17. Bracing the trunk and neck in young adults leads to a more aged-like gait.

    Science.gov (United States)

    Russell, Daniel M; Kelleran, Kyle J; Morrison, Steven

    2016-09-01

    Older individuals typically walk at slower speeds, with shorter step lengths, greater step widths and spend a larger proportion of the gait cycle in double stance. Changes in neck and trunk mobility may underlie some of the changes in walking seen with increasing age. Consequently, this study was designed to assess whether externally increasing trunk/neck stiffness in young adults leads to similar changes in gait pattern observed with aging. Twelve young adults (20-29 years), sixteen old adults (60-69 years) and fifteen older adults (70-79 years) walked across a 20' pressure sensitive GAITRite© instrumented walkway at their preferred speed. The young adults also walked under three bracing conditions: (1) Neck braced, (2) Trunk braced, and (3) Neck and Trunk braced. The results revealed that the old and older age groups walked significantly slower, with a shorter step length and with a narrower base of support (p'syoung adults. In young adults, combined neck and trunk bracing led to reduced walking speed, shorter step length, wider base of support and a larger proportion of the gait cycle spent in double stance (p'sadults remained less than fully braced young adults (p'syoung individuals leads to systematic gait changes similar to aging. Consequently, age-related changes in mobility of the neck and torso may in part contribute to the decrements in walking seen for older adults.

  18. Tooth loss inhibits neurogenesis in the dentate gyrus of adult mice

    Institute of Scientific and Technical Information of China (English)

    Shaochen Su; Tao Qi; Baoli Su; Huibin Gu; Jianlin Wang; Lan Yang

    2014-01-01

    Tooth loss has been shown to affect learning and memory in mice and increases the risk of Alz-heimer’s disease. The dentate gyrus is strongly associated with cognitive function. This study hypothesized that tooth loss affects neurons in the dentate gyrus. Adult male mice were random-ly assigned to either the tooth loss group or normal control group. In the tooth loss group, the left maxillary and mandibular molars were extracted. Normal control mice did not receive any intervention. Immunolfuorescence staining revealed that the density and absorbance of double-cortin-and neuronal nuclear antigen-positive cells were lower in the tooth loss group than in the normal control group. These data suggest that tooth loss may inhibit neurogenesis in the dentate gyrus of adult mice.

  19. Nutritional intervention restores muscle but not kidney phenotypes in adult calcineurin aα null mice

    DEFF Research Database (Denmark)

    Madsen, Kirsten; Reddy, Ramesh N; Price, S Russ;

    2013-01-01

    to thrive and early lethality of most null pups. Work in our laboratory led to the rescue of CnAα-/- mice by supplemental feeding to compensate for a defect in salivary enzyme secretion. The data revealed that, without intervention, knockout mice suffer from severe caloric restriction. Since nutritional...... and function persist in adult CnAα-/- mice including a significant decrease in glomerular filtration rate and an increase in blood urea nitrogen levels. These data indicate that impaired renal development we previously reported was not due to caloric restriction but rather a specific role for CnAα in renal......Aα likely alters insulin response due to a reduction in insulin receptor substrate-2 (IRS2) expression and signaling in muscle. This study illustrates the importance of re-examining the phenotypes of CnAα-/- mice and the advances that are now possible with the use of adult, rescued knockout animals....

  20. Sex-specific attentional deficits in adult vitamin D deficient BALB/c mice.

    Science.gov (United States)

    Groves, Natalie J; Burne, Thomas H J

    2016-04-01

    Epidemiological studies have shown an association between vitamin D deficiency and cognitive impairment. However, there is a paucity of preclinical data showing that vitamin D deficiency is a causal factor for impaired cognitive processing. The aim of this study was to assess two cognitive tasks, the 5 choice-serial reaction task and the 5 choice-continuous performance task in adult vitamin D (AVD) deficient BALB/c mice. Ten-week old male and female BALB/c mice were fed a control or vitamin D deficient diet for 10 weeks prior to, and during behavioural testing. We found sex-dependent impairments in attentional processing and showed that male AVD-deficient mice were less accurate, took longer to respond when making a correct choice and were more likely to make an omission, without a change in the motivation to collect reward. By contrast, female AVD-deficient mice had a reduced latency to collect reward, but no changes on any other measures compared to controls. Therefore, we have shown that in otherwise healthy adult mice, vitamin D deficiency led to mild cognitive impairment in male but not female mice and therefore this model will be useful for future investigations into unravelling the mechanism by which vitamin D affects the adult brain and cognitive function. PMID:26836278

  1. Systemic Immune Activation Leads to Neuroinflammation and Sickness Behavior in Mice

    Directory of Open Access Journals (Sweden)

    Steven Biesmans

    2013-01-01

    Full Text Available Substantial evidence indicates an association between clinical depression and altered immune function. Systemic administration of bacterial lipopolysaccharide (LPS is commonly used to study inflammation-associated behavioral changes in rodents. In these experiments, we tested the hypothesis that peripheral immune activation leads to neuroinflammation and depressive-like behavior in mice. We report that systemic administration of LPS induced astrocyte activation in transgenic GFAP-luc mice and increased immunoreactivity against the microglial marker ionized calcium-binding adapter molecule 1 in the dentate gyrus of wild-type mice. Furthermore, LPS treatment caused a strong but transient increase in cytokine levels in the serum and brain. In addition to studying LPS-induced neuroinflammation, we tested whether sickness could be separated from depressive-like behavior by evaluating LPS-treated mice in a panel of behavioral paradigms. Our behavioral data indicate that systemic LPS administration caused sickness and mild depressive-like behavior. However, due to the overlapping time course and mild effects on depression-related behavior per se, it was not possible to separate sickness from depressive-like behavior in the present rodent model.

  2. Lead exposure in Laysan albatross adults and chicks in Hawaii: prevalence, risk factors, and biochemical effects.

    Science.gov (United States)

    Work, T.M.; Smith, M.R.

    1996-01-01

    Prevalence of lead exposure and elevated tissue lead was determined in Laysan albatross (Diomedea immutabilis) in Hawaii. The relationship between lead exposure and proximity to buildings, between elevated blood lead and droopwing status, and elevated liver lead and presence of lead-containing paint chips in the proventriculus in albatross chicks was also examined. Finally, the effects of lead on the enzyme δ-amino-levulinic acid dehydratase (ALAD) was determined. There was a significant association between lead exposure or elevated tissue lead and proximity to buildings in albatross chicks and presence of lead paint chips in the proventriculus and elevated liver lead in carcasses. Although there was a significant association between elevated blood lead and droopwing chicks, there were notable exceptions. Prevalence of elevated tissue lead in albatross chicks was highest on Sand Island Midway and much less so on Kauai and virtually nonexistent in other areas. Prevalence of lead exposure decreased as numbers of buildings to which chicks were exposed on a given island decreased. Laysan albatross adults had minimal to no lead exposure. There was a significant negative correlation between blood lead concentration and ALAD activity in chicks. Based on ALAD activity, 0.03-0.05 μg/ml was the no effect range for blood lead in albatross chicks.

  3. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer

    OpenAIRE

    Bernardes de Jesus, Bruno; Vera, Elsa; Schneeberger, Kerstin; Tejera, Agueda M.; Ayuso, Eduard; Bosch, Fatima; Blasco, Maria A.

    2012-01-01

    A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness,...

  4. Effect of chronic social defeat stress on behaviors and dopamine receptor in adult mice.

    Science.gov (United States)

    Huang, Guang-Biao; Zhao, Tong; Gao, Xiao-Lei; Zhang, Hong-Xing; Xu, Yu-Ming; Li, Hao; Lv, Lu-Xian

    2016-04-01

    Victims of bullying often undergo depression, low self-esteem, high anxiety and post-traumatic stress disorder symptoms. The social defeat model has become widely accepted for studying experimental animal behavior changes associated with bullying; however, differences in the effects in susceptible and unsusceptible individuals have not been well studied. The present study investigated the effects of social defeat stress on behavior and the expression of dopamine receptors D1 and D2 in the brains of adult mice. Adult mice were divided into susceptible and unsusceptible groups after 10days of social defeat stress. Behavioral tests were conducted, and protein levels in the brains were assessed by Western blotting. The results indicate that all mice undergo decreased locomotion and increased anxiety behavior. However, decreased social interaction and impaired memory performance were only observed in susceptible mice. A significantly decreased expression of D1 was observed in the prefrontal cortex and amygdala of susceptible mice only. No significant differences in D2 expression were shown between control and defeated mice in any area studied. These data indicate that depression-like behavior and cognition impairment caused by social defeat stress in susceptible mice may be related to changes in the dopamine receptor D1. PMID:26655446

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

    Science.gov (United States)

    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. PMID:23869740

  6. Specific Inflammatory Stimuli Lead to Distinct Platelet Responses in Mice and Humans.

    Directory of Open Access Journals (Sweden)

    Lea M Beaulieu

    Full Text Available Diverse and multi-factorial processes contribute to the progression of cardiovascular disease. These processes affect cells involved in the development of this disease in varying ways, ultimately leading to atherothrombosis. The goal of our study was to compare the differential effects of specific stimuli--two bacterial infections and a Western diet--on platelet responses in ApoE-/- mice, specifically examining inflammatory function and gene expression. Results from murine studies were verified using platelets from participants of the Framingham Heart Study (FHS; n = 1819 participants.Blood and spleen samples were collected at weeks 1 and 9 from ApoE-/- mice infected with Porphyromonas gingivalis or Chlamydia pneumoniae and from mice fed a Western diet for 9 weeks. Transcripts based on data from a Western diet in ApoE-/- mice were measured in platelet samples from FHS using high throughput qRT-PCR.At week 1, both bacterial infections increased circulating platelet-neutrophil aggregates. At week 9, these cells individually localized to the spleen, while Western diet resulted in increased platelet-neutrophil aggregates in the spleen only. Microarray analysis of platelet RNA from infected or Western diet-fed mice at week 1 and 9 showed differential profiles. Genes, such as Serpina1a, Ttr, Fgg, Rpl21, and Alb, were uniquely affected by infection and diet. Results were reinforced in platelets obtained from participants of the FHS.Using both human studies and animal models, results demonstrate that variable sources of inflammatory stimuli have the ability to influence the platelet phenotype in distinct ways, indicative of the diverse function of platelets in thrombosis, hemostasis, and immunity.

  7. Acute multiple organ failure in adult mice deleted for the developmental regulator Wt1.

    Directory of Open Access Journals (Sweden)

    You-Ying Chau

    2011-12-01

    Full Text Available There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal-epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1 suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2 highlight the differences between foetal and adult tissue regulation; 3 point to the importance of adult mesenchyme in tissue turnover.

  8. Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice.

    Science.gov (United States)

    Stephenson, Erin J; Ragauskas, Alyse; Jaligama, Sridhar; Redd, JeAnna R; Parvathareddy, Jyothi; Peloquin, Matthew J; Saravia, Jordy; Han, Joan C; Cormier, Stephania A; Bridges, Dave

    2016-06-01

    We have investigated the effects of in utero exposure to environmentally persistent free radicals (EPFRs) on growth, metabolism, energy utilization, and skeletal muscle mitochondria in a mouse model of diet-induced obesity. Pregnant mice were treated with laboratory-generated, combustion-derived particular matter (MCP230). The adult offspring were placed on a high-fat diet for 12 wk, after which we observed a 9.8% increase in their body weight. The increase in body size observed in the MCP230-exposed mice was not associated with increases in food intake but was associated with a reduction in physical activity and lower energy expenditure. The reduced energy expenditure in mice indirectly exposed to MCP230 was associated with reductions in skeletal muscle mitochondrial DNA copy number, lower mRNA levels of electron transport genes, and reduced citrate synthase activity. Upregulation of key genes involved in ameliorating oxidative stress was also observed in the muscle of MCP230-exposed mice. These findings suggest that gestational exposure to MCP230 leads to a reduction in energy expenditure at least in part through alterations to mitochondrial metabolism in the skeletal muscle.

  9. Embryonic caffeine exposure acts via A1 adenosine receptors to alter adult cardiac function and DNA methylation in mice.

    Directory of Open Access Journals (Sweden)

    Daniela L Buscariollo

    Full Text Available 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.

  10. Partial Loss of Rpl11 in Adult Mice Recapitulates Diamond-Blackfan Anemia and Promotes Lymphomagenesis

    Directory of Open Access Journals (Sweden)

    Lucia Morgado-Palacin

    2015-10-01

    Full Text Available Diamond-Blackfan anemia (DBA is characterized by anemia and cancer susceptibility and is caused by mutations in ribosomal genes, including RPL11. Here, we report that Rpl11-heterozygous mouse embryos are not viable and that Rpl11 homozygous deletion in adult mice results in death within a few weeks, accompanied by bone marrow aplasia and intestinal atrophy. Importantly, Rpl11 heterozygous deletion in adult mice results in anemia associated with decreased erythroid progenitors and defective erythroid maturation. These defects are also present in mice transplanted with inducible heterozygous Rpl11 bone marrow and, therefore, are intrinsic to the hematopoietic system. Additionally, heterozygous Rpl11 mice present increased susceptibility to radiation-induced lymphomagenesis. In this regard, total or partial deletion of Rpl11 compromises p53 activation upon ribosomal stress or DNA damage in fibroblasts. Moreover, fibroblasts and hematopoietic tissues from heterozygous Rpl11 mice present higher basal cMYC levels. We conclude that Rpl11-deficient mice recapitulate DBA disorder, including cancer predisposition.

  11. Overexpression of Shox2 Leads to Congenital Dysplasia of the Temporomandibular Joint in Mice

    Directory of Open Access Journals (Sweden)

    Xihai Li

    2014-07-01

    Full Text Available Our previous study reported that inactivation of Shox2 led to dysplasia and ankylosis of the temporomandibular joint (TMJ, and that replacing Shox2 with human Shox partially rescued the phenotype with a prematurely worn out articular disc. However, the mechanisms of Shox2 activity in TMJ development remain to be elucidated. In this study, we investigated the molecular and cellular basis for the congenital dysplasia of TMJ in Wnt1-Cre; pMes-stop Shox2 mice. We found that condyle and glenoid fossa dysplasia occurs primarily in the second week after the birth. The dysplastic TMJ of Wnt1-Cre; pMes-stop Shox2 mice exhibits a loss of Collagen type I, Collagen type II, Ihh and Gli2. In situ zymography and immunohistochemistry further demonstrate an up-regulation of matrix metalloproteinases (MMPs, MMP9 and MMP13, accompanied by a significantly increased cell apoptosis. In addition, the cell proliferation and expressions of Sox9, Runx2 and Ihh are no different in the embryonic TMJ between the wild type and mutant mice. Our results show that overexpression of Shox2 leads to the loss of extracellular matrix and the increase of cell apoptosis in TMJ dysplasia by up-regulating MMPs and down-regulating the Ihh signaling pathway.

  12. Conditional expression of Wnt4 during chondrogenesis leads to dwarfism in mice.

    Directory of Open Access Journals (Sweden)

    Hu-Hui Lee

    Full Text Available Wnts are expressed in the forming long bones, suggesting roles in skeletogenesis. To examine the action of Wnts in skeleton formation, we developed a genetic system to conditionally express Wnt4 in chondrogenic tissues of the mouse. A mouse Wnt4 cDNA was introduced into the ubiquitously expressed Rosa26 (R26 locus by gene targeting in embryonic stem (ES cells. The expression of Wnt4 from the R26 locus was blocked by a neomycin selection cassette flanked by loxP sites (floxneo that was positioned between the Rosa26 promoter and the Wnt4 cDNA, creating the allele designated R26(floxneoWnt4. Wnt4 expression was activated during chondrogenesis using Col2a1-Cre transgenic mice that express Cre recombinase in differentiating chondrocytes. R26(floxneoWnt4; Col2a1-Cre double heterozygous mice exhibited a growth deficiency, beginning approximately 7 to 10 days after birth, that resulted in dwarfism. In addition, they also had craniofacial abnormalities, and delayed ossification of the lumbar vertebrae and pelvic bones. Histological analysis revealed a disruption in the organization of the growth plates and a delay in the onset of the primary and secondary ossification centers. Molecular studies showed that Wnt4 overexpression caused decreased proliferation and altered maturation of chondrocytes. In addition, R26(floxneoWnt4; Col2a1-Cre mice had decreased expression of vascular endothelial growth factor (VEGF. These studies demonstrate that Wnt4 overexpression leads to dwarfism in mice. The data indicate that Wnt4 levels must be regulated in chondrocytes for normal growth plate development and skeletogenesis. Decreased VEGF expression suggests that defects in vascularization may contribute to the dwarf phenotype.

  13. Effects of Chronic Lead Acetate Intoxication on Blood Indices of Male Adult Rat

    Directory of Open Access Journals (Sweden)

    Mohammadhosein Noori Mugahi

    2003-10-01

    Full Text Available Lead as one of the environmental pollutants can threats the life of living creatures in many ways. In this study, hematological effects of chronic toxicity of the lead acetate in adult male rats through measurement of the lead concentration in the blood of animal’s heart by atomic absorption as well as hematological analyses and differential cell count were investigated. Results showed that lead concentration in the treatment group was significantly higher than that of the control groups (P<0.001, and basophilic stippling, Howell-Jolly bodies, decreased RBC count (anemia, increased leukocyte count (leukocytosis, monocytosis, eosinopenia, neutrophilia, and thrombocytosis were observed in the test group (P<0.001. It is concluded that microcytic hypochromic anemia can be attributed to the interaction of lead with iron and copper metabolism and increased leukocyte count may be linked to the inflammatory effects of lead on lymphatic organs.

  14. Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice.

    Science.gov (United States)

    Dolejší, Eva; Liraz, Ori; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; Michaelson, Daniel M

    2016-02-01

    Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4-month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For ChAT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of ChAT and the extent of the M2 receptor-mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. Evoked ACh release from hippocampal and cortical slices is similar in 4-month-old apoE4 and apoE3 mice but is specifically and significantly reduced in hippocampus, but not cortex, of 12-month-old apoE4 mice. This effect is accompanied by decreased VAChT levels. These findings show that

  15. Human-derived neural progenitors functionally replace astrocytes in adult mice

    Science.gov (United States)

    Chen, Hong; Qian, Kun; Chen, Wei; Hu, Baoyang; Blackbourn, Lisle W.; Du, Zhongwei; Ma, Lixiang; Liu, Huisheng; Knobel, Karla M.; Ayala, Melvin; Zhang, Su-Chun

    2015-01-01

    Astrocytes are integral components of the homeostatic neural network as well as active participants in pathogenesis of and recovery from nearly all neurological conditions. Evolutionarily, compared with lower vertebrates and nonhuman primates, humans have an increased astrocyte-to-neuron ratio; however, a lack of effective models has hindered the study of the complex roles of human astrocytes in intact adult animals. Here, we demonstrated that after transplantation into the cervical spinal cords of adult mice with severe combined immunodeficiency (SCID), human pluripotent stem cell–derived (PSC-derived) neural progenitors migrate a long distance and differentiate to astrocytes that nearly replace their mouse counterparts over a 9-month period. The human PSC-derived astrocytes formed networks through their processes, encircled endogenous neurons, and extended end feet that wrapped around blood vessels without altering locomotion behaviors, suggesting structural, and potentially functional, integration into the adult mouse spinal cord. Furthermore, in SCID mice transplanted with neural progenitors derived from induced PSCs from patients with ALS, astrocytes were generated and distributed to a similar degree as that seen in mice transplanted with healthy progenitors; however, these mice exhibited motor deficit, highlighting functional integration of the human-derived astrocytes. Together, these results indicate that this chimeric animal model has potential for further investigating the roles of human astrocytes in disease pathogenesis and repair. PMID:25642771

  16. Morphometric study of Schistosoma mansoni adult worms recovered from undernourished infected mice

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    Oliveira Sheilla A

    2003-01-01

    Full Text Available Some unfavourable effects of malnutrition of the host on Schistosoma mansoni worm biology and structure have been reported based upon brigthfield microscopy. This paper aims to study by morphometric techniques, some morphological parameters in male and female adult worms recovered from undernourished albino mice in comparison with parasites recovered from well-fed infected mice. Undernourished animals were fed a multideficient and essentially low protein diet (RBD diet and compared to well-fed control mice fed with the commercial diet NUVILAB. Seventy-five days post-infection with 80 cercarie (BL strain animals were sacrificed. All adult worms were fixed in 10% formalin and stained with carmine chloride. One hundred male and 60 female specimens from each group (undernourished and control were examined using an image system analysis Leica Quantimet 500C and the Sigma Scan Measurement System. The following morphometrical parameters were studied: body length and width, oral and ventral suckers, number and area of testicular lobes, length and width of ovary and uterine egg. For statistical analysis, the Student's t test for unpaired samples was applied. Significant differences (p < 0.05 were detected in body length and width, in parameters of suckers, uterine egg width, ovary length and area of testicular lobes, with lower values for specimens from undernourished mice. The nutritional status of the host has negative influence on S. mansoni adult worms, probably through unavailability of essential nutrients to the parasites.

  17. Impairment in Spatial Memory in adult Rats following developmental Low Lead Exposure

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    Rajashekar Rao Barkur

    2012-11-01

    Full Text Available The present study was aimed to investigate the effect of environmentally relevant levels of lead exposure during gestational and early postnatal period on hippocampal dependent spatial memory in rats during adulthood. The pregnant rats were allowed to drink either normal water (control group or 0.2% lead acetate solution (Leadtreated group during pregnancy and lactation. Thus rats pups of lead treated group where exposed to lead indirectly through their mothers during this period. At weaning pups of lead treated group were allowed to drink normal water till they attain the adult hood. Blood lead level was estimated on postnatal day 22 and 120. Birth weight and weight gain of the rat pups as they grew were measured at regular intervals. Both the control and lead treated groups of rats were subjected to water maze test on postnatal day 30 and 120. Results showed that lead treatment had no effect on birth weight or weight gain. Blood lead level on postnatal day 22 was significantly high in treated group compared to the control group and it was normalized by end of four months. The rats born to lead treated mothers showed impaired in spatial memory during water maze test both on postnatal day 36 and 126. These data suggests that exposure to environmentally relevant levels of lead during intrauterine and early postnatal period of brain development causes impairment in spatial memory not only during infancy but also lasts till adulthood.

  18. Lead exposure in adult males in urban Transvaal Province, South Africa during the apartheid era.

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    Hess, Catherine A; Cooper, Matthew J; Smith, Martin J; Trueman, Clive N; Schutkowski, Holger

    2013-01-01

    Human exposure to lead is a substantial public health hazard worldwide and is particularly problematic in the Republic of South Africa given the country's late cessation of leaded petrol. Lead exposure is associated with a number of serious health issues and diseases including developmental and cognitive deficiency, hypertension and heart disease. Understanding the distribution of lifetime lead burden within a given population is critical for reducing exposure rates. Femoral bone from 101 deceased adult males living in urban Transvaal Province (now Gauteng Province), South Africa between 1960 and 1998 were analyzed for lead concentration by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Of the 72 black and 29 white individuals sampled, chronic lead exposure was apparent in nearly all individuals. White males showed significantly higher median bone lead concentration (ME = 10.04 µg·g(-1)), than black males (ME = 3.80 µg·g(-1)) despite higher socioeconomic status. Bone lead concentration covaries significantly, though weakly, with individual age. There was no significant temporal trend in bone lead concentration. These results indicate that long-term low to moderate lead exposure is the historical norm among South African males. Unexpectedly, this research indicates that white males in the sample population were more highly exposed to lead.

  19. Emotional disorders in adult mice heterozygous for the transcription factor Phox2b.

    Science.gov (United States)

    Bollen, Bieke; Ramanantsoa, Nelina; Naert, Arne; Matrot, Boris; Van den Bergh, Omer; D'Hooge, Rudi; Gallego, Jorge

    2015-03-15

    Phox2b is an essential transcription factor for the development of the autonomic nervous system. Mice carrying one invalidated Phox2b allele (Phox2b(+/-)) show mild autonomic disorders including sleep apneas, and impairments in chemosensitivity and thermoregulation that recover within 10days of postnatal age. Because Phox2b is not expressed above the pons nor in the cerebellum, this mutation is not expected to affect brain development and cognitive functioning directly. However, the transient physiological disorders in Phox2b(+/-) mice might impair neurodevelopment. To examine this possibility, we conducted a behavioral test battery of emotional, motor, and cognitive functioning in adult Phox2b(+/-) mice and their wildtype littermates (Phox2b(+/+)). Adult Phox2b(+/-) mice showed altered exploratory behavior in the open field and in the elevated plus maze, both indicative of anxiety. Phox2b(+/-) mice did not show cognitive or motor impairments. These results suggest that also mild autonomic control deficits may disturb long-term emotional development. PMID:25582512

  20. Global gene expression patterns in the post-pneumonectomy lung of adult mice

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    Ingenito Edward P

    2009-10-01

    Full Text Available Abstract Background Adult mice have a remarkable capacity to regenerate functional alveoli following either lung resection or injury that exceeds the regenerative capacity observed in larger adult mammals. The molecular basis for this unique capability in mice is largely unknown. We examined the transcriptomic responses to single lung pneumonectomy in adult mice in order to elucidate prospective molecular signaling mechanisms used in this species during lung regeneration. Methods Unilateral left pneumonectomy or sham thoracotomy was performed under general anesthesia (n = 8 mice per group for each of the four time points. Total RNA was isolated from the remaining lung tissue at four time points post-surgery (6 hours, 1 day, 3 days, 7 days and analyzed using microarray technology. Results The observed transcriptomic patterns revealed mesenchymal cell signaling, including up-regulation of genes previously associated with activated fibroblasts (Tnfrsf12a, Tnc, Eln, Col3A1, as well as modulation of Igf1-mediated signaling. The data set also revealed early down-regulation of pro-inflammatory cytokine transcripts and up-regulation of genes involved in T cell development/function, but few similarities to transcriptomic patterns observed during embryonic or post-natal lung development. Immunohistochemical analysis suggests that early fibroblast but not myofibroblast proliferation is important during lung regeneration and may explain the preponderance of mesenchymal-associated genes that are over-expressed in this model. This again appears to differ from embryonic alveologenesis. Conclusion These data suggest that modulation of mesenchymal cell transcriptome patterns and proliferation of S100A4 positive mesenchymal cells, as well as modulation of pro-inflammatory transcriptome patterns, are important during post-pneumonectomy lung regeneration in adult mice.

  1. Situs inversus abdominus and malrotation in an adult with Ladd's band formation leading to intestinal ischaemia

    Institute of Scientific and Technical Information of China (English)

    Ismail H Mallick; Rizwan Iqbal; Justin B Davies

    2006-01-01

    Situs inversus abdominus with rotational anomaly of the intestines is an extremely rare condition. Although intestinal mairotation has been recognized as a cause of obstruction in infants and children and may be complicated by intestinal ischaemia, it is very rare in adults. When it occurs in the adult patient, it may present acutely as bowel obstruction or intestinal ischaemia or chronically as vague intermittent abdominal pain. Herein, we present an acute presentation of a case of situs inversus abdominus and intestinal malrotation with Ladd's band leading to infarction of the intestine in a 32 year old woman.

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

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    Gasco Manuel

    2005-05-01

    Full Text Available Abstract 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

  3. Cellulose supplementation early in life ameliorates colitis in adult mice.

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    Dorottya Nagy-Szakal

    Full Text Available Decreased consumption of dietary fibers, such as cellulose, has been proposed to promote the emergence of inflammatory bowel diseases (IBD: Crohn disease [CD] and ulcerative colitis [UC] where intestinal microbes are recognized to play an etiologic role. However, it is not known if transient fiber consumption during critical developmental periods may prevent consecutive intestinal inflammation. The incidence of IBD peaks in young adulthood indicating that pediatric environmental exposures may be important in the etiology of this disease group. We studied the effects of transient dietary cellulose supplementation on dextran sulfate sodium (DSS colitis susceptibility during the pediatric period in mice. Cellulose supplementation stimulated substantial shifts in the colonic mucosal microbiome. Several bacterial taxa decreased in relative abundance (e.g., Coriobacteriaceae [p = 0.001], and other taxa increased in abundance (e.g., Peptostreptococcaceae [p = 0.008] and Clostridiaceae [p = 0.048]. Some of these shifts persisted for 10 days following the cessation of cellulose supplementation. The changes in the gut microbiome were associated with transient trophic and anticolitic effects 10 days following the cessation of a cellulose-enriched diet, but these changes diminished by 40 days following reversal to a low cellulose diet. These findings emphasize the transient protective effect of dietary cellulose in the mammalian large bowel and highlight the potential role of dietary fibers in amelioration of intestinal inflammation.

  4. Infection with influenza a virus leads to flu antigen-induced cutaneous anaphylaxis in mice.

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    Grunewald, Susanne M; Hahn, Christian; Wohlleben, Gisela; Teufel, Martin; Major, Tamas; Moll, Heidrun; Bröcker, Eva-B; Erb, Klaus J

    2002-04-01

    It is well established, that viral infections may trigger urticaria or allergic asthma; however, as viral infections induce T helper 1 polarized responses, which lead to the inhibition of T helper 2 cell development, the opposite would be plausible. We wanted to investigate how viral infections may mediate allergic symptoms in a mouse model; therefore, we infected BALB/C mice with influenza A virus intranasally. Histologic analyses of lung sections and bronchoalveolar lavages were performed. In addition, cells from the mediastinal lymph nodes were restimulated in vitro to analyze which types of cytokines were induced by the flu infection. Furthermore, flu-specific antibody titers were determined and local anaphylaxis was measured after rechallenge with flu antigen. We found that airways inflammation consisted predominately of macrophages and lymphocytes, whereas only a few eosinophils were observed. interferon-gamma but no interleukin-4 and little interleukin-5 could be detected in the culture supernatants from in vitro restimulated T cells from the draining lymph nodes. The antibody response was characterized by high levels of virus-specific IgG2a, IgG2b, and IgG1 and, surprisingly, low levels of virus-specific IgE antibodies. Interestingly, flu-infected mice developed active and passive cutaneous anaphylaxis after rechallenge with flu-antigen. As the passive cutaneous anaphylaxis reaction persisted over 48 h and was significantly lower after passive transfer of the serum, which was IgE depleted, local anaphylaxis seemed to be mediated predominately by specific IgE antibodies. Taken together, our results demonstrate that mice infected with flu virus develop virus-specific mast cell degranulation in the skin. Our results may also have implications for the pathogenesis of urticaria or other atopic disorders in humans. PMID:11918711

  5. Absence of TI-VAMP/Vamp7 leads to increased anxiety in mice.

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    Danglot, Lydia; Zylbersztejn, Kathleen; Petkovic, Maja; Gauberti, Maxime; Meziane, Hamid; Combe, Roy; Champy, Marie-France; Birling, Marie-Christine; Pavlovic, Guillaume; Bizot, Jean-Charles; Trovero, Fabrice; Della Ragione, Floriana; Proux-Gillardeaux, Véronique; Sorg, Tania; Vivien, Denis; D'Esposito, Maurizio; Galli, Thierry

    2012-02-01

    Vesicular (v)- and target (t)-SNARE proteins assemble in SNARE complex to mediate membrane fusion. Tetanus neurotoxin-insensitive vesicular-associated membrane protein (TI-VAMP/VAMP7), a vesicular SNARE expressed in several cell types including neurons, was previously shown to play a major role in exocytosis involved in neurite growth in cultured neurons. Here we generated a complete constitutive knock-out by deleting the exon 3 of Vamp7. Loss of TI-VAMP expression did not lead to any striking developmental or neurological defect. Knock-out mice displayed decreased brain weight and increased third ventricle volume. Axon growth appeared normal in cultured knock-out neurons. Behavioral characterization unraveled that TI-VAMP knock-out was associated with increased anxiety. Our results thus suggest compensatory mechanisms allowing the TI-VAMP knock-out mice to fulfill major developmental processes. The phenotypic traits unraveled here further indicate an unexpected role of TI-VAMP-mediated vesicular traffic in anxiety and suggest a role for TI-VAMP in higher brain functions.

  6. Salvia miltiorrhiza Injection Ameliorates Renal Damage Induced by Lead Exposure in Mice

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    Lei Li

    2014-01-01

    Full Text Available Exposure to lead (Pb can induce kidney injury and our recent studies have found that Salvia miltiorrhiza (SM injection, a traditional Chinese medicine, could protect against the organ injury induced by iron overload. This study was designed to investigate the protective effects of SM injection on nephrotoxicity induced by Pb acetate in mice and to elucidate the potential mechanism(s. Healthy male mice were randomly divided into four groups: control, Pb, low-dose Salvia miltiorrhiza (L-SM, and high-dose Salvia miltiorrhiza (H-SM. SM injection dose dependently reduced the Pb accumulation in the kidney, decreased kidney coefficients, and ameliorated renal structure and function from the morphology analysis. Meanwhile, SM administration downregulated serum levels of blood urea nitrogen (BUN and creatinine (CR, decreased malondialdehyde (MAD content, and increased activities of super oxide dismutase (SOD and glutathione peroxidase (GSH-Px in the kidney homogenate. Moreover, SM injection reduced the level of renal apoptosis by immunohistochemical staining analysis. Our findings implicate the therapeutic potential of SM injection for Pb-induced nephrotoxicity, which were at least partly due to the decrease of Pb accumulation, inhibition of lipid peroxidation, and suppression of renal apoptosis. These results provided preliminary experimental support for Danshen as a therapeutic drug for Pb poisoning diseases.

  7. Salvia miltiorrhiza injection ameliorates renal damage induced by lead exposure in mice.

    Science.gov (United States)

    Li, Lei; Zhang, Yuanyuan; Ma, Juanjuan; Dong, Weichong; Song, Qiongtao; Zhang, Jianping; Chu, Li

    2014-01-01

    Exposure to lead (Pb) can induce kidney injury and our recent studies have found that Salvia miltiorrhiza (SM) injection, a traditional Chinese medicine, could protect against the organ injury induced by iron overload. This study was designed to investigate the protective effects of SM injection on nephrotoxicity induced by Pb acetate in mice and to elucidate the potential mechanism(s). Healthy male mice were randomly divided into four groups: control, Pb, low-dose Salvia miltiorrhiza (L-SM), and high-dose Salvia miltiorrhiza (H-SM). SM injection dose dependently reduced the Pb accumulation in the kidney, decreased kidney coefficients, and ameliorated renal structure and function from the morphology analysis. Meanwhile, SM administration downregulated serum levels of blood urea nitrogen (BUN) and creatinine (CR), decreased malondialdehyde (MAD) content, and increased activities of super oxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the kidney homogenate. Moreover, SM injection reduced the level of renal apoptosis by immunohistochemical staining analysis. Our findings implicate the therapeutic potential of SM injection for Pb-induced nephrotoxicity, which were at least partly due to the decrease of Pb accumulation, inhibition of lipid peroxidation, and suppression of renal apoptosis. These results provided preliminary experimental support for Danshen as a therapeutic drug for Pb poisoning diseases. PMID:24696648

  8. Developmental lead acetate exposure induces embryonic toxicity and memory deficit in adult zebrafish.

    Science.gov (United States)

    Chen, Jiangfei; Chen, Yuanhong; Liu, Wei; Bai, Chenglian; Liu, Xuexia; Liu, Kai; Li, Rong; Zhu, Jian-Hong; Huang, Changjiang

    2012-01-01

    Lead is a persistent metal and commonly present in our living environment. The present study was aimed to investigate lead-induced embryonic toxicity, behavioral responses, and adult learning/memory deficit in zebrafish. Lead acetate (PbAc) induced malformations such as uninflated swim bladder, bent spine and yolk-sac edema with an EC₅₀ of 0.29 mg/L at 120 h post fertilization (hpf). Spontaneous movement as characterized by tail bend frequency was significantly altered in zebrafish embryos following exposure to PbAc. Behavior assessment demonstrated that lead exposure changed behavioral responses in zebrafish larvae, as hyperactivity was detected within the first minute of light-to-dark transition in the fish exposed to PbAc from 6 to 96 hpf, and a different dose-dependent change was found in swimming speeds in the dark and in the light at 120 hpf following lead exposure. Learning/memory task assay showed that embryos exposed to PbAc from 6 to 120 hpf developed learning/memory deficit at adulthood as exhibited by a significant decrease in accuracy rate to find the food and a significant increase in finding time. Overall, our results suggested that low dose of developmental lead exposure resulted in embryonic toxicity, behavioral alteration, and adult learning/memory deficit in zebrafish. PMID:22975620

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

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    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. Below background levels of blood lead impact cytokine levels in male and female mice

    International Nuclear Information System (INIS)

    A number of studies have documented that Pb exerts immunotoxic effects on T lymphocytes. In studies designed to explore this general response over a broad dose range, female Swiss mice were administered six different diets containing Pb acetate 1 day after mating. During lactation, the mothers received the same feed given during pregnancy, and the same diets were administered to the offspring for 9 months after weaning. At the end of exposure, blood Pb level in the offspring was determined, and possible changes in two type 1 cytokines (IL-2, INF-γ) and one type 2 cytokine (IL-4) in the serum were measured. At higher dietary Pb levels (40 and 400 ppm), a significant increase in IL-4 production was associated with a profound decrease in INF-γ and IL-2 production. At the lowest Pb diet level (0.02 ppm), which resulted in a blood lead level of (0.8 μg/dL), which is below background (2-3 μg/dL) values in humans, increases in INF-γ and IL-2 production along with a significant decrease in IL-4 production were observed. The findings provide evidence of a reversal of lead-induced cytokine skewing depending on the blood lead concentration. As blood lead concentration increases, there is a notable skewing toward Th2, while the pattern is reversed favoring Th1 development at lower blood lead values. The present findings are also notable since they indicate the potential for dietary Pb to have significant biological effects below normal background concentrations

  11. Telomere shortening leads to earlier age of onset in ALS mice

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    Linkus, Birgit; Wiesner, Diana; MeΔner, Martina; Karabatsiakis, Alexander; Scheffold, Annika; Rudolph, K. Lenhard; Thal, Dietmar R.; Weishaupt, Jochen H.; Ludolph, Albert C.; Danzer, Karin M.

    2016-01-01

    Telomere shortening has been linked to a variety of neurodegenerative diseases. Recent evidence suggests that reduced telomerase expression results in shorter telomeres in leukocytes from sporadic patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. Here, we have characterized telomere length in microglia, astroglia and neurons in human post mortem brain tissue from ALS patients and healthy controls. Moreover, we studied the consequences of telomerase deletion in a genetic mouse model for ALS. We found a trend towards longer telomeres in microglia in the brains of ALS patients compared to non-neurologic controls. Knockout of telomerase leading to telomere shortening accelerated the ALS phenotype in SOD1G93A–transgenic mice. Our results suggest that telomerase dysfunction might contribute to the age-related risk for ALS. PMID:26978042

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

    Science.gov (United States)

    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. PMID:26923756

  13. Pannexin 1 Regulates Bidirectional Hippocampal Synaptic Plasticity in Adult Mice

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    Alvaro O. Ardiles

    2014-10-01

    Full Text Available The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR composition of GluN2 subunits. Pannexin 1 (Panx1, a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP, it remains unknown whether these channels also modulate long-term depression (LTD or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory.

  14. Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice

    Science.gov (United States)

    Ardiles, Alvaro O.; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M.; Palacios, Adrian G.; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C.; Martínez, Agustín D.

    2014-01-01

    The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory. PMID:25360084

  15. Developmental lead effects on behavior and brain gene expression in male and female BALB/cAnNTac mice.

    Science.gov (United States)

    Kasten-Jolly, Jane; Pabello, Nina; Bolivar, Valerie J; Lawrence, David A

    2012-10-01

    Lead (Pb) was one of the first poisons identified, and the developing nervous system is particularly vulnerable to its toxic effects. Relatively low, subclinical doses, of Pb that produce no overt signs of encephalopathy can affect cognitive, emotional, and motor functions. In the present study, the effects of developmental Pb-exposure on behavioral performance and gene expression in BALB/cAnNTac mice were evaluated. Pups were exposed to Pb from gestational-day (gd) 8 to postnatal-day (pnd) 21 and later evaluated in exploratory behavior, rotarod, Morris water maze, and resident-intruder assays as adults. Pb-exposure caused significant alterations in exploratory behavior and water maze performance during the probe trial, but rotarod performance was not affected. Pb-exposed males displayed violent behavior towards their cage mates, but not to a stranger in the resident-intruder assay. Gene expression analysis at pnd21 by microarray and qRT-PCR was performed to provide a molecular link to the behavior changes that were observed. Pb strongly up-regulated gene expression within the signaling pathways of mitogen activated protein kinases (MAPKs), extra-cellular matrix (ECM) receptor, focal adhesion, and vascular endothelial growth-factor (VEGF), but Pb down-regulated gene expression within the pathways for glycan structures-biosynthesis 1, purine metabolism, and N-glycan biosynthesis. Pb increased transcription of genes for major histocompatibility (MHC) proteins, the chemokine Ccl28, chemokine receptors, IL-7, IL7R, and proteases. The qRT-PCR analysis indicated an increase of gene expression in the whole brain for caspase 1 and NOS2. Analysis of IL-1β, caspase 1, NOS2, Trail, IL-18 and IL-33 gene expression of brain regions indicated that Pb perturbed the inter-regional expression pattern of pro-inflammatory genes. Brain region protein concentrations for IL-10, an anti-inflammatory cytokine, showed a significant decrease only within the cortex region. Results indicate

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

    Science.gov (United States)

    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. PMID:25393660

  17. How does long-term odor deprivation affect the olfactory capacity of adult mice?

    Directory of Open Access Journals (Sweden)

    Coppola David M

    2010-05-01

    Full Text Available Abstract Background Unilateral naris occlusion (UNO has been the most common method of effecting stimulus deprivation in studies of olfactory plasticity. However, despite the large corpus on the effects of this manipulation, dating back to the 19th century, little is known about its behavioral sequela. Here we report the results of standard olfactory habituation and discrimination studies on adult mice that had undergone perinatal UNO followed by adult contralateral olfactory bulbectomy (bulb-x. Methods The olfactory performance of UNO mice was compared to matched controls that had unilateral bulb-x but open nares. Both habituation and discrimination (operant experiments employed a protocol in which after successful dishabituation or discrimination to dilute individual odors (A = 0.01% isoamyl acetate; B = 0.01% ethyl butyrate; each v/v in mineral oil, mice were challenged with a single odor versus a mixture comparison (A vs. A + B. In a series of tests the volume portion of Odor B in the mixture was systematically decreased until dishabituation or discrimination thresholds were reached. Results For the habituation experiment, UNOs (n = 10 and controls (n = 9 dishabituated to a 10% mixture of Odor B in Odor A after being habituated to A alone, while both groups failed to show differential responding to a 2% mixture of B in A. However, the UNO group's increased investigation durations for the 2% mixture approached significance (p Conclusions Adult mice relying on an olfactory system deprived of odor by naris occlusion from near the time of birth display enhanced olfactory capacity compared to control mice. This counterintuitive result suggests that UNO is neither an absolute method of deprivation nor does it diminish olfactory capabilities. Enhanced olfactory capacity, as observed in the current study, that is a consequence of deprivation, is consistent with recent molecular and physiological evidence that stimulus deprivation triggers

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

    OpenAIRE

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

    2014-01-01

    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 i...

  19. Neonatal oxygen adversely affects lung function in adult mice without altering surfactant composition or activity

    OpenAIRE

    Yee, Min; Chess, Patricia R.; McGrath-Morrow, Sharon A.; Wang, Zhengdong; Gelein, Robert; Zhou, Rui; Dean, David A.; Notter, Robert H.; O'Reilly, Michael A.

    2009-01-01

    Despite its potentially adverse effects on lung development and function, supplemental oxygen is often used to treat premature infants in respiratory distress. To understand how neonatal hyperoxia can permanently disrupt lung development, we previously reported increased lung compliance, greater alveolar simplification, and disrupted epithelial development in adult mice exposed to 100% inspired oxygen fraction between postnatal days 1 and 4. Here, we investigate whether oxygen-induced changes...

  20. A Biomonitoring Study of Lead, Cadmium, and Mercury in the Blood of New York City Adults

    OpenAIRE

    McKelvey, Wendy; Gwynn, R. Charon; Jeffery, Nancy; Kass, Daniel; Thorpe, Lorna E.; Garg, Renu K.; Palmer, Christopher D.; Parsons, Patrick J.

    2007-01-01

    Objectives We assessed the extent of exposure to lead, cadmium, and mercury in the New York City (NYC) adult population. Methods We measured blood metal concentrations in a representative sample of 1,811 NYC residents as part of the NYC Health and Nutrition Examination Survey, 2004. Results The geometric mean blood mercury concentration was 2.73 μg/L [95% confidence interval (CI), 2.58–2.89]; blood lead concentration was 1.79 μg/dL (95% CI, 1.73–1.86); and blood cadmium concentration was 0.77...

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

    Science.gov (United States)

    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.

  2. Theory of hantavirus infection spread incorporating localized adult and itinerant juvenile mice

    Science.gov (United States)

    Kenkre, V. M.; Giuggioli, L.; Abramson, G.; Camelo-Neto, G.

    2007-02-01

    A generalized model of the spread of the Hantavirus in mice populations is presented on the basis of recent observational findings concerning the movement characteristics of the mice that carry the infection. The factual information behind the generalization is based on mark-recapture observations reported in Giuggioli et al. [Bull. Math. Biol. 67, 1135 (2005)] that have necessitated the introduction of home ranges in the simple model of Hantavirus spread presented by Abramson and Kenkre [Phys. Rev. E 66, 11912 (2002)]. The essential feature of the model presented here is the existence of adult mice that remain largely confined to locations near their home ranges, and itinerant juvenile mice that are not so confined, and, during their search for their own homes, move and infect both other juveniles and adults that they meet during their movement. The model is presented at three levels of description: mean field, kinetic and configuration. Results of calculations are shown explicitly from the mean field equations and the simulation rules, and are found to agree in some respects and to differ in others. The origin of the differences is shown to lie in spatial correlations. It is indicated how mark-recapture observations in the field may be employed to verify the applicability of the theory.

  3. Repeated inhalation of crack-cocaine affects spermatogenesis in young and adult mice.

    Science.gov (United States)

    Pires, A; Pieri, P; Hage, M; Santos, A B G; Medeiros, M C R; Garcia, R C T; Yonamine, M; Hallak, J; Saldiva, P H N; Zorzetto, J C; Bueno, H M S

    2012-06-01

    To investigate the effects of repeated crack-cocaine inhalation on spermatogenesis of pubertal and mature Balb/c mice, ten young (Y(ex)) and ten adult (A(ex)) Balb/c mice were exposed to the smoke from 5 g of crack with 57.7% of pure cocaine in an inhalation chamber, 5 days/week for 2 months. The young (Y(c)) and adult (A(c)) control animals (n = 10) were kept in a specially built and controlled animal house facility. The morphologic analysis of both testes of all animals included the analysis of quantitative and qualitative histologic parameters to assess the effect of crack-cocaine on spermatogenesis and Leydig cells. Apoptosis was determined by immunolabeling with caspase-3 antibodies. Compared to the Y(c) animals, Y(ex) animals showed a significant reduction in the number of stage VII tubules per testis (p = 0.02), Sertoli cells (p cocaine smoke inhalation induced spermatogenesis disruption in chronically exposed mice, particularly in pubertal mice. PMID:22642293

  4. Effects of Kerack used in addict Iranian people on fertility of adult mice

    Directory of Open Access Journals (Sweden)

    Mehdi Amini

    2013-08-01

    Full Text Available Background: Infertility is one of the most serious social problems. Illicit drug use can be an important cause of male factor infertility. Kerack which its use is rising up in Iran refers to a high purity street-level heroin (heroin Kerack. Heroin Kerack used in Iran is an opioid and has harmful effects on body organs. The aim of this study is to investigate the effects of Kerack used in Iran on fertility adult mice.Methods: In this study, 25 male mice were divided into five groups (control, sham and three experimental. Experimental groups of Kerack-dependent mice (received ascend-ing dose of Kerack for seven days were divided into three categories, experimental I, II and III. Experimental I was given Kerack at a dose of 5 mg/kg, experimental II 35 mg/kg and experimental III 70 mg/kg, intraperitoneally twice a day for a period of 35 days. The sham group received normal saline and lemon juice (2.6 µl/ml whilst the control group just received water and food. Mice were then scarified and sperm removed from cauda epididymis were analyzed for sperm count, motility, morphology (normal/abnormal and viability. Testes were also removed, weighed and processed for light microscopic studies.Results: The results showed that fertility were significantly decreased in addicted mice compared with control groups (P≤0.05. Epididymal sperm parameters and thickness of seminiferous epithelium were significantly decreased in experimental groups (dose-dependent compared with sham and control groups (P≤0.05. Gonadosomatic index was significantly reduced with high dose Kerack injected (70 mg/kg in comparison with control testes (P≤0.05.Conclusion: This study has shown the deleterious effects of Kerack used in addicted Iranian people on fertility for the first time. This effect is especially on epididymal sperm parameters in adult mice.

  5. Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice.

    Science.gov (United States)

    Baerenwaldt, Anne; von Burg, Nicole; Kreuzaler, Matthias; Sitte, Selina; Horvath, Edit; Peter, Annick; Voehringer, David; Rolink, Antonius G; Finke, Daniela

    2016-03-15

    Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7(-) and α4β7(+) lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer's patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46(-) group 3 ILCs in wild-type and even in Il7(-/-) mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer's patches development by targeting lymphoid progenitor cells during fetal and adult life.

  6. Sex- and Tissue-Specific Methylome Changes in Brains of Mice Perinatally Exposed to Lead

    Science.gov (United States)

    Sánchez-Martín, Francisco Javier; Lindquist, Diana M.; Landero-Figueroa, Julio; Zhang, Xiang; Chen, Jing; Cecil, Kim M.; Medvedovic, Mario; Puga, Alvaro

    2014-01-01

    Changes in DNA methylation and subsequent changes in gene expression regulation are the hallmarks of age- and tissue-dependent epigenetic drift and plasticity resulting from the combinatorial integration of genetic determinants and environmental cues. To determine whether perinatal lead exposure caused persistent DNA methylation changes in target tissues, we exposed mouse dams to 0, 3 or 30 ppm of lead acetate in drinking water for a period extending from 2 months prior to mating, through gestation, until weaning of pups at postnatal day-21, and analyzed whole-genome DNA methylation in brain cortex and hippocampus of 2-month old exposed and unexposed progeny. Lead exposure resulted in hypermethylation of three differentially methylated regions in the hippocampus of females, but not males. These regions mapped to Rn4.5s, Sfi1, and Rn45s loci in mouse chromosomes 2, 11 and 17, respectively. At a conservative fdr<0.001, 1,623 additional CpG sites were differentially methylated in female hippocampus, corresponding to 117 unique genes. Sixty of these genes were tested for mRNA expression and showed a trend towards negative correlation between mRNA expression and methylation in exposed females but not males. No statistically significant methylome changes were detected in male hippocampus or in cortex of either sex. We conclude that exposure to lead during embryonic life, a time when the organism is most sensitive to environmental cues, appears to have a sex- and tissue-specific effect on DNA methylation that may produce pathological or physiological deviations from the epigenetic plasticity operative in unexposed mice. PMID:25530354

  7. Milk lacking α-casein leads to permanent reduction in body size in mice.

    Directory of Open Access Journals (Sweden)

    Andreas F Kolb

    Full Text Available The major physiological function of milk is the transport of amino acids, carbohydrates, lipids and minerals to mammalian offspring. Caseins, the major milk proteins, are secreted in the form of a micelle consisting of protein and calcium-phosphate.We have analysed the role of the milk protein α-casein by inactivating the corresponding gene in mice. Absence of α-casein protein significantly curtails secretion of other milk proteins and calcium-phosphate, suggesting a role for α-casein in the establishment of casein micelles. In contrast, secretion of albumin, which is not synthesized in the mammary epithelium, into milk is not reduced. The absence of α-casein also significantly inhibits transcription of the other casein genes. α-Casein deficiency severely delays pup growth during lactation and results in a life-long body size reduction compared to control animals, but has only transient effects on physical and behavioural development of the pups. The data support a critical role for α-casein in casein micelle assembly. The results also confirm lactation as a critical window of metabolic programming and suggest milk protein concentration as a decisive factor in determining adult body weight.

  8. Association of lead and cadmium exposure with frailty in US older adults

    Energy Technology Data Exchange (ETDEWEB)

    García-Esquinas, Esther, E-mail: esthergge@gmail.com [Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid/ IdiPAZ, Madrid (Spain); CIBER of Epidemiology and Public Health (CIBERESP), Madrid (Spain); Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (United States); Navas-Acien, Ana [Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (United States); Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (United States); Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (United States); Pérez-Gómez, Beatriz [CIBER of Epidemiology and Public Health (CIBERESP), Madrid (Spain); Environmental Epidemiology and Cancer Unit, National Center for Epidemiology, Carlos III Institute of Health, Madrid (Spain); Artalejo, Fernando Rodríguez [Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid/ IdiPAZ, Madrid (Spain); CIBER of Epidemiology and Public Health (CIBERESP), Madrid (Spain)

    2015-02-15

    Background: Environmental lead and cadmium exposure is associated with higher risk of several age-related chronic diseases, including cardiovascular disease, chronic kidney disease and osteoporosis. These diseases may lead to frailty, a geriatric syndrome characterized by diminished physiologic reserve in multiple systems with decreased ability to cope with acute stressors. However, no previous study has evaluated the association between lead or cadmium exposure and frailty. Methods: Cross-sectional study among individuals aged ≥60 years who participated in the third U.S. National Health and Nutrition Examination Survey and had either blood lead (N=5272) or urine cadmium (N=4887) determinations. Frailty was ascertained with a slight modification of the Fried criteria, so that individuals meeting ≥3 of 5 pre-defined criteria (exhaustion, low body weight, low physical activity, weakness and slow walking speed), were considered as frail. The association between lead and cadmium with frailty was evaluated using logistic regression with adjustment for relevant confounders. Results: Median (intertertile range) concentrations of blood lead and urine cadmium were 3.9 µg/dl (2.9–4.9) and 0.62 µg/l (0.41–0.91), respectively. The prevalence of frailty was 7.1%. The adjusted odds ratios (95% confidence interval) of frailty comparing the second and third to the lowest tertile of blood lead were, respectively, 1.40 (0.96–2.04) and 1.75 (1.33–2.31). Lead concentrations were also associated with the frequency of exhaustion, weakness and slowness. The corresponding odds ratios (95% confidence interval) for cadmium were, respectively, 0.97 (0.68–1.39) and 1.55 (1.03–2.32), but this association did not hold after excluding participants with reduced glomerular filtration rate: 0.70 (0.43–1.14) and 1.09 (0.56–2.11), respectively. Conclusions: In the US older adult population, blood lead but not urine cadmium concentrations showed a direct dose

  9. Association of lead and cadmium exposure with frailty in US older adults

    International Nuclear Information System (INIS)

    Background: Environmental lead and cadmium exposure is associated with higher risk of several age-related chronic diseases, including cardiovascular disease, chronic kidney disease and osteoporosis. These diseases may lead to frailty, a geriatric syndrome characterized by diminished physiologic reserve in multiple systems with decreased ability to cope with acute stressors. However, no previous study has evaluated the association between lead or cadmium exposure and frailty. Methods: Cross-sectional study among individuals aged ≥60 years who participated in the third U.S. National Health and Nutrition Examination Survey and had either blood lead (N=5272) or urine cadmium (N=4887) determinations. Frailty was ascertained with a slight modification of the Fried criteria, so that individuals meeting ≥3 of 5 pre-defined criteria (exhaustion, low body weight, low physical activity, weakness and slow walking speed), were considered as frail. The association between lead and cadmium with frailty was evaluated using logistic regression with adjustment for relevant confounders. Results: Median (intertertile range) concentrations of blood lead and urine cadmium were 3.9 µg/dl (2.9–4.9) and 0.62 µg/l (0.41–0.91), respectively. The prevalence of frailty was 7.1%. The adjusted odds ratios (95% confidence interval) of frailty comparing the second and third to the lowest tertile of blood lead were, respectively, 1.40 (0.96–2.04) and 1.75 (1.33–2.31). Lead concentrations were also associated with the frequency of exhaustion, weakness and slowness. The corresponding odds ratios (95% confidence interval) for cadmium were, respectively, 0.97 (0.68–1.39) and 1.55 (1.03–2.32), but this association did not hold after excluding participants with reduced glomerular filtration rate: 0.70 (0.43–1.14) and 1.09 (0.56–2.11), respectively. Conclusions: In the US older adult population, blood lead but not urine cadmium concentrations showed a direct dose

  10. Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein.

    Science.gov (United States)

    Marxreiter, Franz; Nuber, Silke; Kandasamy, Mahesh; Klucken, Jochen; Aigner, Robert; Burgmayer, Ralf; Couillard-Despres, Sebastien; Riess, Olaf; Winkler, Jürgen; Winner, Beate

    2009-03-01

    In familial and sporadic forms of Parkinson's disease (PD), alpha-synuclein pathology is present in the brain stem nuclei and olfactory bulb (OB) long before Lewy bodies are detected in the substantia nigra. The OB is an active region of adult neurogenesis, where newly generated neurons physiologically integrate. While accumulation of wild-type alpha-synuclein is one of the pathogenic hallmarks of non-genetic forms of PD, the A30P alpha-synuclein mutation results in an earlier disease onset and a severe clinical phenotype. Here, we study the regulation of adult neurogenesis in the subventricular zone (SVZ)/OB system in a tetracycline-suppressive (tet-off) transgenic model of synucleinopathies, expressing human mutant A30P alpha-synuclein under the control of the calcium/calmodulin-dependent protein kinase II alpha (CaMK) promoter. In A30P transgenic mice alpha-synuclein was abundant at the site of integration in the glomerular cell layer of the OB. Without changes in proliferation in the SVZ, significantly fewer newly generated neurons were observed in the OB granule cell and glomerular layers of A30P transgenic mice than in controls, most probably due to increased cell death. By tetracycline-dependent abrogation of A30P alpha-synuclein expression, OB neurogenesis and programmed cell death was restored to control levels. Our results indicate that, using A30P conditional (tet-off) mice, A30P alpha-synuclein has a negative impact on olfactory neurogenesis and suppression of A30P alpha-synuclein enhances survival of newly generated neurons. This finding suggests that interfering with alpha-synuclein pathology can rescue newly generated neurons, possibly leading to new targets for therapeutic interventions in synucleinopathies. PMID:19291219

  11. Developmental Exposure to Xenoestrogens at Low Doses Alters Femur Length and Tensile Strength in Adult Mice1

    OpenAIRE

    Pelch, Katherine E.; Carleton, Stephanie M.; Phillips, Charlotte L.; Nagel, Susan C.

    2011-01-01

    Developmental exposure to high doses of the synthetic xenoestrogen diethylstilbestrol (DES) has been reported to alter femur length and strength in adult mice. However, it is not known if developmental exposure to low, environmentally relevant doses of xenoestrogens alters adult bone geometry and strength. In this study we investigated the effects of developmental exposure to low doses of DES, bisphenol A (BPA), or ethinyl estradiol (EE2) on bone geometry and torsional strength. C57BL/6 mice ...

  12. Effects of lead exposure on histological structure and antioxidant capacity in the cerebellum of 30-day-old mice

    Institute of Scientific and Technical Information of China (English)

    Yu Wang; Shengqing Wang

    2011-01-01

    The current study sought to observe the effects of lead on histological structure and antioxidant capacity in 30-day-old mice. Spectrophotometry was used to detect the activities of superoxide dismutase, catalase, alkaline phosphatase, acid phosphatase and the malondialdehyde content. The results revealed that Purkinje cells in the lead-exposed group exhibited obvious pyknosis, atrophy and a decrease in overall number. Granular cells exhibited a disorderly arrangement, and were reduced in number. Administration of lead decreased the activities of superoxide dismutase, catalase, alkaline phosphatase and acid phosphatase, while malondialdehyde content increased. Two-way analysis of variance indicated that dose contributed more to lead-induced cerebellum damage than treatment time. The present study demonstrated that lead exerted strong effects on histological structure and inhibited antioxidant capacity of the cerebellum in 30-day-old mice.

  13. Dietary stearic acid leads to a reduction of visceral adipose tissue in athymic nude mice.

    Directory of Open Access Journals (Sweden)

    Ming-Che Shen

    Full Text Available Stearic acid (C18:0 is a long chain dietary saturated fatty acid that has been shown to reduce metastatic tumor burden. Based on preliminary observations and the growing evidence that visceral fat is related to metastasis and decreased survival, we hypothesized that dietary stearic acid may reduce visceral fat. Athymic nude mice, which are used in models of human breast cancer metastasis, were fed a stearic acid, linoleic acid (safflower oil, or oleic acid (corn oil enriched diet or a low fat diet ad libitum. Total body weight did not differ significantly between dietary groups over the course of the experiment. However visceral fat was reduced by ∼70% in the stearic acid fed group compared to other diets. In contrast total body fat was only slightly reduced in the stearic acid diet fed mice when measured by dual-energy x-ray absorptiometry and quantitative magnetic resonance. Lean body mass was increased in the stearic acid fed group compared to all other groups by dual-energy x-ray absorptiometry. Dietary stearic acid significantly reduced serum glucose compared to all other diets and increased monocyte chemotactic protein-1 (MCP-1 compared to the low fat control. The low fat control diet had increased serum leptin compared to all other diets. To investigate possible mechanisms whereby stearic acid reduced visceral fat we used 3T3L1 fibroblasts/preadipocytes. Stearic acid had no direct effects on the process of differentiation or on the viability of mature adipocytes. However, unlike oleic acid and linoleic acid, stearic acid caused increased apoptosis (programmed cell death and cytotoxicity in preadipocytes. The apoptosis was, at least in part, due to increased caspase-3 activity and was associated with decreased cellular inhibitor of apoptosis protein-2 (cIAP2 and increased Bax gene expression. In conclusion, dietary stearic acid leads to dramatically reduced visceral fat likely by causing the apoptosis of preadipocytes.

  14. Excretory/secretory products from Trichinella spiralis adult worms ameliorate DSS-induced colitis in mice.

    Directory of Open Access Journals (Sweden)

    Xiaodi Yang

    Full Text Available BACKGROUND: Many evidences show the inverse correlation between helminth infection and allergic or autoimmune diseases. Identification and characterization of the active helminth-derived products responsible for the beneficial effects on allergic or inflammatory diseases will provide another feasible approach to treat these diseases. METHODS AND FINDINGS: Colitis was induced in C57BL/6 mice by giving 3% DSS orally for 7 days. During this period, the mice were treated daily with the excretory/secretory products from T. spiralis adult worms (AES intraperitoneally. The severity of colitis was monitored by measuring body weight, stool consistency or bleeding, colon length and inflammation. To determine the T. spiralis AES product-induced immunological response, Th1, Th2, Th17 and regulatory cytokine profiles were measured in lymphocytes isolated from colon, mesenteric lymph nodes (MLN, and the spleen of treated mice. The CD4+ CD25+ FOXP3+ regulatory T cells (Tregs were also measured in the spleens and MLN of treated mice. Mice treated with AES significantly ameliorated the severity of the DSS-induced colitis indicated by the reduced disease manifestations, improved macroscopic and microscopic inflammation correlated with the up-regulation of Treg response (increased regulatory cytokines IL-10, TGF-beta and regulatory T cells and down-regulation of pro-inflammatory cytokines (IFN-gamma, IL-6 and IL-17 in the spleens, MLN and colon of treated mice. CONCLUSIONS: Our results provide direct evidences that T. spiralis AES have a therapeutic potential for alleviating inflammatory colitis in mice. This effect is possibly mediated by the immunomodulation of regulatory T cells to produce regulatory and anti-inflammatory cytokines and inhibit pro-inflammatory cytokines.

  15. Early life stress differentially modulates distinct forms of brain plasticity in young and adult mice.

    Directory of Open Access Journals (Sweden)

    Inga Herpfer

    Full Text Available BACKGROUND: Early life trauma is an important risk factor for many psychiatric and somatic disorders in adulthood. As a growing body of evidence suggests that brain plasticity is disturbed in affective disorders, we examined the short-term and remote effects of early life stress on different forms of brain plasticity. METHODOLOGY/PRINCIPAL FINDINGS: Mice were subjected to early deprivation by individually separating pups from their dam in the first two weeks after birth. Distinct forms of brain plasticity were assessed in the hippocampus by longitudinal MR volumetry, immunohistochemistry of neurogenesis, and whole-cell patch-clamp measurements of synaptic plasticity. Depression-related behavior was assessed by the forced swimming test in adult animals. Neuropeptides and their receptors were determined by real-time PCR and immunoassay. Early maternal deprivation caused a loss of hippocampal volume, which returned to normal in adulthood. Adult neurogenesis was unaffected by early life stress. Long-term synaptic potentiation, however, was normal immediately after the end of the stress protocol but was impaired in adult animals. In the forced swimming test, adult animals that had been subjected to early life stress showed increased immobility time. Levels of substance P were increased both in young and adult animals after early deprivation. CONCLUSION: Hippocampal volume was affected by early life stress but recovered in adulthood which corresponded to normal adult neurogenesis. Synaptic plasticity, however, exhibited a delayed impairment. The modulation of synaptic plasticity by early life stress might contribute to affective dysfunction in adulthood.

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

    Science.gov (United States)

    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

  17. Multi-Vitamin B Supplementation Reverses Hypoxia-Induced Tau Hyperphosphorylation and Improves Memory Function in Adult Mice.

    Science.gov (United States)

    Yu, Lixia; Chen, Yuan; Wang, Weiguang; Xiao, Zhonghai; Hong, Yan

    2016-08-01

    Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia. PMID:27497480

  18. Re-expression of IGF-II is important for beta cell regeneration in adult mice.

    Directory of Open Access Journals (Sweden)

    Luxian Zhou

    Full Text Available BACKGROUND: The key factors which support re-expansion of beta cell numbers after injury are largely unknown. Insulin-like growth factor II (IGF-II plays a critical role in supporting cell division and differentiation during ontogeny but its role in the adult is not known. In this study we investigated the effect of IGF-II on beta cell regeneration. METHODOLOGY/PRINCIPAL FINDINGS: We employed an in vivo model of 'switchable' c-Myc-induced beta cell ablation, pIns-c-MycER(TAM, in which 90% of beta cells are lost following 11 days of c-Myc (Myc activation in vivo. Importantly, such ablation is normally followed by beta cell regeneration once Myc is deactivated, enabling functional studies of beta cell regeneration in vivo. IGF-II was shown to be re-expressed in the adult pancreas of pIns-c-MycER(TAM/IGF-II(+/+ (MIG mice, following beta cell injury. As expected in the presence of IGF-II beta cell mass and numbers recover rapidly after ablation. In contrast, in pIns-c-MycER(TAM/IGF-II(+/- (MIGKO mice, which express no IGF-II, recovery of beta cell mass and numbers were delayed and impaired. Despite failure of beta cell number increase, MIGKO mice recovered from hyperglycaemia, although this was delayed. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that beta cell regeneration in adult mice depends on re-expression of IGF-II, and supports the utility of using such ablation-recovery models for identifying other potential factors critical for underpinning successful beta cell regeneration in vivo. The potential therapeutic benefits of manipulating the IGF-II signaling systems merit further exploration.

  19. The retrotrapezoid nucleus stimulates breathing by releasing glutamate in adult conscious mice.

    Science.gov (United States)

    Holloway, Benjamin B; Viar, Kenneth E; Stornetta, Ruth L; Guyenet, Patrice G

    2015-09-01

    The retrotrapezoid nucleus (RTN) is a bilateral cluster of neurons located at the ventral surface of the brainstem below the facial nucleus. The RTN is activated by hypercapnia and stabilises arterial Pco2 by adjusting lung ventilation in a feedback manner. RTN neurons contain vesicular glutamate transporter-2 (Vglut2) transcripts (Slc17a6), and their synaptic boutons are Vglut2-immunoreactive. Here, we used optogenetics to test whether the RTN increases ventilation in conscious adult mice by releasing glutamate. Neurons located below the facial motor nucleus were transduced unilaterally to express channelrhodopsin-2 (ChR2)-enhanced yellow fluorescent protein, with lentiviral vectors that employ the Phox2b-activated artificial promoter PRSx8. The targeted population consisted of two types of Phox2b-expressing neuron: non-catecholaminergic neurons (putative RTN chemoreceptors) and catecholaminergic (C1) neurons. Opto-activation of a mix of ChR2-expressing RTN and C1 neurons produced a powerful stimulus frequency-dependent (5-15 Hz) stimulation of breathing in control conscious mice. Respiratory stimulation was comparable in mice in which dopamine-β-hydroxylase (DβH)-positive neurons no longer expressed Vglut2 (DβH(C) (re/0);;Vglut2(fl/fl)). In a third group of mice, i.e. DβH(+/+);;Vglut2(fl/fl) mice, we injected a mixture of PRSx8-Cre lentiviral vector and Cre-dependent ChR2 adeno-associated virus 2 unilaterally into the RTN; this procedure deleted Vglut2 from ChR2-expressing neurons regardless of whether or not they were catecholaminergic. The ventilatory response elicited by photostimulation of ChR2-positive neurons was almost completely absent in these mice. Resting ventilatory parameters were identical in the three groups of mice, and their brains contained similar numbers of ChR2-positive catecholaminergic and non-catecholaminergic neurons. From these results, we conclude that RTN neurons increase breathing in conscious adult mice by releasing glutamate.

  20. Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood.

    Science.gov (United States)

    Al-Garawi, A; Fattouh, R; Botelho, F; Walker, T D; Goncharova, S; Moore, C-L; Mori, M; Erjefalt, J S; Chu, D K; Humbles, A A; Kolbeck, R; Stampfli, M R; O'Byrne, P M; Coyle, A J; Jordana, M

    2011-11-01

    The origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c+ CD11b+ inflammatory dendritic cell and CD8α+ plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood. PMID:21881572

  1. Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood

    KAUST Repository

    Al-Garawi, A

    2011-08-31

    The origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c + CD11b + inflammatory dendritic cell and CD8α + plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood.

  2. Protective effects of chitosan and its water-soluble derivatives against lead-induced oxidative stress in mice.

    Science.gov (United States)

    Wang, Zhihua; Yan, Yongbin; Yu, Xiaohua; Li, Wei; Li, Bojie; Qin, Caiqin

    2016-02-01

    Lead-induced oxidative stress was generated in mice under lead exposure, and the antioxidant activity of chitosan (CS) and its water-soluble derivatives was compared in vivo. The results indicated that there was significant difference (Pchitosan (HPCS) and quaternary ammonium salt of chitosan (HACC). And the changed biochemical variables showed recovery with different degrees, which indicated that CS and its derivatives were helpful for alleviating lead-induced oxidation damage in vivo. But the antioxidant activity for different CS was different, followed by HPCS>HACC>carboxymethyl chitosan (CMCS)>CS, which was in close with the introduction of different substituent groups. In particular, for the dietary of HPCS, there was significant recovery for the changed biochemical variables (P<0.05) in mice after lead exposure, except GSSG in kidney and MDA in brain. PMID:26454108

  3. Comparative assessment of the effects of salinomycin and monensin on the biodistribution of lead and some essential metal ions in mice, subjected to subacute lead intoxication.

    Science.gov (United States)

    Ivanova, Juliana; Gluhcheva, Yordanka; Dimova, Donika; Pavlova, Ekaterina; Arpadjan, Sonja

    2016-01-01

    In this study, we present a comparative assessment of the effects of two polyether ionophorous antibiotics (monensin and salinomycin) on the concentrations of lead (Pb), cooper (Cu), zinc (Zn) and iron (Fe) in the kidneys, spleen, liver and brain of Pb-intoxicated animals. Our data demonstrated that the intoxication of ICR male mice with Pb salt resulted in a significant accumulation of Pb in all studied organs of the mice compared to the untreated control animals. The biodistribution of the toxic metal was in the order kidneys>spleen>liver>brain. The treatment of the Pb-intoxicated animals with tetraethylammonium salts of monensic and salinomycinic acids significantly decreased the concentration of the toxic metal ion compared to the toxic control. The effect varied in the interval 38% (for kidneys) to 52% (for brain) compared to the toxic control group (Pb). The tetraethylammonium salt of salinomycinic acid was more effective in reducing the Pb concentration in the brain of the Pb-treated mice compared to monensin. Pb-intoxication did not affect significantly the Zn endogenous concentration compared to the normal values. The treatment of ICR male mice with Pb-salt decreased the Cu concentration in the spleen and increased the Cu concentration in the liver compared to the untreated control animals. The detoxification of the Pb-intoxicated mice with tetraethylammonium salts of salinomycinic and monensic acids restored the Cu concentration in the spleen, but did not affect the Cu levels in the liver. The Pb-intoxication of the ICR mice resulted in a significant decrease of the Fe-concentration in the spleen and liver compared to the untreated control animals. The administration of the tetraethylammonium salts of salinomycinic and monensic acids to the Pb-treated animals restored the levels of Fe in both organs. PMID:26653741

  4. Constrained tibial vibration does not produce an anabolic bone response in adult mice.

    Science.gov (United States)

    Christiansen, Blaine A; Kotiya, Akhilesh A; Silva, Matthew J

    2009-10-01

    and exposure to anesthesia was associated with significant loss of trabecular and cortical bone. We conclude that direct vibrational loading of bone in anesthetized, adult mice is not anabolic. PMID:19576309

  5. Abnormal motor phenotype at adult stages in mice lacking type 2 deiodinase.

    Directory of Open Access Journals (Sweden)

    Soledad Bárez-López

    Full Text Available BACKGROUND: Thyroid hormones have a key role in both the developing and adult central nervous system and skeletal muscle. The thyroid gland produces mainly thyroxine (T4 but the intracellular concentrations of 3,5,3'-triiodothyronine (T3; the transcriptionally active hormone in the central nervous system and skeletal muscle are modulated by the activity of type 2 deiodinase (D2. To date no neurological syndrome has been associated with mutations in the DIO2 gene and previous studies in young and juvenile D2-knockout mice (D2KO did not find gross neurological alterations, possibly due to compensatory mechanisms. AIM: This study aims to analyze the motor phenotype of 3-and-6-month-old D2KO mice to evaluate the role of D2 on the motor system at adult stages in which compensatory mechanisms could have failed. RESULTS: Motor abilities were explored by validated tests. In the footprint test, D2KO showed an altered global gait pattern (mice walked slower, with shorter strides and with a hindlimb wider base of support than wild-type mice. No differences were detected in the balance beam test. However, a reduced latency to fall was found in the rotarod, coat-hanger and four limb hanging wire tests indicating impairment on coordination and prehensile reflex and a reduction of muscle strength. In histological analyses of cerebellum and skeletal muscle, D2KO mice did not present gross structural abnormalities. Thyroid hormones levels and deiodinases activities were also determined. In D2KO mice, despite euthyroid T3 and high T4 plasma levels, T3 levels were significantly reduced in cerebral cortex (48% reduction and skeletal muscle (33% reduction, but not in the cerebellum where other deiodinase (type 1 is expressed. CONCLUSIONS: The motor alterations observed in D2KO mice indicate an important role for D2 in T3 availability to maintain motor function and muscle strength. Our results suggest a possible implication of D2 in motor disorders.

  6. Comparison of catalase immunoreactivity in the hippocampus between young, adult and aged mice and rats.

    Science.gov (United States)

    Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Lee, Tae-Kyeong; Cho, Jeong Hwi; Kim, In Hye; Park, Joon Ha; Lee, Jae-Chul; Tae, Hyun-Jin; Lee, Choong-Hyun; Won, Moo-Ho; Lee, Yun Lyul; Choi, Soo Young; Hong, Seongkweon

    2016-07-01

    Catalase (CAT) is an important antioxidant enzyme and is crucial in modulating synaptic plasticity in the brain. In this study, CAT expression as well as neuronal distribution was compared in the hippocampus among young, adult and aged mice and rats. Male ICR mice and Sprague Dawley rats were used at postnatal month (PM) 1, PM 6 and PM 24 as the young, adult and aged groups, respectively (n=14/group). CAT expression was examined by immunohistochemistry and western blot analysis. In addition, neuronal distribution was examined by NeuN immunohistochemistry. In the present study, the mean number of NeuN‑immunoreactive neurons was marginally decreased in mouse and rat hippocampi during aging, although this change was not identified to be significantly different. However, CAT immunoreactivity was significantly increased in pyramidal and granule neurons in the adult mouse and rat hippocampi and was significantly decreased in the aged mouse and rat hippocampi compared with that in the young animals. CAT protein levels in the hippocampus were also lowest in the aged mouse and rat hippocampus. These results indicate that CAT expression is significantly decreased in the hippocampi of aged animals and decreased CAT expression may be closely associated with aging. PMID:27221506

  7. Development of the adult neurogenic niche in the hippocampus of mice

    Directory of Open Access Journals (Sweden)

    Zeina eNicola

    2015-05-01

    Full Text Available When does adult hippocampal neurogenesis begin? We describe the development of the neurogenic niche in the subgranular zone (SGZ of the hippocampal dentate gyrus. We did so from the perspective of the situation in the adult.Ontogeny of the dentate gyrus is complex and results in an ectopic neurogenic niche that lifelong generates new granule cells. Neurogenesis during the fetal and early postnatal periods builds the dentate gyrus and gives way to activity-dependent adult neurogenesis. We used markers most relevant to adult neurogenesis research to describe this transition: Nestin, Sox2, BLBP, GFAP, Tbr2, Doublecortin (DCX, NeuroD1 and Prox1. We found that massive changes and a local condensation of proliferating precursor cells occurs between postnatal day 7 (P7, near the peak in proliferation, and P14. Before and around P7, the spatial distribution of cells and the co-localization of markers were distinct from the situation in the adult. Unlike the adult SGZ, the marker pair Nestin/Sox2 and the radial glial marker BLBP were not overlapping during embryonic development, presumably indicating different types of radial glia-like cells. Before P7 GFAP-positive cells in the hilus lacked the radial orientation that is characteristic of the adult type-1 cells. DCX, which is concentrated in type-2b and type-3 progenitor cells and early postmitotic neurons in the adult, showed diffuse expression before P7. Intermediate progenitor cell marker Tbr2 became restricted to the SGZ but was found in the granule cell layer and hilus before. Lineage markers NeuroD1 and Prox1 confirmed this pattern.We conclude that the neurogenic niche of adult neurogenesis is in place well before true adulthood. This might indicate that consistent with the hypothesized function of adult neurogenesis in activity-dependent plasticity, the early transition from postnatal neurogenesis to adult neurogenesis coincides with the time, when the young mice start to become active themselves.

  8. Distinct effects of chronic dopaminergic stimulation on hippocampal neurogenesis and striatal doublecortin expression in adult mice

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    Rachele eSalvi

    2016-03-01

    Full Text Available 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 hours after a 14-day-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 NeuN 32 days after the last of five BrdU injections (50 mg/kg applied at the beginning of 14-day 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 and

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

    Science.gov (United States)

    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

  10. Regulation of plasma lipid homeostasis by hepatic lipoprotein lipase in adult mice.

    Science.gov (United States)

    Liu, Gan; Xu, Jun-Nan; Liu, Dong; Ding, Qingli; Liu, Meng-Na; Chen, Rong; Fan, Mengdi; Zhang, Ye; Zheng, Chao; Zou, Da-Jin; Lyu, Jianxin; Zhang, Weiping J

    2016-07-01

    LPL is a pivotal rate-limiting enzyme to catalyze the hydrolysis of TG in circulation, and plays a critical role in regulating lipid metabolism. However, little attention has been paid to LPL in the adult liver due to its relatively low expression. Here we show that endogenous hepatic LPL plays an important physiological role in plasma lipid homeostasis in adult mice. We generated a mouse model with the Lpl gene specifically ablated in hepatocytes with the Cre/LoxP approach, and found that specific deletion of hepatic Lpl resulted in a significant decrease in plasma LPL contents and activity. As a result, the postprandial TG clearance was markedly impaired, and plasma TG and cholesterol levels were significantly elevated. However, deficiency of hepatic Lpl did not change the liver TG and cholesterol contents or glucose homeostasis. Taken together, our study reveals that hepatic LPL is involved in the regulation of plasma LPL activity and lipid homeostasis. PMID:27234787

  11. Determinants of blood lead levels in an adult population from a mining area in Brazil

    Science.gov (United States)

    Bastos Paoliello, M. M.; Mello de Capitani, E.; Gonçalves da Cunha, F.; Carvalho, M. De Fatima; Matsuo, T.; Sakuma, A.; Ribeiro Figueiredo, B.

    2003-05-01

    During the last fifty year the Ribeira river valley, Brazil, had been under the influence of the full activity of a huge lead refinery and mining along the riverside. The plant completely stopped all kind of industrial activities at the end of 1995, and part of the worker population and their families still remain living nearby in smal communities. The objective of the present study was to assess the deterninants of blood lead levels (BLL) in these nining areas, where residual environmental contamination from the past industrial activity still remains. Blood samples of 350 adults aged 15 to 70, residing in areas around the mine and the refinery were collected. A questionnaire was given in order to gather information on food habits, current and former residential places occupationnal activities, among other variables. Blood lead concentrations were analysed by graphite furnace atomic absorption spectrometry using Zeeman background correction. Logistic regression analysis was conducted to examine the independent contribution of selected variables in predicting BLL in those subjects. The following variables showed significant association with high BLL: residential area close to the lead refinery, former dwelling at the refinery village, male gender, smoking habits, and consume of fruits from home back yard.

  12. CD4+ T lymphocytes injected into severe combined immunodeficient (SCID) mice lead to an inflammatory and lethal bowel disease

    DEFF Research Database (Denmark)

    Claesson, Mogens Helweg; Rudolphi, A; Kofoed, S;

    1996-01-01

    Transfer of 2 x 10(5) congenic or semiallogenic purified TCR alphabeta+ CD4+ T cells to SCID mice leads to an infiltration of the recipient gut lamina propria and epithelium with a donor-derived CD4+ T cell subset which induces a lethal inflammatory bowel disease (IBD) in the recipients...... plasma cells were present in the lamina propria of both the small and large intestine. We conclude that low numbers of intraveneously transferred CD4+ T cells induce IBD in SCID mice. In the late stages of CD4+ T cell-induced IBD, the colonic lamina propria becomes infiltrated with macrophages...

  13. Spontaneous tumor development in bone marrow-rescued DNA-PKcs(3A/3A) mice due to dysfunction of telomere leading strand deprotection.

    Science.gov (United States)

    Zhang, S; Matsunaga, S; Lin, Y-F; Sishc, B; Shang, Z; Sui, J; Shih, H-Y; Zhao, Y; Foreman, O; Story, M D; Chen, D J; Chen, B P C

    2016-07-28

    Phosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) at the Thr2609 cluster is essential for its complete function in DNA repair and tissue stem cell homeostasis. This phenomenon is demonstrated by congenital bone marrow failure occurring in DNA-PKcs(3A/3A) mutant mice, which require bone marrow transplantation (BMT) to prevent early mortality. Surprisingly, an increased incidence of spontaneous tumors, especially skin cancer, was observed in adult BMT-rescued DNA-PKcs(3A/3A) mice. Upon further investigation, we found that spontaneous γH2AX foci occurred in DNA-PKcs(3A/3A) skin biopsies and primary keratinocytes and that these foci overlapped with telomeres during mitosis, indicating impairment of telomere replication and maturation. Consistently, we observed significantly elevated frequencies of telomere fusion events in DNA-PKcs(3A/3A) cells as compared with wild-type and DNA-PKcs-knockout cells. In addition, a previously identified DNA-PKcs Thr2609Pro mutation, found in breast cancer, also induces a similar impairment of telomere leading-end maturation. Taken together, our current analyses indicate that the functional DNA-PKcs T2609 cluster is required to facilitate telomere leading strand maturation and prevention of genomic instability and cancer development. PMID:26616856

  14. The importance of basonuclin 2 in adult mice and its relation to basonuclin 1.

    Science.gov (United States)

    Vanhoutteghem, Amandine; Delhomme, Brigitte; Hervé, Françoise; Nondier, Isabelle; Petit, Jean-Maurice; Araki, Masatake; Araki, Kimi; Djian, Philippe

    2016-05-01

    BNC2 is an extremely conserved zinc finger protein with important functions in the development of craniofacial bones and male germ cells. Because disruption of the Bnc2 gene in mice causes neonatal lethality, the function of the protein in adult animals has not been studied. Until now BNC2 was considered to have a wider tissue distribution than its paralog, BNC1, but the precise cell types expressing Bnc2 are largely unknown. We identify here the cell types containing BNC2 in the mouse and we show the unexpected presence of BNC1 in many BNC2-containing cells. BNC1 and BNC2 are colocalized in male and female germ cells, ovarian epithelial cells, sensory neurons, hair follicle keratinocytes and connective cells of organ capsules. In many cell lineages, the two basonuclins appear and disappear synchronously. Within the male germ cell lineage, BNC1 and BNC2 are found in prospermatogonia and undifferentiated spermatogonia, and disappear abruptly from differentiating spermatogonia. During oogenesis, the two basonuclins accumulate specifically in maturing oocytes. During the development of hair follicles, BNC1 and BNC2 concentrate in the primary hair germs. As follicle morphogenesis proceeds, cells possessing BNC1 and BNC2 invade the dermis and surround the papilla. During anagen, BNC1 and BNC2 are largely restricted to the basal layer of the outer root sheath and the matrix. During catagen, the compartment of cells possessing BNC1 and BNC2 regresses, and in telogen, the two basonuclins are confined to the secondary hair germ. During the next anagen, the BNC1/BNC2-containing cell population regenerates the hair follicle. By examining Bnc2(-/-) mice that have escaped the neonatal lethality usually associated with lack of BNC2, we demonstrate that BNC2 possesses important functions in many of the cell types where it resides. Hair follicles of postnatal Bnc2(-/-) mice do not fully develop during the first cycle and thereafter remain blocked in telogen. It is concluded that

  15. Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons.

    Science.gov (United States)

    Jiang, Haisong; Kang, Sung-Ung; Zhang, Shuran; Karuppagounder, Senthilkumar; Xu, Jinchong; Lee, Yong-Kyu; Kang, Bong-Gu; Lee, Yunjong; Zhang, Jianmin; Pletnikova, Olga; Troncoso, Juan C; Pirooznia, Shelia; Andrabi, Shaida A; Dawson, Valina L; Dawson, Ted M

    2016-01-01

    Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder. Recent studies have implicated a role for peroxisome proliferator-activated receptor γ coactivator protein-1α (PGC-1α) in PD and in animal or cellular models of PD. The role of PGC-1α in the function and survival of substantia nigra pars compacta (SNpc) dopamine neurons is not clear. Here we find that there are four different PGC-1α isoforms expressed in SH-SY5Y cells, and these four isoforms are expressed across subregions of mouse brain. Adult conditional PGC-1α knock-out mice show a significant loss of dopaminergic neurons that is accompanied by a reduction of dopamine in the striatum. In human PD postmortem tissue from the SNpc, there is a reduction of PGC-1α isoforms and mitochondria markers. Our findings suggest that all four isoforms of PGC-1α are required for the proper expression of mitochondrial proteins in SNpc DA neurons and that PGC-1α is essential for SNpc DA neuronal survival, possibly through the maintenance of mitochondrial function. PMID:27622213

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

    Science.gov (United States)

    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

  17. Redox proteomic analysis of the gastrocnemius muscle from adult and old mice.

    Science.gov (United States)

    McDonagh, Brian; Sakellariou, Giorgos K; Smith, Neil T; Brownridge, Philip; Jackson, Malcolm J

    2015-09-01

    The data provides information in support of the research article, "Differential Cysteine Labeling and Global Label-Free Proteomics Reveals an Altered Metabolic State in Skeletal Muscle Aging", Journal of Proteome Research, 2014, 13 (11), 2008-21 [1]. Raw data is available from ProteomeXchange [2] with identifier PDX001054. The proteome of gastrocnemius muscle from adult and old mice was analyzed by global label-free proteomics and the relative quantification of specific reduced and reversibly oxidized Cysteine (Cys) residues was performed using Skyline [3]. Briefly, reduced Cysteine (Cys) containing peptides was alkylated using N-ethylmalemide (d0-NEM). Samples were desalted and reversibly oxidized Cys residues were reduced using tris(2-carboxyethyl)phosphine (TCEP) and the newly formed reduced Cys residues were labeled with heavy NEM( d5-NEM). Label-free analysis of the global proteome of adult (n=5) and old (n=4) gastrocnemius muscles was performed using Peaks7™ mass spectrometry data analysis software [4]. Relative quantification of Cys containing peptides that were identified as reduced (d(0) NEM labeled) and reversibly oxidized d(5)-NEM labeled was performed using the intensity of their precursor ions in Skyline. Results indicate that muscles from old mice show reduced redox flexibility particularly in proteins involved in the generation of precursor metabolites and energy metabolism, indicating a loss in the flexibility of the redox energy response. PMID:26217813

  18. Redox proteomic analysis of the gastrocnemius muscle from adult and old mice

    Directory of Open Access Journals (Sweden)

    Brian McDonagh

    2015-09-01

    Full Text Available The data provides information in support of the research article, “Differential Cysteine Labeling and Global Label-Free Proteomics Reveals an Altered Metabolic State in Skeletal Muscle Aging”, Journal of Proteome Research, 2014, 13 (11, 2008–21 [1]. Raw data is available from ProteomeXchange [2] with identifier PDX001054. The proteome of gastrocnemius muscle from adult and old mice was analyzed by global label-free proteomics and the relative quantification of specific reduced and reversibly oxidized Cysteine (Cys residues was performed using Skyline [3]. Briefly, reduced Cysteine (Cys containing peptides was alkylated using N-ethylmalemide (d0-NEM. Samples were desalted and reversibly oxidized Cys residues were reduced using tris(2-carboxyethylphosphine (TCEP and the newly formed reduced Cys residues were labeled with heavy NEM( d5-NEM. Label-free analysis of the global proteome of adult (n=5 and old (n=4 gastrocnemius muscles was performed using Peaks7™ mass spectrometry data analysis software [4]. Relative quantification of Cys containing peptides that were identified as reduced (d(0 NEM labeled and reversibly oxidized d(5–NEM labeled was performed using the intensity of their precursor ions in Skyline. Results indicate that muscles from old mice show reduced redox flexibility particularly in proteins involved in the generation of precursor metabolites and energy metabolism, indicating a loss in the flexibility of the redox energy response.

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

    Directory of Open Access Journals (Sweden)

    Mariangela eMartini

    2014-06-01

    Full Text Available 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 (20µg/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.

  20. Kidney-specific inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice.

    Science.gov (United States)

    Lantinga-van Leeuwen, Irma S; Leonhard, Wouter N; van der Wal, Annemieke; Breuning, Martijn H; de Heer, Emile; Peters, Dorien J M

    2007-12-15

    Autosomal dominant polycystic kidney disease, caused by mutations in the PKD1 gene, is characterized by progressive deterioration of kidney function due to the formation of thousands of cysts leading to kidney failure in mid-life or later. How cysts develop and grow is currently unknown, although extensive research revealed a plethora of cellular changes in cyst lining cells. We have constructed a tamoxifen-inducible, kidney epithelium-specific Pkd1-deletion mouse model. Upon administration of tamoxifen to these mice, a genomic fragment containing exons 2-11 of the Pkd1-gene is specifically deleted in the kidneys and cysts are formed. Interestingly, the timing of Pkd1-deletion has strong effects on the phenotype. At 1 month upon gene disruption, adult mice develop only a very mild cystic phenotype showing some small cysts and dilated tubules. Young mice, however, show massive cyst formation. In these mice, at the moment of gene disruption, cell proliferation takes place to elongate the nephron. Our data indicate that Pkd1 gene deficiency does not initiate sufficient autonomous cell proliferation leading to cyst formation and that additional stimuli are required. Furthermore, we show that one germ-line mutation of Pkd1 is already associated with increased proliferation. PMID:17932118

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

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    Natalie J Groves

    Full Text Available 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.

  2. Androgens inhibit the osteogenic response to mechanical loading in adult male mice.

    Science.gov (United States)

    Sinnesael, Mieke; Laurent, Michaël R; Jardi, Ferran; Dubois, Vanessa; Deboel, Ludo; Delisser, Peter; Behets, Geert J; D'Haese, Patrick C; Carmeliet, Geert; Claessens, Frank; Vanderschueren, Dirk

    2015-04-01

    Androgens are well known to enhance exercise-induced muscle hypertrophy; however, whether androgens also influence bone's adaptive response to mechanical loading remains unclear. We studied the adaptive osteogenic response to unilateral in vivo mechanical loading of tibia in adult male mice in both a long- and a short-term experimental set-up. Mice were divided into four groups: sham operated, orchidectomized (ORX), T (ORX+T), or nonaromatizable dihydrotestosterone (ORX+DHT) replacement. Significant interactions between androgen status and osteogenic response to mechanical loading were observed. Cortical thickness increased by T (0.14 vs 0.11 mm sham, P<.05) and DHT (0.17 vs 0.11 mm sham, P<.05). However, T partially (+36%) and DHT completely (+10%) failed to exhibit the loading-related increase observed in sham (+107%) and ORX (+131%, all P<.05) mice. ORX decreased periosteal bone formation, which was restored to sham levels by T and DHT. However, both androgens completely suppressed the loading-related increase in periosteal bone formation. Short-term loading decreased the number of sclerostin-positive osteocytes in sham, whereas in control fibulas, ORX decreased and T increased the number of sclerostin-positive osteocytes. Loading no longer down-regulated sclerostin in the ORX or T groups. In conclusion, both T and DHT suppress the osteogenic response to mechanical loading.

  3. The impact of Ly6Clow monocytes after cerebral hypoxia-ischemia in adult mice

    Science.gov (United States)

    Michaud, Jean-Philippe; Pimentel-Coelho, Pedro Moreno; Tremblay, Yannick; Rivest, Serge

    2014-01-01

    After an ischemic stroke, mononuclear phagocytic cells such as microglia, macrophages, and monocytes migrate to the lesion site and coordinate an immune response. Monocytes, which are recruited from the bloodstream after ischemic brain injury, can be categorized into two subsets in mice: inflammatory and patrolling monocytes. Although inflammatory monocytes (Ly6Chi) seem to have a protective role in stroke progression, the impact of patrolling monocytes (Ly6Clow) is unknown. To address the role of Ly6Clow monocytes in stroke, we generated bone marrow chimeric mice in which their hematopoietic system was replaced by Nr4a1−/− cells, allowing the complete and permanent ablation of Ly6Clow monocytes without affecting the Ly6Chi subset. We then subjected adult mice to cerebral hypoxia-ischemia using the Levine/Vannucci model. Functional outcomes after stroke such as body weight change, neurologic score, motor functions and spatial learning were not affected. Moreover, depletion in Ly6Clow monocytes did not change significantly the total infarct size, cell loss, atrophy, the number, or the activation state of microglia/macrophages at the lesion site. These data suggest that Ly6Clow patrolling monocytes are redundant in the progression and recovery of ischemic stroke. PMID:24780898

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

    Science.gov (United States)

    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 (p0.05). 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 (pVibrio cholerae infection.

  5. Sustained Engraftment of Cryopreserved Human Bone Marrow CD34(+) Cells in Young Adult NSG Mice.

    Science.gov (United States)

    Wiekmeijer, Anna-Sophia; Pike-Overzet, Karin; Brugman, Martijn H; Salvatori, Daniela C F; Egeler, R Maarten; Bredius, Robbert G M; Fibbe, Willem E; Staal, Frank J T

    2014-06-01

    Hematopoietic stem cells (HSCs) are defined by their ability to repopulate the bone marrow of myeloablative conditioned and/or (lethally) irradiated recipients. To study the repopulating potential of human HSCs, murine models have been developed that rely on the use of immunodeficient mice that allow engraftment of human cells. The NSG xenograft model has emerged as the current standard for this purpose allowing for engraftment and study of human T cells. Here, we describe adaptations to the original NSG xenograft model that can be readily implemented. These adaptations encompass use of adult mice instead of newborns and a short ex vivo culture. This protocol results in robust and reproducible high levels of lympho-myeloid engraftment. Immunization of recipient mice with relevant antigen resulted in specific antibody formation, showing that both T cells and B cells were functional. In addition, bone marrow cells from primary recipients exhibited repopulating ability following transplantation into secondary recipients. Similar results were obtained with cryopreserved human bone marrow samples, thus circumventing the need for fresh cells and allowing the use of patient derived bio-bank samples. Our findings have implications for use of this model in fundamental stem cell research, immunological studies in vivo and preclinical evaluations for HSC transplantation, expansion, and genetic modification.

  6. Ischemic stroke induces gut permeability and enhances bacterial translocation leading to sepsis in aged mice

    Science.gov (United States)

    Verma, Rajkumar; Venna, Venugopal R.; Liu, Fudong; Chauhan, Anjali; Koellhoffer, Edward; Patel, Anita; Ricker, Austin; Maas, Kendra; Graf, Joerg; McCullough, Louise D.

    2016-01-01

    Aging is an important risk factor for post-stroke infection, which accounts for a large proportion of stroke-associated mortality. Despite this, studies evaluating post-stroke infection rates in aged animal models are limited. In addition, few studies have assessed gut microbes as a potential source of infection following stroke. Therefore we investigated the effects of age and the role of bacterial translocation from the gut in post-stroke infection in young (8-12 weeks) and aged (18-20 months) C57Bl/6 male mice following transient middle cerebral artery occlusion (MCAO) or sham surgery. Gut permeability was examined and peripheral organs were assessed for the presence of gut-derived bacteria following stroke. Furthermore, sickness parameters and components of innate and adaptive immunity were examined. We found that while stroke induced gut permeability and bacterial translocation in both young and aged mice, only young mice were able to resolve infection. Bacterial species seeding peripheral organs also differed between young (Escherichia) and aged (Enterobacter) mice. Consequently, aged mice developed a septic response marked by persistent and exacerbated hypothermia, weight loss, and immune dysfunction compared to young mice following stroke. PMID:27115295

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

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    Jennifer A Phan

    Full Text Available 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.

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

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    Rupert W Overall

    Full Text Available 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.

  9. Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2−/− mice

    OpenAIRE

    Gil-Henn, Hava; Destaing, Olivier; Sims, Natalie A.; Aoki, Kazuhiro; Alles, Neil; Neff, Lynn; Sanjay, Archana; Bruzzaniti, Angela; De Camilli, Pietro; Baron, Roland; Schlessinger, Joseph

    2007-01-01

    The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microt...

  10. Vitamin E attenuates liver injury induced by exposure to lead, mercury, cadmium and copper in albino mice

    OpenAIRE

    Atef M. Al-Attar

    2011-01-01

    Water pollution is the contamination of water resources by harmful wastes or toxins. Both community and private sources of drinking water are susceptible to a myriad of chemical contaminants. Heavy metals pollution of surface water can create health risks. The present study was aimed to investigate the effect of vitamin E supplementation on male mice exposed to a mixture of some heavy metals (lead, mercury, cadmium and copper) in their drinking water for seven weeks. Significant increases of ...

  11. The Protective Effect of Ascorbic Acid and Thiamine Supplementation against Damage Caused by Lead in the Testes of Mice

    Institute of Scientific and Technical Information of China (English)

    Guang SHAN; Tian TANG; Xiaobin ZHANG

    2009-01-01

    Lead is a ubiquitous environmental and industrial pollutant that may have toxic effects on the male.Vitamins may protect against toxic effects of lead in the liver and reproductive system,which is confirmed by our initial research.The aim of this study was to further investigate the protec-tive effects of vitamins (ascorbic acid combined with thiamine) on lead acetate (Pb)-induced repro-ductive toxicities in mice and study the possible mechanisms underlying these effects.Forty-five male mice were randomly divided into 3 groups,15 mice in each and received daily intragastric ad-ministration with control,Pb (20 mg/kg),and Pb+vitamins (ascorbic acid of 420 mg/kg+thiamine of 30 mg/kg) for 6 weeks,respectively.The Pb-treated animals showed significant decreases in the epididymal sperm count and motility compared to the control group,while the Pb+vitamins group had significant increases for these variables.Moreover,an increasing apoptosis of germinal cells in-duced by Pb was reduced by vitamin treatment.Pb induced the activation of Caspase-3,Fas/Fas-L and Bcl-2 with elevated levels,and the adaptor protein primarily regulated signaling through Fas and required for Fas-induced apoptosis.In conclusion,ascorbic acid combined with thiamine exhibited protective effect on reproductive system by inhibiting Pb-induced excessive cell apoptosis.

  12. Protective Effect of Porcine Cerebral Hydrolysate Peptides on Learning and Memory Deficits and Oxidative Stress in Lead-Exposed Mice.

    Science.gov (United States)

    Zou, Ye; Feng, Weiwei; Wang, Wei; Chen, Yao; Zhou, Zhaoxiang; Li, Qian; Zhao, Ting; Mao, Guanghua; Wu, Xiangyang; Yang, Liuqing

    2015-12-01

    In this study, lead acetate solution and porcine cerebral hydrolysate peptides (PCHPs) were administered to developing mice. Porcine cerebral protein pretreated by ultrasound was hydrolyzed with alcalase, and 11 peptide fragments were obtained by Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of PCHPs. Our data showed that PCHPs significantly decreased Pb2+-induced spontaneous locomotor activity, latencies to reach the platform, and the time in target quadrant. It also decreased the accumulation of lead in the blood and brain of Pb2+-exposed developing mice. Co-administration of PCHPs and dimercaptosuccinic acid (DMSA) did not only reduce the accumulation of lead in blood but also increased the absorption of zinc and iron in Pb2+-exposed mice. Administration of PCHPs individually significantly enhanced hematopoietic parameters compared with the Pb2+-exposed group. PCHPs significantly reduced the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) but increased glutathione (GSH) content and anti-oxidant enzymes and nitric oxide synthase (NOS) activities in Pb2+-exposed brain. Our findings suggest that PCHPs have the ability to protect against Pb2+-exposed learning and memory deficits and oxidative damage. PMID:25956150

  13. Potential Association of Lead Exposure During Early Development of Mice With Alteration of Hippocampus Nitric Oxide Levels and Learning Memory

    Institute of Scientific and Technical Information of China (English)

    LI SUN; ZHENG-YAN ZHAO; JIAN HU; XIE-LAI ZHOU

    2005-01-01

    Objective Chronic lead (Pb) exposure during development is known to produce learning deficits. Nitric oxide participates in the synaptic mechanisms involved in certain forms of learning and memory. This study was designed to clarify whether Pb-induced impairment in learning and memory was associated with the changes of nitric oxide levels in mice brains.Methods Sixty Balb/c mice aged 10 days were chosen. A model of lead exposure was established by drinking 0.025%, 0.05%,0.075% lead acetate, respectively for 8 weeks. The controls were orally given distilled water. The ability to learn and memorize was examined by open field test, T-water maze test. In parallel with the behavioral data, NO level of hippocampus tissue was detected by biochemical assay. Results Compared with control groups, (1) the weight of 0.075% group was significantly reduced (P<0.05); (2) The number of times in mice attaining the required standards in T-water maze test was lower in 0.075%group (P<0.01). No significant difference was found between experimental and control groups in open field test (P>0.05); (3)NO level of mouse hippocampus tissue was decreased in 0.075% group (P<0.01). Conclusions The findings suggest that decreased hippocampus NO level may contribute to the Pb-induced deficits in learning and memory processes.

  14. Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life.

    Directory of Open Access Journals (Sweden)

    Dani Smith

    Full Text Available Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains.Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not.Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.

  15. Long-term low carbohydrate diet leads to deleterious metabolic manifestations in diabetic mice.

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    Keiko Handa

    Full Text Available We investigated long-term effects of low carbohydrate diets on wild type mice, streptozotocin-injected and KKAy obese diabetic mice. These mice were pair-fed three different types of diets, standard chow (SC, C∶P∶F = 63∶15∶22, a low carbohydrate (LC, C∶P∶F = 38∶25∶37 diet and a severely carbohydrate restricted (SR, C∶P∶F = 18∶45∶37 diet for 16 weeks. Despite comparable body weights and serum lipid profiles, wild type and diabetic mice fed the low carbohydrate diets exhibited lower insulin sensitivity and this reduction was dependent on the amount of carbohydrate in the diet. When serum fatty acid compositions were investigated, monounsaturation capacity, i.e. C16:1/C16:0 and C18:1/C18:0, was impaired in all murine models fed the low carbohydrate diets, consistent with the decreased expression of hepatic stearoyl-CoA desaturase-1 (SCD1. Interestingly, both the hepatic expressions and serum levels of fibroblast growth factor 21 (FGF21, which might be related to longevity, were markedly decreased in both wild type and KKAy mice fed the SR diet. Taking into consideration that fat compositions did not differ between the LC and SR diets, we conclude that low carbohydrate diets have deleterious metabolic effects in both wild type and diabetic mice, which may explain the association between diets relatively low in carbohydrate and the elevated risk of cardiovascular events observed in clinical studies.

  16. Long-term low carbohydrate diet leads to deleterious metabolic manifestations in diabetic mice.

    Science.gov (United States)

    Handa, Keiko; Inukai, Kouichi; Onuma, Hirohisa; Kudo, Akihiko; Nakagawa, Fumiyuki; Tsugawa, Kazue; Kitahara, Atsuko; Moriya, Rie; Takahashi, Kazuto; Sumitani, Yoshikazu; Hosaka, Toshio; Kawakami, Hayato; Oyadomari, Seiichi; Ishida, Hitoshi

    2014-01-01

    We investigated long-term effects of low carbohydrate diets on wild type mice, streptozotocin-injected and KKAy obese diabetic mice. These mice were pair-fed three different types of diets, standard chow (SC, C∶P∶F = 63∶15∶22), a low carbohydrate (LC, C∶P∶F = 38∶25∶37) diet and a severely carbohydrate restricted (SR, C∶P∶F = 18∶45∶37) diet for 16 weeks. Despite comparable body weights and serum lipid profiles, wild type and diabetic mice fed the low carbohydrate diets exhibited lower insulin sensitivity and this reduction was dependent on the amount of carbohydrate in the diet. When serum fatty acid compositions were investigated, monounsaturation capacity, i.e. C16:1/C16:0 and C18:1/C18:0, was impaired in all murine models fed the low carbohydrate diets, consistent with the decreased expression of hepatic stearoyl-CoA desaturase-1 (SCD1). Interestingly, both the hepatic expressions and serum levels of fibroblast growth factor 21 (FGF21), which might be related to longevity, were markedly decreased in both wild type and KKAy mice fed the SR diet. Taking into consideration that fat compositions did not differ between the LC and SR diets, we conclude that low carbohydrate diets have deleterious metabolic effects in both wild type and diabetic mice, which may explain the association between diets relatively low in carbohydrate and the elevated risk of cardiovascular events observed in clinical studies.

  17. Multiple Events Lead to Dendritic Spine Loss in Triple Transgenic Alzheimer's Disease Mice

    OpenAIRE

    Tobias Bittner; Martin Fuhrmann; Steffen Burgold; Ochs, Simon M.; Nadine Hoffmann; Gerda Mitteregger; Hans Kretzschmar; LaFerla, Frank M.; Jochen Herms

    2010-01-01

    The pathology of Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptide, hyperphosphorylated tau protein, neuronal death, and synaptic loss. By means of long-term two-photon in vivo imaging and confocal imaging, we characterized the spatio-temporal pattern of dendritic spine loss for the first time in 3xTg-AD mice. These mice exhibit an early loss of layer III neurons at 4 months of age, at a time when only soluble Aβ is abundant. Later on, dendritic spines ar...

  18. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

    OpenAIRE

    Pristerà, A; Lin, W.; Kaufmann, AK; Brimblecombe, KR; Threlfell, S.; Dodson, PD; Magill, PJ; Fernandes, C; Cragg, SJ; Ang, SL

    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 ...

  19. Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice.

    OpenAIRE

    Pristerà, A; Lin, W.; Kaufmann, AK; Brimblecombe, KR; Threlfell, S.; Dodson, PD; Magill, PJ; Fernandes, C; Cragg, SJ; Ang, SL

    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 ...

  20. iRhom2 mutation leads to aberrant hair follicle differentiation in mice.

    Directory of Open Access Journals (Sweden)

    Yang Leilei

    Full Text Available iRhom1 and iRhom2 are inactive homologues of rhomboid intramembrane serine proteases lacking essential catalytic residues, which are necessary for the maturation of TNFα-converting enzyme (TACE. In addition, iRhoms regulate epidermal growth factor family secretion. The functional significance of iRhom2 during mammalian development is largely unclear. We have identified a spontaneous single gene deletion mutation of iRhom2 in Uncv mice. The iRhom2Uncv/Uncv mice exhibit hairless phenotype in a BALB/c genetic background. In this study, we observed dysplasia hair follicles in iRhom2Uncv/Uncv mice from postnatal day 3. Further examination found decreased hair matrix proliferation and aberrant hair shaft and inner root sheath differentiation in iRhom2Uncv/Uncv mutant hair follicles. iRhom2 is required for the maturation of TACE. Our data demonstrate that iRhom2Uncv cannot induce the maturation of TACE in vitro and the level of mature TACE is also significantly reduced in the skin of iRhom2Uncv/Uncv mice. The activation of Notch1, a substrate of TACE, is disturbed, associated with dramatically down-regulation of Lef1 in iRhom2Uncv/Uncv hair follicle matrix. This study identifies iRhom2 as a novel regulator of hair shaft and inner root sheath differentiation.

  1. Skeletal myofiber VEGF regulates contraction-induced perfusion and exercise capacity but not muscle capillarity in adult mice.

    Science.gov (United States)

    Knapp, Amy E; Goldberg, Daniel; Delavar, Hamid; Trisko, Breanna M; Tang, Kechun; Hogan, Michael C; Wagner, Peter D; Breen, Ellen C

    2016-07-01

    A single bout of exhaustive exercise signals expression of vascular endothelial growth factor (VEGF) in the exercising muscle. Previous studies have reported that mice with life-long deletion of skeletal myofiber VEGF have fewer capillaries and a severe reduction in endurance exercise. However, in adult mice, VEGF gene deletion conditionally targeted to skeletal myofibers limits exercise capacity without evidence of capillary regression. To explain this, we hypothesized that adult skeletal myofiber VEGF acutely regulates skeletal muscle perfusion during muscle contraction. A tamoxifen-inducible skeletal myofiber-specific VEGF gene deletion mouse (skmVEGF-/-) was used to reduce skeletal muscle VEGF protein by 90% in adult mice. Three weeks after inducing deletion of the skeletal myofiber VEGF gene, skmVEGF-/- mice exhibited diminished maximum running speed (-10%, P < 0.05) and endurance capacity (-47%; P < 0.05), which did not persist after 8 wk. In skmVEGF-/- mice, gastrocnemius complex time to fatigue measured in situ was 71% lower than control mice. Contraction-induced perfusion measured by optical imaging during a period of electrically stimulated muscle contraction was 85% lower in skmVEGF-/- than control mice. No evidence of capillary rarefication was detected in the soleus, gastrocnemius, and extensor digitorum longus (EDL) up to 8 wk after tamoxifen-induced VEGF ablation, and contractility and fatigue resistance of the soleus measured ex vivo were also unchanged. The force-frequency of the EDL showed a small right shift, but fatigue resistance did not differ between EDL from control and skmVEGF-/- mice. These data suggest myofiber VEGF is required for regulating perfusion during periods of contraction and may in this manner affect endurance capacity. PMID:27225953

  2. Dispase rapidly and effectively purifies Schwann cells from newborn mice and adult rats

    Institute of Scientific and Technical Information of China (English)

    Jiaxue Zhu; Jinbao Qin; Zunli Shen; James D. Kretlow; Xiaopan Wang; Zhangyin Liu; Yuqing Jin

    2012-01-01

    In the present study, Schwann cells were isolated from the sciatic nerve of neonatal mice and purified using dispase and collagenase. Results showed that after the first round of purification with dispase, most of the Schwann cells appeared round in shape and floated in culture solution after 15 minutes. In addition, cell yield and cell purity were higher when compared to the collagenase group. After the second round of purification, the final cell yield for the dispase group was higher than that for the collagenase group, but no significant difference was found in cell purity. Moreover, similar results in cell quantity and purity were observed in adult Sprague-Dawley rats. These findings indicate that purification with dispase can result in the rapid isolation of Schwann cells with a high yield and purity.

  3. DKK1 mediated inhibition of Wnt signaling in postnatal mice leads to loss of TEC progenitors and thymic degeneration.

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    Masako Osada

    Full Text Available BACKGROUND: Thymic epithelial cell (TEC microenvironments are essential for the recruitment of T cell precursors from the bone marrow, as well as the subsequent expansion and selection of thymocytes resulting in a mature self-tolerant T cell repertoire. The molecular mechanisms, which control both the initial development and subsequent maintenance of these critical microenvironments, are poorly defined. Wnt signaling has been shown to be important to the development of several epithelial tissues and organs. Regulation of Wnt signaling has also been shown to impact both early thymocyte and thymic epithelial development. However, early blocks in thymic organogenesis or death of the mice have prevented analysis of a role of canonical Wnt signaling in the maintenance of TECs in the postnatal thymus. METHODOLOGY/PRINCIPAL FINDINGS: Here we demonstrate that tetracycline-regulated expression of the canonical Wnt inhibitor DKK1 in TECs localized in both the cortex and medulla of adult mice, results in rapid thymic degeneration characterized by a loss of DeltaNP63(+ Foxn1(+ and Aire(+ TECs, loss of K5K8DP TECs thought to represent or contain an immature TEC progenitor, decreased TEC proliferation and the development of cystic structures, similar to an aged thymus. Removal of DKK1 from DKK1-involuted mice results in full recovery, suggesting that canonical Wnt signaling is required for the differentiation or proliferation of TEC populations needed for maintenance of properly organized adult thymic epithelial microenvironments. CONCLUSIONS/SIGNIFICANCE: Taken together, the results of this study demonstrate that canonical Wnt signaling within TECs is required for the maintenance of epithelial microenvironments in the postnatal thymus, possibly through effects on TEC progenitor/stem cell populations. Downstream targets of Wnt signaling, which are responsible for maintenance of these TEC progenitors may provide useful targets for therapies aimed at

  4. Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult.

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    Vinicius S Carreira

    Full Text Available The Developmental Origins of Health and Disease (DOHaD Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR, either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease.

  5. Memory-enhancing effects of Cuscuta japonica Choisy via enhancement of adult hippocampal neurogenesis in mice.

    Science.gov (United States)

    Moon, Minho; Jeong, Hyun Uk; Choi, Jin Gyu; Jeon, Seong Gak; Song, Eun Ji; Hong, Seon-Pyo; Oh, Myung Sook

    2016-09-15

    It is generally accepted that functional and structural changes within the hippocampus are involved in learning and memory and that adult neurogenesis in this region may modulate cognition. The extract of Cuscuta japonica Choisy (CJ) is a well-known traditional Chinese herbal medicine that has been used since ancient times as a rejuvenation remedy. The systemic effects of this herb are widely known and can be applied for the treatment of a number of physiological diseases, but there is a lack of evidence describing its effects on brain function. Thus, the present study investigated whether CJ would enhance memory function and/or increase hippocampal neurogenesis using mice orally administered with CJ water extract or vehicle for 21days. Performance on the novel object recognition and passive avoidance tests revealed that treatment with CJ dose-dependently improved the cognitive function of mice. Additionally, CJ increased the Ki-67-positive proliferating cells and the number of doublecortin-stained neuroblasts in the dentate gyrus (DG) of the hippocampus, and double labeling with 5-bromo-2-deoxyuridine and neuronal specific nuclear protein showed that CJ increased the number of mature neurons in the DG. Finally, CJ resulted in the upregulated expression of neurogenic differentiation factor, which is essential for the maturation and differentiation of granule cells in the hippocampus. Taken together, the present findings indicate that CJ stimulated neuronal cell proliferation, differentiation, and maturation, which are all processes associated with neurogenesis. Additionally, these findings suggest that CJ may improve learning and memory via the enhancement of adult hippocampal neurogenesis. PMID:27185736

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

    Science.gov (United States)

    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.'.

  7. Co-Occurrence of Leading Lifestyle-Related Chronic Conditions Among Adults in the United States, 2002-2009

    OpenAIRE

    Ford, Earl S.; Croft, Janet B.; Posner, Samuel F.; Goodman, Richard A.; Giles, Wayne H.

    2013-01-01

    Introduction Public health and clinical strategies for meeting the emerging challenges of multiple chronic conditions must address the high prevalence of lifestyle-related causes. Our objective was to assess prevalence and trends in the chronic conditions that are leading causes of disease and death among adults in the United States that are amenable to preventive lifestyle interventions. Methods We used self-reported data from 196,240 adults aged 25 years or older who participated in the Nat...

  8. Genetically induced oxidative stress in mice causes thrombocytosis, splenomegaly and placental angiodysplasia that leads to recurrent abortion

    Directory of Open Access Journals (Sweden)

    Takamasa Ishii

    2014-01-01

    Full Text Available Historical data in the 1950s suggests that 7%, 11%, 33%, and 87% of couples were infertile by ages 30, 35, 40 and 45, respectively. Up to 22.3% of infertile couples have unexplained infertility. Oxidative stress is associated with male and female infertility. However, there is insufficient evidence relating to the influence of oxidative stress on the maintenance of a viable pregnancy, including pregnancy complications and fetal development. Recently, we have established Tet-mev-1 conditional transgenic mice, which can express the doxycycline-induced mutant SDHCV69E transgene and experience mitochondrial respiratory chain dysfunction leading to intracellular oxidative stress. In this report, we demonstrate that this kind of abnormal mitochondrial respiratory chain-induced chronic oxidative stress affects fertility, pregnancy and delivery rates as well as causes recurrent abortions, occasionally resulting in maternal death. Despite this, spermatogenesis and early embryogenesis are completely normal, indicating the mutation's effects to be rather subtle. Female Tet-mev-1 mice exhibit thrombocytosis and splenomegaly in both non-pregnant and pregnant mice as well as placental angiodysplasia with reduced Flt-1 protein leading to hypoxic conditions, which could contribute to placental inflammation and fetal abnormal angiogenesis. Collectively these data strongly suggest that chronic oxidative stress caused by mitochondrial mutations provokes spontaneous abortions and recurrent miscarriage resulting in age-related female infertility.

  9. Renal and hepatotoxic alterations in adult mice on inhalation of specific mixture of organic solvents.

    Science.gov (United States)

    Ketan, Vaghasia K; Bhavyata, Kalariya; Linzbuoy, George; Hyacinth, Highland N

    2015-12-01

    This study was aimed at investigating alterations in renal and hepatic toxicity induced by exposing to a combination of three solvents, namely, benzene, toluene and xylene in adult mice. The mice were divided into three groups (control, low-dose-treated (450 ppm) and high-dose (675 ppm) groups) using randomization methods. The treated groups were exposed to vapours of a mixture of benzene, toluene and xylene at doses of 450 and 675 ppm, for 6 h day(-1) for a short-term of 7-day exposure period. The study revealed that the solvent exposure resulted in an increase in the weight of liver and kidney as compared to the control. Biochemical analyses indicated a significant decline in the activities of superoxide dismutase and catalase in both the treated groups, with concomitant increase in lipid peroxidation. Liver aminotransferases (alanine aminotransferase and aspartate aminotransferase) were elevated with significant alterations in the levels of protein, creatinine and cholesterol in these tissues upon solvent exposure. Correlated with these changes, serum thyroid hormones T3 and T4 were also significantly altered. This study, therefore, demonstrates that inhalation of vapours from the solvent mixture resulted in significant dose-dependent biochemical and functional changes in the vital tissues (liver and kidney) studied. The study has specific relevance since humans are increasingly being exposed to such solvents due to increased industrial use in such combinations.

  10. Reproductive abnormalities in adult male mice following preimplantation exposures to estradiol or pesticide methoxychlor.

    Science.gov (United States)

    Amstislavsky, Sergei Ya; Amstislavskaya, Tamara G; Amstislavsky, Vjacheslav S; Tibeikina, Marina A; Osipov, Kiril V; Eroschenko, Victor P

    2006-02-01

    Adult females of ICR strain of mice were bred, separated into different experimental groups, and treated as follows. On Days 2-4 of pregnancy, the mice received daily subcutaneous injections of either 0.05 ml sesame oil (vehicle) or same volume of 5.0mg of purified methoxychlor (MXC) suspended in the vehicle. Another group received a single subcutaneous injection of 1.0 microg of estradiol-17beta (E) on Day 2 of pregnancy only. Male offspring were tested at 3 and 6 months of age. At 3 months, E or MXC did not alter the weights of seminal vesicles, preputial glands, or testes, although after exposure for 30 min to a female in estrus behind a partition, testosterone levels were significantly reduced in treated males in comparison to control males exposed to the same partition test. At 6 months, the preputial glands and testes weight remained unchanged, while the seminal vesicles were significantly heavier in E- and MXC-treated males. Same partition tests again revealed that in E and MXC groups, testosterone levels remained significantly lower in comparison to control males. MXC or E exposures during preimplantation appear to induce long-term effects on the sexual development in 3 and 6 month-old-males by compromising their sexual arousal and altering seminal vesicles weights in the older group.

  11. Aberrant neural stem cell proliferation and increased adult neurogenesis in mice lacking chromatin protein HMGB2.

    Directory of Open Access Journals (Sweden)

    Ariel B Abraham

    Full Text Available Neural stem and progenitor cells (NSCs/NPCs are distinct groups of cells found in the mammalian central nervous system (CNS. Previously we determined that members of the High Mobility Group (HMG B family of chromatin structural proteins modulate NSC proliferation and self-renewal. Among them HMGB2 was found to be dynamically expressed in proliferating and differentiating NSCs, suggesting that it may regulate NSC maintenance. We report now that Hmgb2(-/- mice exhibit SVZ hyperproliferation, increased numbers of SVZ NSCs, and a trend towards aberrant increases in newly born neurons in the olfactory bulb (OB granule cell layer. Increases in the levels of the transcription factor p21 and the Neural cell adhesion molecule (NCAM, along with down-regulation of the transcription/pluripotency factor Oct4 in the Hmgb2-/- SVZ point to a possible pathway for this increased proliferation/differentiation. Our findings suggest that HMGB2 functions as a modulator of neurogenesis in young adult mice through regulation of NSC proliferation, and identify a potential target via which CNS repair could be amplified following trauma or disease-based neuronal degeneration.

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

    Science.gov (United States)

    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. PMID:27317578

  13. Environmental modulations of the number of midbrain dopamine neurons in adult mice.

    Science.gov (United States)

    Tomas, Doris; Prijanto, Augustinus H; Burrows, Emma L; Hannan, Anthony J; Horne, Malcolm K; Aumann, Tim D

    2015-01-01

    Long-lasting changes in the brain or 'brain plasticity' underlie adaptive behavior and brain repair following disease or injury. Furthermore, interactions with our environment can induce brain plasticity. Increasingly, research is trying to identify which environments stimulate brain plasticity beneficial for treating brain and behavioral disorders. Two environmental manipulations are described which increase or decrease the number of tyrosine hydroxylase immunopositive (TH+, the rate-limiting enzyme in dopamine (DA) synthesis) neurons in the adult mouse midbrain. The first comprises pairing male and female mice together continuously for 1 week, which increases midbrain TH+ neurons by approximately 12% in males, but decreases midbrain TH+ neurons by approximately 12% in females. The second comprises housing mice continuously for 2 weeks in 'enriched environments' (EE) containing running wheels, toys, ropes, nesting material, etc., which increases midbrain TH+ neurons by approximately 14% in males. Additionally, a protocol is described for concurrently infusing drugs directly into the midbrain during these environmental manipulations to help identify mechanisms underlying environmentally-induced brain plasticity. For example, EE-induction of more midbrain TH+ neurons is abolished by concurrent blockade of synaptic input onto midbrain neurons. Together, these data indicate that information about the environment is relayed via synaptic input to midbrain neurons to switch on or off expression of 'DA' genes. Thus, appropriate environmental stimulation, or drug targeting of the underlying mechanisms, might be helpful for treating brain and behavioral disorders associated with imbalances in midbrain DA (e.g. Parkinson's disease, attention deficit and hyperactivity disorder, schizophrenia, and drug addiction).

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

    Science.gov (United States)

    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. PMID:25392270

  15. An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice.

    Science.gov (United States)

    Runge, Anja; Hu, Junhao; Wieland, Matthias; Bergeest, Jan-Philip; Mogler, Carolin; Neumann, André; Géraud, Cyrill; Arnold, Bernd; Rohr, Karl; Komljenovic, Dorde; Schirmacher, Peter; Goerdt, Sergij; Augustin, Hellmut G

    2014-08-01

    The limited availability of experimental tumor models that faithfully mimic the progression of human tumors and their response to therapy remains a major bottleneck to the clinical translation and application of novel therapeutic principles. To address this challenge in hepatocellular carcinoma (HCC), one of the deadliest and most common cancers in the world, we developed and validated an inducible model of hepatocarcinogenesis in adult mice. Tumorigenesis was triggered by intravenous adenoviral delivery of Cre recombinase in transgenic mice expressing the hepatocyte-specific albumin promoter, a loxP-flanked stop cassette, and the SV40 large T-antigen (iAST). Cre recombinase-mediated excision of the stop cassette led to a transient viral hepatitis and resulted in multinodular tumorigenesis within 5 to 8 weeks. Tumor nodules with histologic characteristics of human HCC established a functional vasculature by cooption, remodeling, and angiogenic expansion of the preexisting sinusoidal liver vasculature with increasing signs of vascular immaturity during tumor progression. Treatment of mice with sorafenib rapidly resulted in the induction of vascular regression, inhibition of tumor growth, and enhanced overall survival. Vascular regression was characterized by loss of endothelial cells leaving behind avascular type IV collagen-positive empty sleeves with remaining pericytes. Sorafenib treatment led to transcriptional changes of Igf1, Id1, and cMet over time, which may reflect the emergence of potential escape mechanisms. Taken together, our results established the iAST model of inducible hepatocarcinogenesis as a robust and versatile preclinical model to study HCC progression and validate novel therapies. PMID:24906623

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

    Science.gov (United States)

    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)…

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

    Science.gov (United States)

    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...

  18. Glutathione restores the mechanism of synaptic plasticity in aged mice to that of the adult.

    Directory of Open Access Journals (Sweden)

    Julie M Robillard

    Full Text Available Glutathione (GSH, the major endogenous antioxidant produced by cells, can modulate the activity of N-methyl-D-aspartate receptors (NMDARs through its reducing functions. During aging, an increase in oxidative stress leads to decreased levels of GSH in the brain. Concurrently, aging is characterized by calcium dysregulation, thought to underlie impairments in hippocampal NMDAR-dependent long-term potentiation (LTP, a form of synaptic plasticity thought to represent a cellular model for memory. Here we show that orally supplementing aged mice with N-acetylcysteine, a precursor for the formation of glutathione, reverses the L-type calcium channel-dependent LTP seen in aged animals to NMDAR-dependent LTP. In addition, introducing glutathione in the intrapipette solution during whole-cell recordings restores LTP obtained in whole-cell conditions in the aged hippocampus. We conclude that aging leads to a reduced redox potential in hippocampal neurons, triggering impairments in LTP.

  19. Postnatal overnutrition in mice leads to impaired pulmonary mechanics in response to salbutamol.

    Science.gov (United States)

    Teixeira, Vanessa P; Cervilha, Daniela A B; Cabral, Layla D M; Oliveira, Luiz M; Incerpi, Erika K; Novaes, Rômulo D; Ionta, Marisa; Soncini, Roseli

    2016-05-01

    Obesity increases the risk of respiratory disease, which is associated with airway hyperresponsiveness. Although the molecular underpinnings of this phenomenon are not well established, lung remodeling is known as an important factor in this process and could potentially explain compromised lung functions. In the present study, the obesity was induced by postnatal overnutrition in Swiss mice and we investigated the pulmonary mechanics after aerosolization of saline, methacholine, and salbutamol. The lungs were prepared for morphometric analysis. Obese animals showed bronchoconstriction in response to methacholine, as evidenced by airway and tissue resistance, tissue elastance, and hysteresivity. Salbutamol was effective at recovering the response only for airway resistance but not for tissue mechanics. We suggest that this impaired response in obese mice is related to collapsed alveolar, to inflammatory cells, and to elevated deposition collagen fibers in parenchymal tissue. PMID:26497334

  20. Fetal alcohol exposure leads to abnormal olfactory bulb development and impaired odor discrimination in adult mice

    NARCIS (Netherlands)

    K.G. Akers (Katherine); S.A. Kushner (Steven); A.T. Leslie (Ana); L. Clarke (Laura); D. van der Kooy (Derek); J.P. Lerch (Jason); P.W. Frankland (Paul)

    2011-01-01

    textabstractBackground: Children whose mothers consumed alcohol during pregnancy exhibit widespread brain abnormalities and a complex array of behavioral disturbances. Here, we used a mouse model of fetal alcohol exposure to investigate relationships between brain abnormalities and specific behavior

  1. Expression of truncated PITX3 in the developing lens leads to microphthalmia and aphakia in mice.

    Science.gov (United States)

    Wada, Kenta; Matsushima, Yoshibumi; Tada, Tomoki; Hasegawa, Sayaka; Obara, Yo; Yoshizawa, Yasuhiro; Takahashi, Gou; Hiai, Hiroshi; Shimanuki, Midori; Suzuki, Sari; Saitou, Junichi; Yamamoto, Naoki; Ichikawa, Masumi; Watanabe, Kei; Kikkawa, Yoshiaki

    2014-01-01

    Microphthalmia is a severe ocular disorder, and this condition is typically caused by mutations in transcription factors that are involved in eye development. Mice carrying mutations in these transcription factors would be useful tools for defining the mechanisms underlying developmental eye disorders. We discovered a new spontaneous recessive microphthalmos mouse mutant in the Japanese wild-derived inbred strain KOR1/Stm. The homozygous mutant mice were histologically characterized as microphthalmic by the absence of crystallin in the lens, a condition referred to as aphakia. By positional cloning, we identified the nonsense mutation c.444C>A outside the genomic region that encodes the homeodomain of the paired-like homeodomain transcription factor 3 gene (Pitx3) as the mutation responsible for the microphthalmia and aphakia. We examined Pitx3 mRNA expression of mutant mice during embryonic stages using RT-PCR and found that the expression levels are higher than in wild-type mice. Pitx3 over-expression in the lens during developmental stages was also confirmed at the protein level in the microphthalmos mutants via immunohistochemical analyses. Although lens fiber differentiation was not observed in the mutants, strong PITX3 protein signals were observed in the lens vesicles of the mutant lens. Thus, we speculated that abnormal PITX3, which lacks the C-terminus (including the OAR domain) as a result of the nonsense mutation, is expressed in mutant lenses. We showed that the expression of the downstream genes Foxe3, Prox1, and Mip was altered because of the Pitx3 mutation, with large reductions in the lens vesicles in the mutants. Similar profiles were observed by immunohistochemical analysis of these proteins. The expression profiles of crystallins were also altered in the mutants. Therefore, we speculated that the microphthalmos/aphakia in this mutant is caused by the expression of truncated PITX3, resulting in the abnormal expression of downstream targets and

  2. Expression of truncated PITX3 in the developing lens leads to microphthalmia and aphakia in mice.

    Directory of Open Access Journals (Sweden)

    Kenta Wada

    Full Text Available Microphthalmia is a severe ocular disorder, and this condition is typically caused by mutations in transcription factors that are involved in eye development. Mice carrying mutations in these transcription factors would be useful tools for defining the mechanisms underlying developmental eye disorders. We discovered a new spontaneous recessive microphthalmos mouse mutant in the Japanese wild-derived inbred strain KOR1/Stm. The homozygous mutant mice were histologically characterized as microphthalmic by the absence of crystallin in the lens, a condition referred to as aphakia. By positional cloning, we identified the nonsense mutation c.444C>A outside the genomic region that encodes the homeodomain of the paired-like homeodomain transcription factor 3 gene (Pitx3 as the mutation responsible for the microphthalmia and aphakia. We examined Pitx3 mRNA expression of mutant mice during embryonic stages using RT-PCR and found that the expression levels are higher than in wild-type mice. Pitx3 over-expression in the lens during developmental stages was also confirmed at the protein level in the microphthalmos mutants via immunohistochemical analyses. Although lens fiber differentiation was not observed in the mutants, strong PITX3 protein signals were observed in the lens vesicles of the mutant lens. Thus, we speculated that abnormal PITX3, which lacks the C-terminus (including the OAR domain as a result of the nonsense mutation, is expressed in mutant lenses. We showed that the expression of the downstream genes Foxe3, Prox1, and Mip was altered because of the Pitx3 mutation, with large reductions in the lens vesicles in the mutants. Similar profiles were observed by immunohistochemical analysis of these proteins. The expression profiles of crystallins were also altered in the mutants. Therefore, we speculated that the microphthalmos/aphakia in this mutant is caused by the expression of truncated PITX3, resulting in the abnormal expression of

  3. Endoplasmic Reticulum Thiol Oxidase Deficiency Leads to Ascorbic Acid Depletion and Noncanonical Scurvy in Mice

    OpenAIRE

    Zito, Ester; Hansen, Henning Gram; Yeo, Giles S.H.; Fujii, Junichi; Ron, David

    2012-01-01

    Summary Endoplasmic reticulum (ER) thiol oxidases initiate a disulfide relay to oxidatively fold secreted proteins. We found that combined loss-of-function mutations in genes encoding the ER thiol oxidases ERO1α, ERO1β, and PRDX4 compromised the extracellular matrix in mice and interfered with the intracellular maturation of procollagen. These severe abnormalities were associated with an unexpectedly modest delay in disulfide bond formation in secreted proteins but a profound, 5-fold lower pr...

  4. Overproduction of Upper-Layer Neurons in the Neocortex Leads to Autism-like Features in Mice

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    Wei-Qun Fang

    2014-12-01

    Full Text Available The functional integrity of the neocortex depends upon proper numbers of excitatory and inhibitory neurons; however, the consequences of dysregulated neuronal production during the development of the neocortex are unclear. As excess cortical neurons are linked to the neurodevelopmental disorder autism, we investigated whether the overproduction of neurons leads to neocortical malformation and malfunction in mice. We experimentally increased the number of pyramidal neurons in the upper neocortical layers by using the small molecule XAV939 to expand the intermediate progenitor population. The resultant overpopulation of neurons perturbs development of dendrites and spines of excitatory neurons and alters the laminar distribution of interneurons. Furthermore, these phenotypic changes are accompanied by dysregulated excitatory and inhibitory synaptic connection and balance. Importantly, these mice exhibit behavioral abnormalities resembling those of human autism. Thus, our findings collectively suggest a causal relationship between neuronal overproduction and autism-like features, providing developmental insights into the etiology of autism.

  5. Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2−/− mice

    Science.gov (United States)

    Gil-Henn, Hava; Destaing, Olivier; Sims, Natalie A.; Aoki, Kazuhiro; Alles, Neil; Neff, Lynn; Sanjay, Archana; Bruzzaniti, Angela; De Camilli, Pietro; Baron, Roland; Schlessinger, Joseph

    2007-01-01

    The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2−/− mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions. PMID:17846174

  6. Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-/-) mice.

    Science.gov (United States)

    Gil-Henn, Hava; Destaing, Olivier; Sims, Natalie A; Aoki, Kazuhiro; Alles, Neil; Neff, Lynn; Sanjay, Archana; Bruzzaniti, Angela; De Camilli, Pietro; Baron, Roland; Schlessinger, Joseph

    2007-09-10

    The protein tyrosine kinase Pyk2 is highly expressed in osteoclasts, where it is primarily localized in podosomes. Deletion of Pyk2 in mice leads to mild osteopetrosis due to impairment in osteoclast function. Pyk2-null osteoclasts were unable to transform podosome clusters into a podosome belt at the cell periphery; instead of a sealing zone only small actin rings were formed, resulting in impaired bone resorption. Furthermore, in Pyk2-null osteoclasts, Rho activity was enhanced while microtubule acetylation and stability were significantly reduced. Rescue experiments by ectopic expression of wild-type or a variety of Pyk2 mutants in osteoclasts from Pyk2(-/-) mice have shown that the FAT domain of Pyk2 is essential for podosome belt and sealing zone formation as well as for bone resorption. These experiments underscore an important role of Pyk2 in microtubule-dependent podosome organization, bone resorption, and other osteoclast functions. PMID:17846174

  7. Mitochondrial Pyruvate Carrier 2 Hypomorphism in Mice Leads to Defects in Glucose-Stimulated Insulin Secretion

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    Patrick A. Vigueira

    2014-06-01

    Full Text Available Carrier-facilitated pyruvate transport across the inner mitochondrial membrane plays an essential role in anabolic and catabolic intermediary metabolism. Mitochondrial pyruvate carrier 2 (Mpc2 is believed to be a component of the complex that facilitates mitochondrial pyruvate import. Complete MPC2 deficiency resulted in embryonic lethality in mice. However, a second mouse line expressing an N-terminal truncated MPC2 protein (Mpc2Δ16 was viable but exhibited a reduced capacity for mitochondrial pyruvate oxidation. Metabolic studies demonstrated exaggerated blood lactate concentrations after pyruvate, glucose, or insulin challenge in Mpc2Δ16 mice. Additionally, compared with wild-type controls, Mpc2Δ16 mice exhibited normal insulin sensitivity but elevated blood glucose after bolus pyruvate or glucose injection. This was attributable to reduced glucose-stimulated insulin secretion and was corrected by sulfonylurea KATP channel inhibitor administration. Collectively, these data are consistent with a role for MPC2 in mitochondrial pyruvate import and suggest that Mpc2 deficiency results in defective pancreatic β cell glucose sensing.

  8. Transcriptional repression of the Dspp gene leads to dentinogenesis imperfecta phenotype in Col1a1-Trps1 transgenic mice.

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    Napierala, Dobrawa; Sun, Yao; Maciejewska, Izabela; Bertin, Terry K; Dawson, Brian; D'Souza, Rena; Qin, Chunlin; Lee, Brendan

    2012-08-01

    Dentinogenesis imperfecta (DGI) is a hereditary defect of dentin, a calcified tissue that is the most abundant component of teeth. Most commonly, DGI is manifested as a part of osteogenesis imperfecta (OI) or the phenotype is restricted to dental findings only. In the latter case, DGI is caused by mutations in the DSPP gene, which codes for dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). Although these two proteins together constitute the majority of noncollagenous proteins of the dentin, little is known about their transcriptional regulation. Here we demonstrate that mice overexpressing the Trps1 transcription factor (Col1a1-Trps1 mice) in dentin-producing cells, odontoblasts, present with severe defects of dentin formation that resemble DGI. Combined micro-computed tomography (µCT) and histological analyses revealed tooth fragility due to severe hypomineralization of dentin and a diminished dentin layer with irregular mineralization in Col1a1-Trps1 mice. Biochemical analyses of noncollagenous dentin matrix proteins demonstrated decreased levels of both DSP and DPP proteins in Col1a1-Trps1 mice. On the molecular level, we demonstrated that sustained high levels of Trps1 in odontoblasts lead to dramatic decrease of Dspp expression as a result of direct inhibition of the Dspp promoter by Trps1. During tooth development Trps1 is highly expressed in preodontoblasts, but in mature odontoblasts secreting matrix its expression significantly decreases, which suggests a Trps1 role in odontoblast development. In these studies we identified Trps1 as a potent inhibitor of Dspp expression and the subsequent mineralization of dentin. Thus, we provide novel insights into mechanisms of transcriptional dysregulation that leads to DGI.

  9. Successful small intestine colonization of adult mice by Vibrio cholerae requires ketamine anesthesia and accessory toxins.

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    Verena Olivier

    Full Text Available Vibrio cholerae colonizes the small intestine of adult C57BL/6 mice. In this study, the physical and genetic parameters that facilitate this colonization were investigated. Successful colonization was found to depend upon anesthesia with ketamine-xylazine and neutralization of stomach acid with sodium bicarbonate, but not streptomycin treatment. A variety of common mouse strains were colonized by O1, O139, and non-O1/non-O139 strains. All combinations of mutants in the genes for hemolysin, the multifunctional, autoprocessing RTX toxin (MARTX, and hemagglutinin/protease were assessed, and it was found that hemolysin and MARTX are each sufficient for colonization after a low dose infection. Overall, this study suggests that, after intragastric inoculation, V. cholerae encounters barriers to infection including an acidic environment and an immediate immune response that is circumvented by sodium bicarbonate and the anti-inflammatory effects of ketamine-xylazine. After initial adherence in the small intestine, the bacteria are subjected to additional clearance mechanisms that are evaded by the independent toxic action of hemolysin or MARTX. Once colonization is established, it is suggested that, in humans, these now persisting bacteria initiate synthesis of the major virulence factors to cause cholera disease. This adult mouse model of intestinal V. cholerae infection, now well-characterized and fully optimized, should serve as a valuable tool for studies of pathogenesis and testing vaccine efficacy.

  10. Maternal immune activation differentially impacts mature and adult-born hippocampal neurons in male mice.

    Science.gov (United States)

    Zhang, Zhi; van Praag, Henriette

    2015-03-01

    Schizophrenia is associated with deficits in the hippocampus, a brain area important for learning and memory. The dentate gyrus (DG) of the hippocampus develops both before and after birth. To study the relative contribution of mature and adult-born DG granule cells to disease etiology, we compared both cell populations in a mouse model of psychiatric illness resulting from maternal immune activation. Polyriboinosinic-polyribocytidilic acid (PolyIC, 5mg/kg) or saline was given on gestation day 15 to pregnant female C57Bl/6 mice. Male offspring (n=105), was administered systemic bromodeoxyuridine (BrdU, 50mg/kg) (n=52) or intracerebral retroviral injection into the DG (n=53), to label dividing cells at one month of age. Two months later behavioral tests were performed to evaluate disease phenotype. Immunohistochemistry and whole-cell patch clamping were used to assess morphological and physiological characteristics of DG cells. Three-month-old PolyIC exposed male offspring exhibited deficient pre-pulse inhibition, spatial maze performance and motor coordination, as well as increased depression-like behavior. Histological analysis showed reduced DG volume and parvalbumin positive interneuron number. Both mature and new hippocampal neurons showed modifications in intrinsic properties such as increased input resistance and lower current threshold, and decreased action potential number. Reduced GABAergic inhibitory transmission was observed only in mature DG neurons. Differential impairments in mature DG cells and adult-born new neurons may have implications for behavioral deficits associated with maternal immune activation. PMID:25449671

  11. Ultrastructural study of renal tubular damage induced by captopril in adult and fetal mice

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    Hamdy H. Swelim and Aleya A.Sakr

    2004-12-01

    Full Text Available The present study has been designed to evaluate the possible nephrotoxicity of the angiotensin converting enzyme inhibitor, captopril on renal tubules of adult and maternally treated fetuses of CD-1 mice. The study included the effect of captopril administration for one month up to three months in adults, while in fetuses, they were exposed to the drug through their mothers in two periods. The first was from 6th-12th days of pregnancy, while the second was from 6th -18th day of pregnancy. The dose used in the present study represents the dose equivalent to the therapeutic daily dose taken by human. All the recorded tissue damage was found to be time dependent. The first remarkable feature noticed in all the treated adult animals was the presence of hyaline casts that obstructed most of the renal tubules. The second remarkable feature was the increase of the intertubular space associated with irregularity of the tubules due to the degeneration and vacuolation of the basal regions of the cells. Renal tubule cells showed large blebs, accumulaton of lipids, degeneration and necrosis. In maternally treated fetuses, the proximal convoluted tubule cells displayed moderate vacuolation and marked increase of lysosomes while some of the distal convoluted tubules revealed atrophy and their cells showed loss of mitochondria. In addition, the collecting tubules showed loss of microprojections. Worthy to mention that there was apparent increase of mesenchymal cells as well as fibroblasts in the fetuses maternally treated with captopril. The significance of these changes was discussed and it should be emphasized that captopril must be taken with caution for pregnant women and those who suffer from renal troubles. Moreover, kidney function should be monitored during therapy .

  12. Isoflurane does not cause neuroapoptosis but reduces astroglial processes in young adult mice

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    Dallasen Renee M

    2011-11-01

    Full Text Available Abstract 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.

  13. Lead and radiation induced hepatic lesions in Swiss albino mice and their inhibition by vitamin E

    International Nuclear Information System (INIS)

    The present study has been carried out to access the protective role of vitamin E against hepato-toxicity induced by lead and radiation. The present study demonstrates that the application of vitamin E prior to lead and gamma radiation exposure is quite potential to provide protection against hepatic lesions induced by such teratogens

  14. Early Exposure to Intermediate-Frequency Magnetic Fields Alters Brain Biomarkers without Histopathological Changes in Adult Mice

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    Tin-Tin Win-Shwe

    2015-04-01

    Full Text Available Recently we have reported that intermediate-frequency magnetic field (IF-MF exposure transiently altered the mRNA expression levels of memory function-related genes in the hippocampi of adult male mice. However, the effects of IF-MF exposure during brain development on neurological biomarkers have not yet been clarified. In the present study, we investigated the effect of IF-MF exposure during development on neurological and immunological markers in the mouse hippocampus in 3- and 7-week-old male mice. Pregnant C57BL/6J mice were exposed to IF-MF (21 kHz, 3.8 mT for one hour per day from organogenesis period day 7 to 17. At adolescence, some IF-MF-exposed mice were further divided into exposure, recovery, and sham-exposure groups. The adolescent-exposure groups were exposed again to IF-MF from postnatal day 27 to 48. The expression of mRNA in the hippocampi was examined using a real-time RT-PCR method, and microglia activation was examined by immunohistochemical analysis. The expression levels of NR1 and NR2B as well as transcription factors (CaMKIV, CREB1, inflammatory mediators (COX2, IL-1 b,TNF-α, and the oxidative stress marker heme-oxygenase (HO-1 were significantly increased in the IF-MF-exposed mice, compared with the control group, in the 7-week-old mice, but not in the 3-week-old mice. Microglia activation was not different between the control and other groups. This study provides the first evidence that early exposure to IF-MF reversibly affects the NMDA receptor, its related signaling pathways, and inflammatory mediators in the hippocampus of young adult mice; these changes are transient and recover after termination of exposure without histopathological changes.

  15. Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice

    OpenAIRE

    Beaucage, Kim L.; Xiao, Andrew; Pollmann, Steven I.; Grol, Matthew W.; Beach, Ryan J.; Holdsworth, David W.; Sims, Stephen M.; Darling, Mark R.; Dixon, S. Jeffrey

    2013-01-01

    The P2X7 receptor is an ATP-gated cation channel expressed by a number of cell types. We have shown previously that disruption of P2X7 receptor function results in downregulation of osteogenic markers and upregulation of adipogenic markers in calvarial cell cultures. In the present study, we assessed whether loss of P2X7 receptor function results in changes to adipocyte distribution and lipid accumulation in vivo. Male P2X7 loss-of-function (KO) mice exhibited significantly greater body weigh...

  16. Neonatal infection with neurotropic influenza A virus affects working memory and expression of type III Nrg1 in adult mice.

    Science.gov (United States)

    Asp, Linnéa; Beraki, Simret; Kristensson, Krister; Ogren, Sven Ove; Karlsson, Håkan

    2009-08-01

    Epidemiological studies suggest that early life infections may contribute to the development of psychiatric disorders characterized by cognitive deficits. Here, we studied the effects of a neonatal influenza A/WSN/33 virus infection on locomotor activity, working memory and emotional behavior in adult mice. In addition to wild type mice, immunodeficient (Tap1(-/-)) mice lacking functional CD8(+) T cells, were included in the study to model the potential influence of a genetic deficit relating to virus clearance. Three to four months after the infection, infected Tap1(-/-) mice, but not wild type mice, exhibited deficits in working memory as well as increased rearing activity and anxiety. In the medial prefrontal cortices of these infected Tap1(-/-) mice reduced levels of type III Nrg1 transcripts were observed supporting a role for neuregulin 1 signaling in neuronal circuits involved in working memory. Virus replication, distribution or clearance did not differ between the two genotypes. The lack of CD8(+) T cells, however, appeared to contribute to a more pronounced glia response in Tap1(-/-) than in wild type mice. Thus, the present study suggest that the risk of developing deficits in cognitive and emotional behavior following a CNS infection during brain development is influenced by genetic variation in genes involved in the immune response.

  17. Protective potential of Emblica Officinalis Linn. against radiation and lead induced hepatic lesion in Swiss albino mice

    International Nuclear Information System (INIS)

    Exposure of living systems to ionizing radiation causes a variety of damages to DNA and membranes due to generation of free radicals and reactive oxygen species. So there is a need of hour is to search for an ideal radioprotector which could minimize the deleterious and damaging effects caused by ionizing radiation. Radioprotectors are agents which reduce the radiation effects on cell when applied prior to exposure of radiation. The aim of this study was to access the efficacy of Emblica officinalis in reducing radiation and lead induced changes in mice liver. For the present experiment, healthy male Swiss albino mice (6-8 weeks) were selected and maintained under standard conditions of temperature and light. Fruit extract of Emblica was fed orally at the dose of 0.01 ml/animal/day.The animal were divided into seven groups according to the treatment i.e. lead acetate solution as drinking water (group-II) or exposed to 3.5 or 7.0 Gy gamma radiation (group-III) or combined treatment of radiation and lead acetate (group-IV). The animals of experimental groups were administered Emblica extract seven days prior to radiation or lead acetate treatment (group V, VI and VII) respectively. The animals from all the groups were sacrificed by cervical dislocation at each post-treatment intervals of 1, 2, 4, 7, 14 and 28 days. After sacrificing the animals pieces of liver were taken out and some of them were kept at -20℃ for different biochemical parameters. The histopathological changes included cytoplasmic degranulation, vacuolation, hyperaemia, pycnotic and crenated nuclei. The changes observed in the control groups were compared with the respective experimental groups. An increase in the value of total proteins, glycogen, acid phosphatase, alkaline phosphatase activity and RNA was observed up to day - 14 in the non drug treated group and day 7 in the Emblica treated groups, thereafter value declined up to day - 28 without reaching to normal. Whereas the value of

  18. Adolescent intake of caffeinated energy drinks does not affect adult alcohol consumption in C57BL/6 and BALB/c mice.

    Science.gov (United States)

    Robins, Meridith T; DeFriel, Julia N; van Rijn, Richard M

    2016-08-01

    The rise in marketing and mass consumption of energy drink products by adolescents poses a largely unknown risk on adolescent development and drug reward. Yet, with increasing reports of acute health issues present in young adults who ingest large quantities of energy drinks alone or in combination with alcohol, the need to elucidate these potential risks is pressing. Energy drinks contain high levels of caffeine and sucrose; therefore, exposure to energy drinks may lead to changes in drug-related behaviors since caffeine and sucrose consumption activates similar brain pathways engaged by substances of abuse. With a recent study observing that adolescent caffeine consumption increased cocaine sensitivity, we sought to investigate how prolonged energy drink exposure in adolescence alters alcohol use and preference in adulthood. To do so, we utilized three different energy drink exposure paradigms and two strains of male mice (C57BL/6 and BALB/c) to monitor the effect of caffeine exposure via energy drinks in adolescence on adult alcohol intake. These paradigms included two models of volitional consumption of energy drinks or energy drink-like substances and one model of forced consumption of sucrose solutions with different caffeine concentrations. Following adolescent exposure to these solutions, alcohol intake was monitored in a limited-access, two-bottle choice between water and increasing concentrations of alcohol during adulthood. In none of the three models or two strains of mice did we observe that adolescent 'energy drink' consumption or exposure was correlated with changes in adult alcohol intake or preference. While our current preclinical results suggest that exposure to large amounts of caffeine does not alter future alcohol intake, differences in caffeine metabolism between mice and humans need to be considered before translating these results to humans. PMID:27565749

  19. Adolescent intake of caffeinated energy drinks does not affect adult alcohol consumption in C57BL/6 and BALB/c mice.

    Science.gov (United States)

    Robins, Meridith T; DeFriel, Julia N; van Rijn, Richard M

    2016-08-01

    The rise in marketing and mass consumption of energy drink products by adolescents poses a largely unknown risk on adolescent development and drug reward. Yet, with increasing reports of acute health issues present in young adults who ingest large quantities of energy drinks alone or in combination with alcohol, the need to elucidate these potential risks is pressing. Energy drinks contain high levels of caffeine and sucrose; therefore, exposure to energy drinks may lead to changes in drug-related behaviors since caffeine and sucrose consumption activates similar brain pathways engaged by substances of abuse. With a recent study observing that adolescent caffeine consumption increased cocaine sensitivity, we sought to investigate how prolonged energy drink exposure in adolescence alters alcohol use and preference in adulthood. To do so, we utilized three different energy drink exposure paradigms and two strains of male mice (C57BL/6 and BALB/c) to monitor the effect of caffeine exposure via energy drinks in adolescence on adult alcohol intake. These paradigms included two models of volitional consumption of energy drinks or energy drink-like substances and one model of forced consumption of sucrose solutions with different caffeine concentrations. Following adolescent exposure to these solutions, alcohol intake was monitored in a limited-access, two-bottle choice between water and increasing concentrations of alcohol during adulthood. In none of the three models or two strains of mice did we observe that adolescent 'energy drink' consumption or exposure was correlated with changes in adult alcohol intake or preference. While our current preclinical results suggest that exposure to large amounts of caffeine does not alter future alcohol intake, differences in caffeine metabolism between mice and humans need to be considered before translating these results to humans.

  20. Mutation of Dcdc2 in mice leads to impairments in auditory processing and memory ability.

    Science.gov (United States)

    Truong, D T; Che, A; Rendall, A R; Szalkowski, C E; LoTurco, J J; Galaburda, A M; Holly Fitch, R

    2014-11-01

    Dyslexia is a complex neurodevelopmental disorder characterized by impaired reading ability despite normal intellect, and is associated with specific difficulties in phonological and rapid auditory processing (RAP), visual attention and working memory. Genetic variants in Doublecortin domain-containing protein 2 (DCDC2) have been associated with dyslexia, impairments in phonological processing and in short-term/working memory. The purpose of this study was to determine whether sensory and behavioral impairments can result directly from mutation of the Dcdc2 gene in mice. Several behavioral tasks, including a modified pre-pulse inhibition paradigm (to examine auditory processing), a 4/8 radial arm maze (to assess/dissociate working vs. reference memory) and rotarod (to examine sensorimotor ability and motor learning), were used to assess the effects of Dcdc2 mutation. Behavioral results revealed deficits in RAP, working memory and reference memory in Dcdc2(del2/del2) mice when compared with matched wild types. Current findings parallel clinical research linking genetic variants of DCDC2 with specific impairments of phonological processing and memory ability.

  1. Multiple events lead to dendritic spine loss in triple transgenic Alzheimer's disease mice.

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    Tobias Bittner

    Full Text Available The pathology of Alzheimer's disease (AD is characterized by the accumulation of amyloid-β (Aβ peptide, hyperphosphorylated tau protein, neuronal death, and synaptic loss. By means of long-term two-photon in vivo imaging and confocal imaging, we characterized the spatio-temporal pattern of dendritic spine loss for the first time in 3xTg-AD mice. These mice exhibit an early loss of layer III neurons at 4 months of age, at a time when only soluble Aβ is abundant. Later on, dendritic spines are lost around amyloid plaques once they appear at 13 months of age. At the same age, we observed spine loss also in areas apart from amyloid plaques. This plaque independent spine loss manifests exclusively at dystrophic dendrites that accumulate both soluble Aβ and hyperphosphorylated tau intracellularly. Collectively, our data shows that three spatio-temporally independent events contribute to a net loss of dendritic spines. These events coincided either with the occurrence of intracellular soluble or extracellular fibrillar Aβ alone, or the combination of intracellular soluble Aβ and hyperphosphorylated tau.

  2. Vitamin E attenuates liver injury induced by exposure to lead, mercury, cadmium and copper in albino mice.

    Science.gov (United States)

    Al-Attar, Atef M

    2011-10-01

    Water pollution is the contamination of water resources by harmful wastes or toxins. Both community and private sources of drinking water are susceptible to a myriad of chemical contaminants. Heavy metals pollution of surface water can create health risks. The present study was aimed to investigate the effect of vitamin E supplementation on male mice exposed to a mixture of some heavy metals (lead, mercury, cadmium and copper) in their drinking water for seven weeks. Significant increases of blood alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) were detected in heavy metals-treated mice. Histopathologically, the liver sections from heavy metals-treated mice showed severe changes including disarrangement of hepatic strands, rupture in hepatocytes, advanced hepatocellular necrosis, dilation and congestion of blood vessels with hemorrhage, dense lymphocytic infiltration round the central vein and dark stained hepatocytic nuclei indicating cell pycnosis. Administration of vitamin E at a dose of 50 IU/kg body weight, five times weekly improved the observed biochemical and histopathological changes induced by these heavy metals intoxication. Hence, the results of this study suggest that vitamin E protects against these heavy metals-induced liver injury and the attenuating effect of vitamin E may be due to its antioxidant activity. PMID:23961152

  3. Low-level environmental lead exposure in childhood and adult intellectual function: a follow-up study

    Directory of Open Access Journals (Sweden)

    Gregas Matthew

    2011-03-01

    Full Text Available Abstract Background Early life lead exposure might be a risk factor for neurocognitive impairment in adulthood. Objectives We sought to assess the relationship between early life environmental lead exposure and intellectual function in adulthood. We also attempted to identify which time period blood-lead concentrations are most predictive of adult outcome. Methods We recruited adults in the Boston area who had participated as newborns and young children in a prospective cohort study that examined the relationship between lead exposure and childhood intellectual function. IQ was measured using the Wechsler Abbreviated Scale of Intelligence (WASI. The association between lead concentrations and IQ scores was examined using linear regression. Results Forty-three adults participated in neuropsychological testing. Childhood blood-lead concentration (mean of the blood-lead concentrations at ages 4 and 10 years had the strongest relationship with Full-Scale IQ (β = -1.89 ± 0.70, p = 0.01. Full-scale IQ was also significantly related to blood-lead concentration at age 6 months (β = -1.66 ± 0.75, p = 0.03, 4 years (β = -0.90 ± 0.41, p = 0.03 and 10 years (β = -1.95 ± 0.80, p = 0.02. Adjusting for maternal IQ altered the significance of the regression coefficient. Conclusions Our study suggests that lead exposure in childhood predicts intellectual functioning in young adulthood. Our results also suggest that school-age lead exposure may represent a period of increased susceptibility. Given the small sample size, however, the potentially confounding effects of maternal IQ cannot be excluded and should be evaluated in a larger study.

  4. Single and repeated sevoflurane or desflurane exposure does not impair spatial memory performance of young adult mice.

    Science.gov (United States)

    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.

  5. Environmental enrichment and social interaction improve cognitive function and decrease reactive oxidative species in normal adult mice.

    Science.gov (United States)

    Doulames, Vanessa; Lee, Sangmook; Shea, Thomas B

    2014-05-01

    Environmental stimulation and increased social interactions stimulate cognitive performance, while decrease in these parameters can exacerbate cognitive decline as a function of illness, injury, or age. We examined the impact of environmental stimulation and social interactions on cognitive performance in healthy adult C57B1/6J mice. Mice were housed for 1 month individually or in groups of three (to prevent or allow social interaction) in either a standard environment (SE) or an enlarged cage containing nesting material and items classically utilized to stimulate exploration and activity ("enriched environment"; EE). Cognitive performance was tested by Y maze navigation and Novel Object Recognition (NOR; which compares the relative amount of time mice spent investigating a novel vs. a familiar object). Mice maintained for 1 month under isolated conditions in the SE statistically declined in performance versus baseline in the Y maze (p species (ROS/RNS) in brain. Environmental enrichment did not influence ROS/RNS. These findings indicate that environmental and social enrichment can positively influence cognitive performance in healthy adult mice, and support the notion that proactive approaches may delay age-related cognitive decline.

  6. Adult male mice emit context-specific ultrasonic vocalizations that are modulated by prior isolation or group rearing environment.

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    Jonathan Chabout

    Full Text Available Social interactions in mice are frequently analysed in genetically modified strains in order to get insight of disorders affecting social interactions such as autism spectrum disorders. Different types of social interactions have been described, mostly between females and pups, and between adult males and females. However, we recently showed that social interactions between adult males could also encompass cognitive and motivational features. During social interactions, rodents emit ultrasonic vocalizations (USVs, but it remains unknown if call types are differently used depending of the context and if they are correlated with motivational state. Here, we recorded the calls of adult C57BL/6J male mice in various behavioral conditions, such as social interaction, novelty exploration and restraint stress. We introduced a modulator for the motivational state by comparing males maintained in isolation and males maintained in groups before the experiments. Male mice uttered USVs in all social and non-social situations, and even in a stressful restraint context. They nevertheless emitted the most important number of calls with the largest diversity of call types in social interactions, particularly when showing a high motivation for social contact. For mice maintained in social isolation, the number of calls recorded was positively correlated with the duration of social contacts, and most calls were uttered during contacts between the two mice. This correlation was not observed in mice maintained in groups. These results open the way for a deeper understanding and characterization of acoustic signals associated with social interactions. They can also help evaluating the role of motivational states in the emission of acoustic signals.

  7. Epithelial cell stretching and luminal acidification lead to a retarded development of stria vascularis and deafness in mice lacking pendrin.

    Directory of Open Access Journals (Sweden)

    Hyoung-Mi Kim

    Full Text Available Loss-of-function mutations of SLC26A4/pendrin are among the most prevalent causes of deafness. Deafness and vestibular dysfunction in the corresponding mouse model, Slc26a4(-/-, are associated with an enlargement and acidification of the membranous labyrinth. Here we relate the onset of expression of the HCO(3 (- transporter pendrin to the luminal pH and to enlargement-associated epithelial cell stretching. We determined expression with immunocytochemistry, cell stretching by digital morphometry and pH with double-barreled ion-selective electrodes. Pendrin was first expressed in the endolymphatic sac at embryonic day (E 11.5, in the cochlear hook-region at E13.5, in the utricle and saccule at E14.5, in ampullae at E16.5, and in the upper turn of the cochlea at E17.5. Epithelial cell stretching in Slc26a4(-/- mice began at E14.5. pH changes occurred first in the cochlea at E15.5 and in the endolymphatic sac at E17.5. At postnatal day 2, stria vascularis, outer sulcus and Reissner's membrane epithelial cells, and utricular and saccular transitional cells were stretched, whereas sensory cells in the cochlea, utricle and saccule did not differ between Slc26a4(+/- and Slc26a4(-/- mice. Structural development of stria vascularis, including vascularization, was retarded in Slc26a4(-/- mice. In conclusion, the data demonstrate that the enlargement and stretching of non-sensory epithelial cells precedes luminal acidification in the cochlea and the endolymphatic sac. Stretching and luminal acidification may alter cell-to-cell communication and lead to the observed retarded development of stria vascularis, which may be an important step on the path to deafness in Slc26a4(-/- mice, and possibly in humans, lacking functional pendrin expression.

  8. Antibiotic-induced dysbiosis alters host-bacterial interactions and leads to colonic sensory and motor changes in mice.

    Science.gov (United States)

    Aguilera, M; Cerdà-Cuéllar, M; Martínez, V

    2015-01-01

    Alterations in the composition of the commensal microbiota (dysbiosis) seem to be a pathogenic component of functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and might participate in the secretomotor and sensory alterations observed in these patients.We determined if a state antibiotics-induced intestinal dysbiosis is able to modify colonic pain-related and motor responses and characterized the neuro-immune mechanisms implicated in mice. A 2-week antibiotics treatment induced a colonic dysbiosis (increments in Bacteroides spp, Clostridium coccoides and Lactobacillus spp and reduction in Bifidobacterium spp). Bacterial adherence was not affected. Dysbiosis was associated with increased levels of secretory-IgA, up-regulation of the antimicrobial lectin RegIIIγ, and toll-like receptors (TLR) 4 and 7 and down-regulation of the antimicrobial-peptide Resistin-Like Molecule-β and TLR5. Dysbiotic mice showed less goblet cells, without changes in the thickness of the mucus layer. Neither macroscopical nor microscopical signs of inflammation were observed. In dysbiotic mice, expression of the cannabinoid receptor 2 was up-regulated, while the cannabinoid 1 and the mu-opioid receptors were down-regulated. In antibiotic-treated mice, visceral pain-related responses elicited by intraperitoneal acetic acid or intracolonic capsaicin were significantly attenuated. Colonic contractility was enhanced during dysbiosis. Intestinal dysbiosis induce changes in the innate intestinal immune system and modulate the expression of pain-related sensory systems, an effect associated with a reduction in visceral pain-related responses. Commensal microbiota modulates gut neuro-immune sensory systems, leading to functional changes, at least as it relates to viscerosensitivity. Similar mechanisms might explain the beneficial effects of antibiotics or certain probiotics in the treatment of IBS. PMID:25531553

  9. Histopathology related to cadmium and lead bioaccumulation in chronically exposed wood mice, Apodemus sylvaticus, around a former smelter.

    Science.gov (United States)

    Tête, Nicolas; Durfort, Mercè; Rieffel, Dominique; Scheifler, Renaud; Sánchez-Chardi, Alejandro

    2014-05-15

    The ceasing of industrial activities often reduces the emission of pollutants but also often leaves disturbed areas without remediation and with persistent pollutants that can still be transferred along the food chain. This study examines the potential relationships between non-essential trace metals and histopathology in target tissues of wood mice (Apodemus sylvaticus) collected along a gradient of contamination around the former smelter, Metaleurop Nord (northern France). Cadmium and lead concentrations were measured, and histological alterations attributable to chronic trace metal exposure were assessed in the liver and the kidneys of 78 individuals. Metal concentrations quantified in the present study were among the highest observed for this species. Some histological alterations significantly increased with Cd or Pb concentrations in the soil and in the organs. Sixteen mice from polluted sites were considered at risk for metal-induced stress because their Cd and/or Pb tissue concentrations exceeded the LOAELs for single exposure to these elements. These mice also exhibited a higher severity of histological alterations in their organs than individuals with lower metal burdens. These results indicate that the Metaleurop smelter, despite its closure in 2003, still represents a threat to the local ecosystem because of the high levels and high bioavailability of Cd and Pb in the soil. However, among the mice not considered at risk for metal-induced stress based on the metal levels in their tissues, a large percentage of individuals still exhibited histological alterations. Thus, the present study suggests that the evaluation of toxic effects based only on the LOAELs for single metal exposure may result in the underestimation of the real risks when specimens are exposed to multiple stressors.

  10. Neonatal Nicotine Exposure Leads to Hypothalamic Gliosis in Adult Overweight Rats.

    Science.gov (United States)

    Younes-Rapozo, V; Moura, E G; Manhães, A C; Pinheiro, C R; Carvalho, J C; Barradas, P C; de Oliveira, E; Lisboa, P C

    2015-12-01

    Astrocytes and microglia, the immune competent cells of central nercous system, can be activated in response to metabolic signals such as obesity and hyperleptinaemia. In rats, maternal exposure to nicotine during lactation leads to central obesity, hyperleptinaemia, leptin resistance and alterations in hypothalamic neuropeptides in the offspring during adulthood. In the present study, we studied the activation of astrocytes and microglia, as well as the pattern of inflammatory mediators, in adult offspring of this experimental model. On postnatal day 2 (P2), osmotic minipumps releasing nicotine (NIC) (-6 mg/kg/day) or saline for 14 days were s.c. implanted in dams. Male offspring were killed on P180 and hypothalamic immunohistochemistry, retroperitoneal white adipose tissue (WAT) polymerase chain reaction analysis and multiplex analysis for plasma inflammatory mediators were carried out. At P180, NIC astrocyte cell number was higher in the arcuate nucleus (ARC) (medial: +82%; lateral: +110%), in the paraventricular nucleus (PVN) (+144%) and in the lateral hypothalamus (+121%). NIC glial fibrillary acidic protein fibre density was higher in the lateral ARC (+178%) and in the PVN (+183%). Interleukin-6 was not affected in the hypothalamus. NIC monocyte chemotactic protein 1 was only higher in the periventricular nucleus (+287%). NIC microglia (iba-1-positive) cell number was higher (+68%) only in the PVN, as was the chemokine (C-X3-C motif) receptor 1 density (+93%). NIC interleukin-10 was lower in the WAT (-58%) and plasma (-50%). Thus, offspring of mothers exposed to nicotine during lactation present hypothalamic astrogliosis at adulthood and microgliosis in the PVN.

  11. Combination Therapy for the Cardiovascular Effects of Perinatal Lead Exposure in Young and Adult Rats

    Energy Technology Data Exchange (ETDEWEB)

    Gaspar, Andréia Fresneda [Departamento de Farmacologia, Instituto de Biociências - Universidade Estadual Paulista (UNESP), Botucatu, SP (Brazil); Faculdade da Alta Paulista (FAP), Tupã, SP (Brazil); Cordellini, Sandra, E-mail: cordelli@ibb.unesp.br [Departamento de Farmacologia, Instituto de Biociências - Universidade Estadual Paulista (UNESP), Botucatu, SP (Brazil)

    2014-09-15

    Combination therapy can play a significant role in the amelioration of several toxic effects of lead (Pb) and recovery from associated cardiovascular changes. To investigate the effects of combination therapy on the cardiovascular effects of perinatal lead exposure in young and adult rats Female Wistar rats received drinking water with or without 500 ppm of Pb during pregnancy and lactation. Twenty-two- and 70-day-old rat offspring who were or were not exposed to Pb in the perinatal period received meso-dimercaptosuccinic acid (DMSA), L-arginine, or enalapril and a combination of these compounds for 30 additional days. Noradrenaline response curves were plotted for intact and denuded aortas from 23-, 52-, 70-, and 100-day-old rats stratified by perinatal Pb exposure (exposed/unexposed) and treatment received (treated/untreated). Systolic blood pressure was evaluated and shown to be higher in the 23-, 52-, 70-, and 100-day age groups with Pb exposure than in the corresponding control age groups: 117.8 ± 3.9*, 135.2 ± 1.3*, 139.6 ± 1.6*, and 131.7 ± 2.8*, respectively and 107.1 ± 1.8, 118.8 ± 2.1, 126.1 ± 1.1, and 120.5 ± 2.2, respectively (p < 0.05). Increased reactivity to noradrenaline was observed in intact, but not denuded, aortas from 52-, 70-, and 100-day-old exposed rats, and the maximum responses (g of tension) in the respective Pb-exposed and control age groups were as follows: 3.43 ± 0.16*, 4.32 ± 0.18*, and 4.21 ± 0.23*, respectively and 2.38 ± 0.33, 3.37 ± 0.13, and 3.22 ± 0.21, respectively (p < 0.05). All treatments reversed the changes in vascular reactivity to noradrenaline in rats perinatally exposed to Pb. The combination therapy resulted in an earlier restoration of blood pressure in Pb-exposed rats compared with the monotherapies, except for enalapril therapy in young rats. These findings represent a new approach to the development of therapeutic protocols for the treatment of Pb-induced hypertension.

  12. Chronic minocycline treatment improves social recognition memory in adult male Fmr1 knockout mice.

    Science.gov (United States)

    Yau, Suk Yu; Chiu, Christine; Vetrici, Mariana; Christie, Brian R

    2016-10-01

    Fragile X syndrome (FXS) is caused by a mutation in the Fmr1 gene that leads to silencing of the gene and a loss of its gene product, Fragile X mental retardation protein (FMRP). Some of the key behavioral phenotypes for FXS include abnormal social anxiety and sociability. Here we show that Fmr1 knock-out (KO) mice exhibit impaired social recognition when presented with a novel mouse, and they display normal social interactions in other sociability tests. Administering minocycline to Fmr1 KO mice throughout critical stages of neural development improved social recognition memory in the novel mouse recognition task. To determine if synaptic changes in the prefrontal cortex (PFC) could have played a role in this improvement, we examined PSD-95, a member of the membrane-associated guanylate kinase family, and signaling molecules (ERK1/2, and Akt) linked to synaptic plasticity in the PFC. Our analyses indicated that while minocycline treatment can enhance behavioral performance, it does not enhance expression of PSD-95, ERK1/2 or Akt in the PFC. PMID:27291517

  13. Transgenic expression of an expanded (GCG)13 repeat PABPN1 leads to weakness and coordination defects in mice.

    Science.gov (United States)

    Dion, Patrick; Shanmugam, Vijayalakshmi; Gaspar, Claudia; Messaed, Christiane; Meijer, Inge; Toulouse, André; Laganiere, Janet; Roussel, Julie; Rochefort, Daniel; Laganiere, Simon; Allen, Carol; Karpati, George; Bouchard, Jean-Pierre; Brais, Bernard; Rouleau, Guy A

    2005-04-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder caused by a (GCG)n trinucleotide repeat expansion in the poly(A) binding protein nuclear-1 (PABPN1) gene, which in turn leads to an expanded polyalanine tract in the protein. We generated transgenic mice expressing either the wild type or the expanded form of human PABPN1, and transgenic animals with the expanded form showed clear signs of abnormal limb clasping, muscle weakness, coordination deficits, and peripheral nerves alterations. Analysis of mitotic and postmitotic tissues in those transgenic animals revealed ubiquitinated PABPN1-positive intranuclear inclusions (INIs) in neuronal cells. This latter observation led us to test and confirm the presence of similar INIs in postmortem brain sections from an OPMD patient. Our results indicate that expanded PABPN1, presumably via the toxic effects of its polyalanine tract, can lead to inclusion formation and neurodegeneration in both the mouse and the human. PMID:15755680

  14. Transgenic expression of an expanded (GCG)13 repeat PABPN1 leads to weakness and coordination defects in mice.

    Science.gov (United States)

    Dion, Patrick; Shanmugam, Vijayalakshmi; Gaspar, Claudia; Messaed, Christiane; Meijer, Inge; Toulouse, André; Laganiere, Janet; Roussel, Julie; Rochefort, Daniel; Laganiere, Simon; Allen, Carol; Karpati, George; Bouchard, Jean-Pierre; Brais, Bernard; Rouleau, Guy A

    2005-04-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder caused by a (GCG)n trinucleotide repeat expansion in the poly(A) binding protein nuclear-1 (PABPN1) gene, which in turn leads to an expanded polyalanine tract in the protein. We generated transgenic mice expressing either the wild type or the expanded form of human PABPN1, and transgenic animals with the expanded form showed clear signs of abnormal limb clasping, muscle weakness, coordination deficits, and peripheral nerves alterations. Analysis of mitotic and postmitotic tissues in those transgenic animals revealed ubiquitinated PABPN1-positive intranuclear inclusions (INIs) in neuronal cells. This latter observation led us to test and confirm the presence of similar INIs in postmortem brain sections from an OPMD patient. Our results indicate that expanded PABPN1, presumably via the toxic effects of its polyalanine tract, can lead to inclusion formation and neurodegeneration in both the mouse and the human.

  15. Sex and laterality differences in medial amygdala neurons and astrocytes of adult mice.

    Science.gov (United States)

    Pfau, Daniel R; Hobbs, Nicholas J; Breedlove, S Marc; Jordan, Cynthia L

    2016-08-15

    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/6(J) 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. J. Comp. Neurol. 524:2492-2502, 2016. © 2016 Wiley Periodicals, Inc. PMID:26780286

  16. Protective effect of Chufa Tubers (Cyperus esculentus on induction of sperm abnormalities In mice treated with lead acetate

    Directory of Open Access Journals (Sweden)

    Mahera N Al-Shaikh

    2013-06-01

    Full Text Available The effect of the extract of Cyperus esculentus on the changes in sperm count, activity, morphology and testicular histology induces by lead acetate was studied.18 adult male rats were randomly divided into three experimental groups. Group 1 (control were given clean drinking water and rat chow, group 2 were given intraperitoneally injection 8mg/kg body weight + water + rat chow. Group 3 were given intraperitoneally injection 8mg/kg body weight + water with extract of Cyperus esculentu+ rat cho . The results show a destruction in the testicular histology, decreased sperm count, activity and morphology of Group 2 administered with lead acetate only, which was statistically significant (P<0.05, and there was also a dose-dependent improvement in the parameters studied in the Group 3 given extract of Cyperus esculentus. This shows that the extract of Cyperus esculentus has a regenerative effect on the destroyed testicular histology induced by lead acetate.

  17. COX-2 disruption leads to increased central vasopressin stores and impaired urine concentrating ability in mice

    DEFF Research Database (Denmark)

    Norregaard, Rikke; Madsen, Kirsten Morill; Hansen, Pernille Bl;

    2011-01-01

    RNA and peptide level, AVP plasma concentration, and AVP-regulated renal transport protein abundances were measured. In male COX-2(-/-), basal urine output and water intake were elevated while urine osmolality was decreased compared with WT. Water deprivation resulted in lower urine osmolality, higher plasma......It was hypothesized that cyclooxygenase-2 (COX-2) activity promotes urine concentrating ability through stimulation of vasopressin (AVP) release after water deprivation (WD). COX-2-deficient (COX-2(-/-), C57BL/6) and wild-type (WT) mice were water deprived for 24 h, and water balance, central AVP m...... is not necessary for enhanced AVP expression and secretion in response to water deprivation. Renal medullary COX-2 activity negatively regulates AQP2 and -3. The urine concentrating defect in COX-2(-/-) is likely caused by developmental glomerular injury and not dysregulation of AVP or collecting duct aquaporins....

  18. Effects of blood lead levels on airflow limitations in Korean adults: Findings from the 5th KNHNES 2011

    International Nuclear Information System (INIS)

    This study aimed to examine whether blood levels of heavy metals, such as lead, mercury and cadmium, are related with pulmonary function in Korean adults. This investigation included 870 Korean adults (≥40 years) who received pulmonary function testing in the Korea National Health and Nutrition Examination Survey (KNHANES) V-2, 2011. Data of blood levels of heavy metals, pulmonary function tests and anthropometric measurements were acquired. Blood lead levels showed inverse correlations with the FEV1/FVC ratio before (r=−0.276, p<0.001) and after adjustment of multiple compounding factors (r=−0.115, p=0.001). A logistic multiple regression analysis revealed that blood lead levels were a significant influencing factor for the FEV1/FVC ratio (β=−0.017, p=0.001, adjusted R2=0.267). The odds ratios (ORs) for the FEV1/FVC ratio were significantly lower in the highest tertile group of the blood lead levels than in the lowest tertile group in Model 1 (OR=0.007, 95% CI=0.000−0.329) and Model 2 (OR=0.006, 95% CI=0.000−0.286). These findings imply that environmental exposure to lead might be an important factor that may cause airflow limitations in Korean adults. - Highlights: • Blood lead levels showed inverse correlations with the FEV1/FVC ratio. • Blood lead level was a significant influencing factor for the FEV1/FVC ratio. • ORs for FEV1/FVC were lower in the highest blood lead group than in the lowest group. • Environmental exposure to lead might be an important factor for airflow limitations

  19. Effects of blood lead levels on airflow limitations in Korean adults: Findings from the 5th KNHNES 2011

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Hye Kyung [Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul 120-749 (Korea, Republic of); Chang, Yoon Soo, E-mail: yschang@yuhs.ac [Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-749 (Korea, Republic of); Ahn, Chul Woo [Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul 120-749 (Korea, Republic of); Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-749 (Korea, Republic of)

    2015-01-15

    This study aimed to examine whether blood levels of heavy metals, such as lead, mercury and cadmium, are related with pulmonary function in Korean adults. This investigation included 870 Korean adults (≥40 years) who received pulmonary function testing in the Korea National Health and Nutrition Examination Survey (KNHANES) V-2, 2011. Data of blood levels of heavy metals, pulmonary function tests and anthropometric measurements were acquired. Blood lead levels showed inverse correlations with the FEV{sub 1}/FVC ratio before (r=−0.276, p<0.001) and after adjustment of multiple compounding factors (r=−0.115, p=0.001). A logistic multiple regression analysis revealed that blood lead levels were a significant influencing factor for the FEV{sub 1}/FVC ratio (β=−0.017, p=0.001, adjusted R{sup 2}=0.267). The odds ratios (ORs) for the FEV{sub 1}/FVC ratio were significantly lower in the highest tertile group of the blood lead levels than in the lowest tertile group in Model 1 (OR=0.007, 95% CI=0.000−0.329) and Model 2 (OR=0.006, 95% CI=0.000−0.286). These findings imply that environmental exposure to lead might be an important factor that may cause airflow limitations in Korean adults. - Highlights: • Blood lead levels showed inverse correlations with the FEV{sub 1}/FVC ratio. • Blood lead level was a significant influencing factor for the FEV{sub 1}/FVC ratio. • ORs for FEV{sub 1}/FVC were lower in the highest blood lead group than in the lowest group. • Environmental exposure to lead might be an important factor for airflow limitations.

  20. Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

    Science.gov (United States)

    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. PMID:25870909

  1. Uterine dysfunction in biglycan and decorin deficient mice leads to dystocia during parturition.

    Directory of Open Access Journals (Sweden)

    Zhiping Wu

    Full Text Available Cesarean birth rates are rising. Uterine dysfunction, the exact mechanism of which is unknown, is a common indication for Cesarean delivery. Biglycan and decorin are two small leucine-rich proteoglycans expressed in the extracellular matrix of reproductive tissues and muscle. Mice deficient in biglycan display a mild muscular dystrophy, and, along with mice deficient in decorin, are models of Ehlers-Danlos Syndrome, a connective tissue anomaly associated with uterine rupture. As a variant of Ehlers-Danlos Syndrome is caused by a genetic mutation resulting in abnormal biglycan and decorin secretion, we hypothesized that biglycan and decorin play a role in uterine function. Thus, we assessed wild-type, biglycan, decorin and double knockout pregnancies for timing of birth and uterine function. Uteri were harvested at embryonic days 12, 15 and 18. Nonpregnant uterine samples of the same genotypes were assessed for tissue failure rate and spontaneous and oxytocin-induced contractility. We discovered that biglycan/decorin mixed double-knockout dams displayed dystocia, were at increased risk of delayed labor onset, and showed increased tissue failure in a predominantly decorin-dependent manner. In vitro spontaneous uterine contractile amplitude and oxytocin-induced contractile force were decreased in all biglycan and decorin knockout genotypes compared to wild-type. Notably, we found no significant compensation between biglycan and decorin using quantitative real time PCR or immunohistochemistry. We conclude that the biglycan/decorin mixed double knockout mouse is a model of dystocia and delayed labor onset. Moreover, decorin is necessary for uterine function in a dose-dependent manner, while biglycan exhibits partial compensatory mechanisms in vivo. Thus, this model is poised for use as a model for testing novel targets for preventive or therapeutic manipulation of uterine dysfunction.

  2. Protective effects of vitamin E and Cornus mas fruit extract on methotrexate-induced cytotoxicity in sperms of adult mice

    OpenAIRE

    Zarei, Leila; Sadrkhanlou, Rajabali; Shahrooz, Rasoul; Malekinejad, Hassan; Eilkhanizadeh, Behroz; Ahmadi, Abbas

    2014-01-01

    This study was aimed to assess the protective effects of Cornus mas fruit extract (CMFE) and vitamin E (Vit E) on sperm quality parameters in the methotrexate (MTX)-treated mice. Forty-eight young adult male mice (8-12 weeks) were randomly divided into six groups including control and test groups. The control group received normal saline orally , and the test groups were treated MTX (20 mg kg-1, ip, once weekly), MTX + CMFE (250 mg kg-1), MTX + CMFE (500 mg kg-1), MTX + CMFE (1000 mg kg-1), a...

  3. Regional-specific effects of ovarian hormone loss on synaptic plasticity in adult human APOE targeted replacement mice.

    Directory of Open Access Journals (Sweden)

    Rebecca C Klein

    Full Text Available The human apolipoprotein ε4 allele (APOE4 has been implicated as one of the strongest genetic risk factors associated with Alzheimer's disease (AD and in influencing normal cognitive functioning. Previous studies have demonstrated that mice expressing human apoE4 display deficits in behavioral and neurophysiological outcomes compared to those with apoE3. Ovarian hormones have also been shown to be important in modulating synaptic processes underlying cognitive function, yet little is known about how their effects are influenced by apoE. In the current study, female adult human APOE targeted replacement (TR mice were utilized to examine the effects of human APOE genotype and long-term ovarian hormone loss on synaptic plasticity in limbic regions by measuring dendritic spine density and electrophysiological function. No significant genotype differences were observed on any outcomes within intact mice. However, there was a significant main effect of genotype on total spine density in apical dendrites in the hippocampus, with post-hoc t-tests revealing a significant reduction in spine density in apoE3 ovariectomized (OVX mice compared to sham operated mice. There was also a significant main effect of OVX on the magnitude of LTP, with post-hoc t-tests revealing a decrease in apoE3 OVX mice relative to sham. In contrast, apoE4 OVX mice showed increased synaptic activity relative to sham. In the lateral amygdala, there was a significant increase in total spine density in apoE4 OVX mice relative to sham. This increase in spine density was consistent with a significant increase in spontaneous excitatory activity in apoE4 OVX mice. These findings suggest that ovarian hormones differentially modulate synaptic integrity in an apoE-dependent manner within brain regions that are susceptible to neurophysiological dysfunction associated with AD.

  4. Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice

    Directory of Open Access Journals (Sweden)

    Klaus Fabel

    2009-11-01

    Full Text Available Voluntary physical exercise (wheel running, RUN and environmental enrichment (ENR both stimulate adult hippocampal neurogenesis but do so by different mechanisms. RUN induces precursor cell proliferation, whereas ENR exerts a survival-promoting effect on newborn cells. In addition, continued RUN prevented the physiologically occurring age-related decline in precursor cell in the dentate gyrus but did not lead to a corresponding increase in net neurogenesis. We hypothesized that in the absence of appropriate cognitive stimuli the potential for neurogenesis could not be realized but that an increased potential by proliferating precursor cells due to RUN could actually lead to more adult neurogenesis if an appropriate survival-promoting stimulus follows the exercise. We thus asked whether a sequential combination of RUN and ENR (RUNENR would show additive effects that are distinct from the application of either paradigm alone. We found that the effects of 10 days of RUN followed by 35 days of ENR were additive in that the combined stimulation yielded an approximately 30% greater increase in new neurons than either stimulus alone, which also increased neurogenesis. Surprisingly, this result indicates that although overall the amount of proliferating cells in the dentate gyrus is poorly predictive of net adult neurogenesis, an increased neurogenic potential nevertheless provides the basis for a greater efficiency of the same survival-promoting stimulus. We thus propose that physical activity can “prime” the neurogenic region of the dentate gyrus for increased neurogenesis in the case the animal is exposed to an additional cognitive stimulus, here represented by the enrichment paradigm.

  5. Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment--role of brain kynurenic acid.

    Science.gov (United States)

    Liu, Xi-Cong; Holtze, Maria; Powell, Susan B; Terrando, Niccolò; Larsson, Markus K; Persson, Anna; Olsson, Sara K; Orhan, Funda; Kegel, Magdalena; Asp, Linnea; Goiny, Michel; Schwieler, Lilly; Engberg, Göran; Karlsson, Håkan; Erhardt, Sophie

    2014-02-01

    Exposure to infections in early life is considered a risk-factor for developing schizophrenia. Recently we reported that a neonatal CNS infection with influenza A virus in mice resulted in a transient induction of the brain kynurenine pathway, and subsequent behavioral disturbances in immune-deficient adult mice. The aim of the present study was to investigate a potential role in this regard of kynurenic acid (KYNA), an endogenous antagonist at the glycine site of the N-methyl-D-aspartic acid (NMDA) receptor and at the cholinergic α7 nicotinic receptor. C57BL/6 mice were injected i.p. with neurotropic influenza A/WSN/33 virus (2400 plaque-forming units) at postnatal day (P) 3 or with L-kynurenine (2×200 mg/kg/day) at P7-16. In mice neonatally treated with L-kynurenine prepulse inhibition of the acoustic startle, anxiety, and learning and memory were also assessed. Neonatally infected mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as adults. Neonatally L-kynurenine treated mice showed enhanced sensitivity to D-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as well as mild impairments in prepulse inhibition and memory. Also, D-amphetamine tended to potentiate dopamine release in the striatum in kynurenine-treated mice. These long-lasting behavioral and neurochemical alterations suggest that the kynurenine pathway can link early-life infection with the development of neuropsychiatric disturbances in adulthood. PMID:24140727

  6. Zinc deficiency with reduced mastication impairs spatial memory in young adult mice.

    Science.gov (United States)

    Kida, Kumiko; Tsuji, Tadataka; Tanaka, Susumu; Kogo, Mikihiko

    2015-12-01

    Sufficient oral microelements such as zinc and fully chewing of foods are required to maintain cognitive function despite aging. No knowledge exists about the combination of factors such as zinc deficiency and reduced mastication on learning and memory. Here we show that tooth extraction only in 8-week-old mice did not change the density of glial fibrillary acidic protein-labeled astrocytes in the hippocampus or spatial memory parameters. However, tooth extraction followed by zinc deprivation strongly impaired spatial memory and led to an increase in astrocytic density in the hippocampal CA1 region. The impaired spatial performance in the zinc-deficient only (ZD) mice also coincided well with the increase in the astrocytic density in the hippocampal CA1 region. After switching both zinc-deficient groups to a normal diet with sufficient zinc, spatial memory recovered, and more time was spent in the quadrant with the goal in the probe test in the mice with tooth extraction followed by zinc deprivation (EZD) compared to the ZD mice. Interestingly, we found no differences in astrocytic density in the CA1 region among all groups at 22 weeks of age. Furthermore, the escape latency in a visible probe test at all times was longer in zinc-deficient groups than the others and demonstrated a negative correlation with body weight. No significant differences in escape latency were observed in the visible probe test among the ZD, EZD, and normal-fed control at 4 weeks (CT4w) groups in which body weight was standardized to that of the EZD group, or in the daily reduction in latency between the normal-fed control and CT4w groups. Our data showed that zinc-deficient feeding during a young age impairs spatial memory performance and leads to an increase in astrocytic density in the hippocampal CA1 region and that zinc-sufficient feeding is followed by recovery of the impaired spatial memory along with changes in astrocytic density. The combination of the two factors, zinc deficiency

  7. The protein kinase KIS impacts gene expression during development and fear conditioning in adult mice.

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    Valérie Manceau

    Full Text Available 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 U2AF(65-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.

  8. Mass mortality of adult male subantarctic fur seals: are alien mice the culprits?

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    P J Nico de Bruyn

    Full Text Available BACKGROUND: Mass mortalities of marine mammals due to infectious agents are increasingly reported. However, in contrast to previous die-offs, which were indiscriminate with respect to sex and age, here we report a land-based mass mortality of Subantarctic fur seals with apparent exclusivity to adult males. An infectious agent with a male-predilection is the most plausible explanation for this die-off. Although pathogens with gender-biased transmission and pathologies are unusual, rodents are known sources of male-biased infectious agents and the invasive Mus musculus house mouse, occurs in seal rookeries. METHODOLOGY/ PRINCIPAL FINDINGS: Molecular screening for male-biased pathogens in this potential rodent reservoir host revealed the absence of Cardiovirus and Leptospirosis genomes in heart and kidney samples, respectively, but identified a novel Streptococcus species with 30% prevalence in mouse kidneys. CONCLUSIONS/ SIGNIFICANCE: Inter-species transmission through environmental contamination with this novel bacterium, whose congenerics display male-bias and have links to infirmity in seals and terrestrial mammals (including humans, highlights the need to further evaluate disease risks posed by alien invasive mice to native species, on this and other islands.

  9. Adolescent, but not adult, binge ethanol exposure leads to persistent global reductions of choline acetyltransferase expressing neurons in brain.

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    Ryan P Vetreno

    Full Text Available During the adolescent transition from childhood to adulthood, notable maturational changes occur in brain neurotransmitter systems. The cholinergic system is composed of several distinct nuclei that exert neuromodulatory control over cognition, arousal, and reward. Binge drinking and alcohol abuse are common during this stage, which might alter the developmental trajectory of this system leading to long-term changes in adult neurobiology. In Experiment 1, adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P] 25 to P55 treatment led to persistent, global reductions of choline acetyltransferase (ChAT expression. Administration of the Toll-like receptor 4 agonist lipopolysaccharide to young adult rats (P70 produced a reduction in ChAT+IR that mimicked AIE. To determine if the binge ethanol-induced ChAT decline was unique to the adolescent, Experiment 2 examined ChAT+IR in the basal forebrain following adolescent (P28-P48 and adult (P70-P90 binge ethanol exposure. Twenty-five days later, ChAT expression was reduced in adolescent, but not adult, binge ethanol-exposed animals. In Experiment 3, expression of ChAT and vesicular acetylcholine transporter expression was found to be significantly reduced in the alcoholic basal forebrain relative to moderate drinking controls. Together, these data suggest that adolescent binge ethanol decreases adult ChAT expression, possibly through neuroimmune mechanisms, which might impact adult cognition, arousal, or reward sensitivity.

  10. Non-occupational lead and cadmium exposure of adult women in Bangkok, Thailand

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Z.-W.; Shimbo, S. [Department of Food and Nutrition, Kyoto Women' s University, Kyoto (Japan); Watanabe, T. [Miyagi University of Education, Sendai (Japan); Srianujata, S. [Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok (Thailand); Banjong, O.; Chitchumroonchokchai, C. [Institute of Nutrition, Mahidol University, Salaya, Phuthamonthon, Nakhonpathom (Thailand); Nakatsuka, H.; Matsuda-Inoguchi, N. [Miyagi University, Taiwa-cho (Japan); Higashikawa, K.; Ikeda, M. [Kyoto Industrial Health Association, Kyoto (Japan)

    1999-02-02

    This survey was conducted to examine the extent of the exposure of Bangkok citizens to lead (Pb) and cadmium (Cd), and to evaluate the role of rice as the source of these heavy metals. In practice, 52 non-smoking adult women in an institution in the vicinity of Bangkok, volunteered to offer blood, spot urine, boiled rice and 24-h total food duplicate samples. Samples were wet-ashed, and then analyzed for Pb and Cd by ICP-MS. Geometric means for the levels in blood (Pb-B and Cd-B) and urine (Pb-U and Cd-U as corrected for creatinine concentration), and also for dietary intake (Pb-F and Cd-F) were 32.3 {mu}g/l for Pb-B, 0.41 {mu}g/l for Cd-B, 2.06 {mu}g/g creatinine for Pb-U, 1.40 {mu}g/g creatinine for Cd-U, 15.1 {mu}g/day for Pb-F and 7.1 {mu}g/day for Cd-F. Rice contributed 30% and 4% of dietary Cd and Pb burden, respectively. When compared with the counterpart values obtained in four neighboring cities in southeast Asia (i.e. Nanning, Tainan, Manila, and Kuala Lumpur), dietary Pb burden of the women in Bangkok was middle in the order among the values for the five cities. Pb level in the blood was the lowest of the levels among the five cities and Pb in urine was also among the low group. This apparent discrepancy in the order between Pb-B (i.e. the fifth) and Pb-F (the third) might be attributable to recent reduction of Pb levels in the atmosphere in Bangkok. Regarding Cd exposure, Cd levels in blood and urine as well as dietary Cd burden of Bangkok women were either the lowest or the next lowest among those in the five cities. (Copyright (c) 1999 Elsevier Science B.V., Amsterdam. All rights reserved.)

  11. Neonatal Whisker Trimming Impairs Fear/Anxiety-Related Emotional Systems of the Amygdala and Social Behaviors in Adult Mice

    Science.gov (United States)

    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

  12. TNF-like weak inducer of apoptosis (TWEAK promotes beta cell neogenesis from pancreatic ductal epithelium in adult mice.

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    Fei Wu

    Full Text Available AIM/HYPOTHESIS: The adult mammalian pancreas has limited ability to regenerate in order to restore adequate insulin production from multipotent progenitors, the identity and function of which remain poorly understood. Here we test whether the TNF family member TWEAK (TNF-like weak inducer of apoptosis promotes β-cell neogenesis from proliferating pancreatic ductal epithelium in adult mice. METHODS: C57Bl/6J mice were treated with Fc-TWEAK and pancreas harvested at different time points for analysis by histology and immunohistochemistry. For lineage tracing, 4 week old double transgenic mice CAII-CreER(TM: R26R-eYFP were implanted with tamoxifen pellet, injected with Fc-TWEAK or control Ig twice weekly and analyzed at day 18 for TWEAK-induced duct cell progeny by costaining for insulin and YFP. The effect of TWEAK on pancreatic regeneration was determined by pancytokeratin immunostaining of paraffin embedded sections from wildtype and TWEAK receptor (Fn14 deficient mice after Px. RESULTS: TWEAK stimulates proliferation of ductal epithelial cells through its receptor Fn14, while it has no mitogenic effect on pancreatic α- or β-cells or acinar cells. Importantly, TWEAK induces transient expression of endogenous Ngn3, a master regulator of endocrine cell development, and induces focal ductal structures with characteristics of regeneration foci. In addition, we identify by lineage tracing TWEAK-induced pancreatic β-cells derived from pancreatic duct epithelial cells. Conversely, we show that Fn14 deficiency delays formation of regenerating foci after Px and limits their expansion. CONCLUSIONS/INTERPRETATION: We conclude that TWEAK is a novel factor mediating pancreatic β-cell neogenesis from ductal epithelium in normal adult mice.

  13. Neonatal Whisker Trimming Impairs Fear/Anxiety-Related Emotional Systems of the Amygdala and Social Behaviors in Adult Mice.

    Directory of Open Access Journals (Sweden)

    Hitomi Soumiya

    Full Text Available 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.

  14. Blood Lead Concentration Is Not Altered by High Dose Vitamin D Supplementation in Children and Young Adults with HIV

    Science.gov (United States)

    Groleau, Veronique; Herold, Rachel A; Schall, Joan I; Wagner, Julia L; Dougherty, Kelly A; Zemel, Babette S; Rutstein, Richard M; Stallings, Virginia A

    2014-01-01

    OBJECTIVES Optimal vitamin D status is known to have beneficial health effects and vitamin D supplements are commonly used. It has been suggested that vitamin D supplementation may increase blood lead in children and adults with previous lead exposure. The objective was to determine the safety regarding lead toxicity during 12 weeks of high dose vitamin D3 supplementation in children and young adults with HIV. METHODS Subjects with HIV (age 8 to 24 yrs) were randomized to vitamin D3 supplementation of 4000 IU/day or 7000 IU/day and followed at 6 and 12 weeks for changes in 25D and whole blood lead concentration. This was a secondary analysis of a larger study of vitamin D3 supplementation in children and adolescents with HIV. RESULTS In 44 subjects (75% African American), the baseline mean ± SD serum 25D was 48.3 ± 18.6 nmol/L. 50% of subjects had baseline serum 25D 5.0 μg/dL at baseline or during subsequent visits. Whole blood lead and 25D were not correlated at baseline, and were negatively correlated after 12 weeks of supplementation (p= 0.014). Whole blood lead did not differ between those receiving 4000 IU versus 7000 IU of vitamin D3. CONCLUSION High dose vitamin D3 supplementation and the concomitant increased serum 25D did not result in increased whole blood lead concentration in this sample of children and young adults living in a northeastern urban city. PMID:23059649

  15. Exercise training and antioxidant supplementation independently improve cognitive function in adult male and female GFAP-APOE mice

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    Kiran Chaudhari

    2014-09-01

    Conclusion: Exercise was the most effective treatment at improving cognitive function in both genotypes and sex, while antioxidants seemed to be effective only in the APOE4. In young adult mice only non-spatial learning and memory were improved. The combination of the two treatments did not yield further improvement in cognition, and there was no antagonistic action of the antioxidant supplementation on the beneficial effects of exercise.

  16. Activity of Artemether and Mefloquine against Juvenile and Adult Schistosoma mansoni in Athymic and Immunocompetent NMRI Mice

    OpenAIRE

    Keiser, Jennifer; Vargas, Mireille; Doenhoff, Michael J.

    2010-01-01

    Immune effector mechanisms can enhance the activity of antischistosomal drugs. We examined the in vivo effect of single oral doses of the antimalarials artemether (400 mg/kg) and mefloquine (200 mg/kg), recently described to have promising antischistosomal properties, against juvenile and adult Schistosoma mansoni in T cell-deficient and in comparably infected age- and sex-matched immunologically intact control mice. Artemether and mefloquine are equally effective in athymic and immunocompete...

  17. Functional Analysis of Neurovascular Adaptations to Exercise in the Dentate Gyrus of Young Adult Mice Associated With Cognitive Gain

    OpenAIRE

    Clark, Peter J.; Brzezinska, Weronika J.; Puchalski, Emily K.; Krone, David A.; Rhodes, Justin S.

    2009-01-01

    The discovery that aerobic exercise increases adult hippocampal neurogenesis and can enhance cognitive performance holds promise as a model for regenerative medicine. This study adds two new pieces of information to the rapidly growing field. First, we tested whether exercise increases vascular density in the granular layer of the dentate gyrus, whole hippocampus, and striatum in C57BL/6J mice known to display procognitive effects of exercise. Second, we determined the extent to which new neu...

  18. Monoacylglycerol lipase inhibition by organophosphorus compounds leads to elevation of brain 2-arachidonoylglycerol and the associated hypomotility in mice

    International Nuclear Information System (INIS)

    Three components of the cannabinoid system are sensitive to selected organophosphorus (OP) compounds: monoacylglycerol (MAG) lipase that hydrolyzes the major endogenous agonist 2-arachidonoylglycerol (2-AG); fatty acid amide hydrolase (FAAH) that cleaves the agonist anandamide present in smaller amounts; the CB1 receptor itself. This investigation considers which component of the cannabinoid system is the most likely contributor to OP-induced hypomotility in mice. Structure-activity studies by our laboratory and others rule against major involvement of a direct toxicant-CB1 receptor interaction for selected OPs. Attention was therefore focused on the OP sensitivities of MAG lipase and FAAH, assaying 19 structurally diverse OP chemicals (pesticides, their metabolites and designer compounds) for in vitro inhibition of both enzymes. Remarkably high potency and low selectivity is observed with three O-alkyl (C1, C2, C3) alkylphosphonofluoridates (C8, C12) (IC50 0.60-3.0 nM), five S-alkyl (C5, C7, C9) and alkyl (C1, C12) benzodioxaphosphorin oxides (IC50 0.15-5.7 nM) and one OP insecticide metabolite (chlorpyrifos oxon, IC50 34-40 nM). In ip-treated mice, the OPs at 1-30 mg/kg more potently inhibit brain FAAH than MAG lipase, but FAAH inhibition is not correlated with hypomotility. However, the alkylphosphonofluoridate-treated mice show dose-dependent increases in severity of hypomotility, inhibition of MAG lipase activity and elevation of 2-AG. Moderate to severe hypomotility is accompanied by 64 to 86% MAG lipase inhibition and about 6-fold elevation of brain 2-AG level. It therefore appears that OP-induced MAG lipase inhibition leads to elevated 2-AG and the associated hypomotility

  19. Effect of Infection Duration on Habitat Selection and Morphology of Adult Echinostoma caproni (Digenea: Echinostomatidae) in ICR Mice.

    Science.gov (United States)

    Platt, Thomas R; Zelmer, Derek A

    2016-02-01

    The course of infection of Echinostoma caproni was followed in female ICR mice, a permissive laboratory host, from infection to natural termination. Twenty-one mice were infected with 20 metacercariae via oral intubation and housed 3 per cage. Three mice from a randomly selected cage were necropsied at 1 mo intervals. A second group of 15 mice was infected approximately 1 yr later to replace mice negative at necropsy in the first group. Mice in the second group were examined weekly for the presence of eggs in the feces. Mice negative for eggs on consecutive days were killed and necropsied. The location of individual worms and worm clusters were located in 20 segments of the small intestine. Adult worms were killed and fixed in hot formalin, stained, and prepared as whole mounts. Standard measurements were taken using a compound microscope fitted with an ocular micrometer. The infection spontaneously resolved in 10 mice from 7 to 32 wk PI, indicating the host response is highly variable and extending the maximum recorded length of E. caproni infections in ICR mice to 31 wk. A moribund worm was found in the feces of an animal that continued to pass eggs for an additional 2 mo indicating individual variation in worm responses. Worms located preferentially in the ileum (segments 11-13) during the first 3 mo of the infection but shifted to the jejunum (segments 8-9) during weeks 4-6. Morphologically, worms of different ages clustered together in multivariate space, with substantial overlap between the 3- and 4-mo-old infrapopulations and between the 5- and 6-mo-old infrapopulations. Muscular structures increased in size throughout the experiment, while the gonads increased in size for the first 3 mo and then declined during the last 3 mo. The relationship between E. caproni and ICR mice is more nuanced than previously reported. The reduction in gonad size and the shift from the ileum to the jejunum in the last 3 mo likely are related. These changes might be attributable

  20. Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice.

    Science.gov (United States)

    Li, Cui; Xu, Dan; Ye, Qing; Hong, Shuai; Jiang, Yisheng; Liu, Xinyi; Zhang, Nana; Shi, Lei; Qin, Cheng-Feng; Xu, Zhiheng

    2016-07-01

    The link between Zika virus (ZIKV) infection and microcephaly has raised urgent global alarm. The historical African ZIKV MR766 was recently shown to infect cultured human neural precursor cells (NPCs), but unlike the contemporary ZIKV strains, it is not believed to cause microcephaly. Here we investigated whether the Asian ZIKV strain SZ01 could infect NPCs in vivo and affect brain development. We found that SZ01 replicates efficiently in embryonic mouse brain by directly targeting different neuronal linages. ZIKV infection leads to cell-cycle arrest, apoptosis, and inhibition of NPC differentiation, resulting in cortical thinning and microcephaly. Global gene expression analysis of infected brains reveals upregulation of candidate flavirus entry receptors and dysregulation of genes associated with immune response, apoptosis, and microcephaly. Our model provides evidence for a direct link between Zika virus infection and microcephaly, with potential for further exploration of the underlying mechanisms and management of ZIKV-related pathological effects during brain development.

  1. Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice.

    Science.gov (United States)

    Li, Cui; Xu, Dan; Ye, Qing; Hong, Shuai; Jiang, Yisheng; Liu, Xinyi; Zhang, Nana; Shi, Lei; Qin, Cheng-Feng; Xu, Zhiheng

    2016-07-01

    The link between Zika virus (ZIKV) infection and microcephaly has raised urgent global alarm. The historical African ZIKV MR766 was recently shown to infect cultured human neural precursor cells (NPCs), but unlike the contemporary ZIKV strains, it is not believed to cause microcephaly. Here we investigated whether the Asian ZIKV strain SZ01 could infect NPCs in vivo and affect brain development. We found that SZ01 replicates efficiently in embryonic mouse brain by directly targeting different neuronal linages. ZIKV infection leads to cell-cycle arrest, apoptosis, and inhibition of NPC differentiation, resulting in cortical thinning and microcephaly. Global gene expression analysis of infected brains reveals upregulation of candidate flavirus entry receptors and dysregulation of genes associated with immune response, apoptosis, and microcephaly. Our model provides evidence for a direct link between Zika virus infection and microcephaly, with potential for further exploration of the underlying mechanisms and management of ZIKV-related pathological effects during brain development. PMID:27179424

  2. Metabolism of meso-2,3-dimercaptosuccinic acid in lead-poisoned children and normal adults.

    OpenAIRE

    P. ASIEDU; Moulton, T; Blum, C B; Roldan, E.; Lolacono, N J; Graziano, J H

    1995-01-01

    Meso-2,3-dimercaptosuccinic acid (DMSA, or succimer) is an oral chelating agent for heavy-metal poisoning. While studying the urinary elimination of unaltered DMSA, altered DMSA (i.e., its mixed disulfides), and lead in children with lead poisoning, we observed a pattern of urinary drug elimination after meals suggestive of enterohepatic circulation. The excretion of lead in urine patterned the elimination of altered DMSA rather than the parent molecule. In addition, the half-life of eliminat...

  3. Learning and Leading for Growth: Preparing Leaders to Support Adult Development in Our Schools

    Science.gov (United States)

    Drago-Severson, Eleanor; Blum-Destefano, Jessica; Asghar, Anila

    2013-01-01

    Currently, scholars and practitioners seek to improve leadership programs so that educational leaders can more effectively support adult development--especially since it is connected to improved student achievement. Interview findings presented here stem from a larger mixed methods study. This research investigated how a university course on…

  4. Cerebral cell renewal in adult mice controls the onset of obesity.

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    Alexandra Gouazé

    Full Text Available 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.

  5. Genetic pharmacotherapy as an early CNS drug development strategy: testing glutaminase inhibition for schizophrenia treatment in adult mice

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    Susana eMingote

    2016-01-01

    Full Text Available 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 test the therapeutic potential of glutaminase inhibition. We specifically asked whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG ERT2 cre/+ 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

  6. Recql4 haploinsufficiency in mice leads to defects in osteoblast progenitors: Implications for low bone mass phenotype

    International Nuclear Information System (INIS)

    The cellular and molecular mechanisms that underlie skeletal abnormalities in defective Recql4-related syndromes are poorly understood. Our objective in this study was to explore the function of Recql4 in osteoblast biology both in vitro and in vivo. Immunohistochemistry on adult mouse bone showed Recql4 protein localization in active osteoblasts around growth plate, but not in fully differentiated osteocytes. Consistent with this finding, Recql4 gene expression was high in proliferating mouse osteoblastic MC3T3.E1 cells and decreased as cells progressively lost their proliferation activity during differentiation. Recql4 overexpression in osteoblastic cells exhibited higher proliferation activity, while its depletion impeded cell growth. In addition, bone marrow stromal cells from male Recql4+/- mice had fewer progenitor cells, including osteoprogenitors, indicated by reduced total fibroblast colony forming units (CFU-f) and alkaline phosphatase-positive CFU-f colonies concomitant with reduced bone mass. These findings provide evidence that Recql4 functions as a regulatory protein during osteoprogenitor proliferation, a critical cellular event during skeleton development

  7. Post-training, intrahippocampal HDAC inhibition differentially impacts neural circuits underlying spatial memory in adult and aged mice.

    Science.gov (United States)

    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.

  8. Effect of acute lead poisoning on pathological damage in mice testis%急性铅中毒对小鼠睾丸病理损伤研究

    Institute of Scientific and Technical Information of China (English)

    孙相和; 孔令芸; 李冲; 陈玲丽; 宁红梅; 葛亚明

    2014-01-01

    为了研究急性铅中毒对小鼠睾丸病理变化的影响,通过对小鼠饲喂含有醋酸铅的去离子水建立铅负荷小鼠模型.处理10 d后取材,分析体质量、睾丸指数和睾丸病理剖检变化.结果显示:与对照组相比,铅中毒组小鼠体质量无明显变化,睾丸指数降低,且差异显著(P<0.05);小鼠睾丸中支持细胞、生精细胞和间质细胞数量减少.铅对小鼠睾丸具有显著损害作用,从而影响小鼠的生殖健康.%To investigate the effect of acute lead poisoning on pathological changes in mice testis,mice were orally administered with lead acetate for 10 days to establish a lead poisoning mice model.After 10 days,some indexes,such as body weight,testis index,necropsy and histopathology,were analyzed.The results showed that the body weight change of mice was not relevant significantly to the dosage of lead acetate.Compared with the control group,the difference of testis relative index in dosage group was significant (P<0.05).The amount of sertoli cells,germ cells and Leydig’s cells in mice tesis was decreased.The results suggested that lead could damage mice testis significantly and then affect the reproductive health of mice.

  9. ALTERED HIPPOCAMPAL NEUROGENESIS AND AMYGDALAR NEURONAL ACTIVITY IN ADULT MICE WITH REPEATED EXPERIENCE OF AGGRESSION

    Directory of Open Access Journals (Sweden)

    Dmitriy eSmagin

    2015-12-01

    Full Text Available The repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos positive cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights.

  10. Environmental Enrichment Reduces the Likelihood of Alopecia in Adult C57BL/6J Mice

    OpenAIRE

    Bechard, Allison; Meagher, Rebecca; Mason, Georgia

    2011-01-01

    Barbering (incessant grooming) is an abnormal behavior causing alopecia and commonly affects various strains of laboratory mice, including C57BL/6J. Barbering-induced alopecia is a potential symptom of brain impairment and can indicate a stressful environment. We compared alopecia prevalence and severity in mice housed in enriched or standard cages. Providing an enriched environment delayed the onset and reduced the prevalence and overall severity of alopecia in C57BL/6J mice. Husbandry metho...

  11. Current sources of lead exposure and their relative contributions to the blood lead levels in the general adult population of Northern France: The IMEPOGE Study, 2008-2010.

    Science.gov (United States)

    Tagne-Fotso, Romuald; Leroyer, Ariane; Howsam, Mike; Dehon, Betty; Richeval, Camille; Nisse, Catherine

    2016-01-01

    There is justification for limiting lead (Pb) exposure as much as possible, given its impact on health at low concentrations. Consequently, the aim of this study was to measure blood lead levels (BLL) and examine exposure factors related to BLL variations in the general adult population of northern France, a current and past industrial area. Two thousand inhabitants of northern France, aged between 20 and 59 years, were recruited using the quota method with caution. Blood lead levels were quantified by inductively coupled plasma-mass spectroscopy (ICP-MS), and variation factors were studied separately in men and women using multivariate stepwise linear and logistic regression models. The geometric mean of the BLL was 18.8 μg/L (95% confidence interval [CI]: 18.3-19.3). Occupational factors affected BLL only in men and represented 14% of total explained variance of BLL. External occupational factors significantly increasing mean levels of BLL were tobacco, consumption of some beverages (wine, coffee, tea, and/or tap water), raw vegetables, housing characteristics (built prior to 1948, Pb piping in the home) and do-it-yourself or leisure activities (paint stripping or rifle shooting). Consumption habits accounted together for 25% and 18% of the total explained variance, respectively, in men and women. Industrial environment did not significantly contribute to BLL variations. Blood lead levels observed in the general population of this industrial part of France did not appear to be excessively elevated compared to values found internationally. Nonetheless, these BLL remain a public health issue in regard to nonthreshold toxicity attributed to Pb. PMID:27074096

  12. Neonatal Bacillus Calmette-Guérin vaccination alleviates lipopolysaccharide-induced neurobehavioral impairments and neuroinflammation in adult mice.

    Science.gov (United States)

    Yang, Junhua; Qi, Fangfang; Yao, Zhibin

    2016-08-01

    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

  13. Expression of Autoactivated Stromelysin-1 in Mammary Glands of Transgenic Mice Leads to a Reactive Stroma During Early Development

    Energy Technology Data Exchange (ETDEWEB)

    Thomasset, N.; Lochter, A.; Sympson, C.J.; Lund, L.R.; Williams, D.R.; Behrendtsen, O.; Werb, Z.; Bissell, M.J.

    1998-04-24

    cells produce fibronectin, collagens, proteoglycans, and some components of the BM, as well as a number of proteinases that can effectively degrade BM constituents. Stromal and epithelial cells of the mammary gland interact to regulate BM synthesis and degradation and, thus, mammary function. Matrix metalloproteinases (MMPs) are extracellular matrix (ECM)-degrading enzymes involved in mammary gland morphogenesis and involution. During late pregnancy and lactation, when the gland becomes fully functional, the expression of MMPs is low however, during involution, when the gland loses function and is remodeled, synthesis of ECM-degrading proteinases increases dramatically.11 Disturbance of the balance between MMPs and MMP inhibitors leads to either unscheduled involution or prolonged lactation. Mammary glands of virgin mice expressing an autoactivating stromelysin-1 (SL-1) transgene display supernumerary branches and precocious alveolar development, accompanied by the synthesis of {beta}-casein at levels found normally only during early pregnancy. During late pregnancy, increased expression of the SL-1 transgene leads to a reduction in expression of pregnancy-specific genes. Later in life, some SL-1 transgenic mice develop hyperplastic, dysplastic, and ductal carcinoma in situ-like lesions, as well as malignant tumors. Little is known about the sequence of changes that occurs before formation of an overt reactive stroma in breast cancer. In the present study, we address the question of whether and how the stromal compartment is altered as a consequence of inappropriate SL-1 transgene expression in the epithelium.

  14. Frequency of Teriparatide Administration Affects the Histological Pattern of Bone Formation in Young Adult Male Mice.

    Science.gov (United States)

    Yamamoto, Tomomaya; Hasegawa, Tomoka; Sasaki, Muneteru; Hongo, Hiromi; Tsuboi, Kanako; Shimizu, Tomohiro; Ota, Masahiro; Haraguchi, Mai; Takahata, Masahiko; Oda, Kimimitsu; Luiz de Freitas, Paulo Henrique; Takakura, Aya; Takao-Kawabata, Ryoko; Isogai, Yukihiro; Amizuka, Norio

    2016-07-01

    Evidence supports that daily and once-weekly administration of teriparatide, human (h)PTH(1-34), enhance bone mass in osteoporotic patients. However, it is uncertain whether different frequencies of hPTH(1-34) administration would induce bone formation similarly in terms of quantity and quality. To investigate that issue, mice were subjected to different frequencies of PTH administration, and their bones were histologically examined. Frequencies of administration were 1 time/2 days, 1 time a day, and 2 and 4 times a day. Mice were allocated to either to control or to 3 different dosing regimens: 80 μg/kg of hPTH(1-34) per injection (80 μg/kg per dose), 80 μg/kg of hPTH(1-34) per day (80 μg/kg · d), or 20 μg/kg of hPTH(1-34) per day (20 μg/kg · d). With the regimens of 80 μg/kg per dose and 80 μg/kg · d, high-frequency hPTH(1-34) administration increased metaphyseal trabecular number. However, 4 doses per day induced the formation of thin trabeculae, whereas the daily PTH regimen resulted in thicker trabeculae. A similar pattern was observed with the lower daily hPTH(1-34) dose (20 μg/kg · d): more frequent PTH administration led to the formation of thin trabeculae, showing a thick preosteoblastic cell layer, several osteoclasts, and scalloped cement lines that indicated accelerated bone remodeling. On the other hand, low-frequency PTH administration induced new bone with mature osteoblasts lying on mildly convex surfaces representative of arrest lines, which suggests minimodeling-based bone formation. Thus, high-frequency PTH administration seems to increase bone mass rapidly by forming thin trabeculae through accelerated bone remodeling. Alternatively, low-frequency PTH administration leads to the formation of thicker trabeculae through bone remodeling and minimodeling. PMID:27227535

  15. Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress.

    Science.gov (United States)

    Arp, J Marit; Ter Horst, Judith P; Loi, Manila; den Blaauwen, Jan; Bangert, Eline; Fernández, Guillén; Joëls, Marian; Oitzl, Melly S; Krugers, Harm J

    2016-09-01

    Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated (i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal day 2 to 9 - affects conditioned fear in adult mice and (ii) whether these effects can be prevented by blocking glucocorticoid receptors (GRs) at adolescent age. In adult male and female mice, ELS did not affect freezing behavior to the first tone 24h after training in an auditory fear-conditioning paradigm. Exposure to repeated tones 24h after training also resulted in comparable freezing behavior in ELS and control mice, both in males and females. However, male (but not female) ELS compared to control mice showed significantly more freezing behavior between the tone-exposures, i.e. during the cue-off periods. Intraperitoneal administration of the GR antagonist RU38486 during adolescence (on postnatal days 28-30) fully prevented enhanced freezing behavior during the cue-off period in adult ELS males. Western blot analysis revealed no effects of ELS on hippocampal expression of glucocorticoid receptors, neither at postnatal day 28 nor at adult age, when mice were behaviorally tested. We conclude that ELS enhances freezing behavior in adult mice in a potentially safe context after cue-exposure, which can be normalized by brief blockade of glucocorticoid receptors during the critical developmental window of adolescence. PMID:27246249

  16. Circadian cycle-dependent EEG biomarkers of pathogenicity in adult mice following prenatal exposure to in utero inflammation.

    Science.gov (United States)

    Adler, D A; Ammanuel, S; Lei, J; Dada, T; Borbiev, T; Johnston, M V; Kadam, S D; Burd, I

    2014-09-01

    Intrauterine infection or inflammation in preterm neonates is a known risk for adverse neurological outcomes, including cognitive, motor and behavioral disabilities. Our previous data suggest that there is acute fetal brain inflammation in a mouse model of intrauterine exposure to lipopolysaccharides (LPS). We hypothesized that the in utero inflammation induced by LPS produces long-term electroencephalogram (EEG) biomarkers of neurodegeneration in the exposed mice that could be determined by using continuous quantitative video/EEG/electromyogram (EMG) analyses. A single LPS injection at E17 was performed in pregnant CD1 dams. Control dams were injected with same volumes of saline (LPS n=10, Control n=8). At postnatal age of P90-100, 24-h synchronous video/EEG/EMG recordings were done using a tethered recording system and implanted subdural electrodes. Behavioral state scoring was performed blind to treatment group, on each 10s EEG epoch using synchronous video, EMG and EEG trace signatures to generate individual hypnograms. Automated EEG power spectrums were analyzed for delta and theta-beta power ratios during wake vs. sleep cycles. Both control and LPS hypnograms showed an ultradian wake/sleep cycling. Since rodents are nocturnal animals, control mice showed the expected diurnal variation with significantly longer time spent in wake states during the dark cycle phase. In contrast, the LPS-treated mice lost this circadian rhythm. Sleep microstructure also showed significant alteration in the LPS mice specifically during the dark cycle, caused by significantly longer average non-rapid eye movement (NREM) cycle durations. No significance was found between treatment groups for the delta power data; however, significant activity-dependent changes in theta-beta power ratios seen in controls were absent in the LPS-exposed mice. In conclusion, exposure to in utero inflammation in CD1 mice resulted in significantly altered sleep architecture as adults that were circadian

  17. Effect of insulin supplementation on in vitro maturation of pre-antral follicles from adult and pre-pubertal mice.

    Science.gov (United States)

    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. PMID:26956357

  18. Chronic early postnatal scream sound stress induces learning deficits and NMDA receptor changes in the hippocampus of adult mice.

    Science.gov (United States)

    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. PMID:27015584

  19. CT-GalNAc transferase overexpression in adult mice is associated with extrasynaptic utrophin in skeletal muscle fibres.

    Science.gov (United States)

    Durko, Margaret; Allen, Carol; Nalbantoglu, Josephine; Karpati, George

    2010-09-01

    Duchenne muscular dystrophy is a genetic muscle disease characterized by the absence of sub-sarcolemmal dystrophin that results in muscle fibre necrosis, progressive muscle wasting and is fatal. Numerous experimental studies with dystrophin-deficient mdx mice, an animal model for the disease, have demonstrated that extrasynaptic upregulation of utrophin, an analogue of dystrophin, can prevent muscle fibre deterioration and reduce or negate the dystrophic phenotype. A different approach for ectopic expression of utrophin relies on augmentation of CT-GalNAc transferase in muscle fibre. We investigated whether CT-GalNAc transferase overexpression in adult mice influence appearance of utrophin in the extrasynaptic sarcolemma. After electrotransfer of plasmid DNA carrying an expression cassette of CT-GalNAc transferase into tibialis anterior muscle of wild type and dystrophic mice, muscle sections were examined by immunofluorescence. CT-GalNAc transgene expression augmented sarcolemmal carbohydrate glycosylation and was accompanied by extrasynaptic utrophin. A 6-week time course study showed that the highest efficiency of utrophin overexpression in a plasmid harboured muscle fibres was 32.2% in CD-1 and 52% in mdx mice, 2 and 4 weeks after CT-GalNAc gene transfer, respectively. The study provides evidence that postnatal CT-GalNAc transferase overexpression stimulates utrophin upregulation that is inherently beneficial for muscle structure and strength restoration. Thus CT-GalNAc may provide an important therapeutic molecule for treatment of dystrophin deficiency in Duchenne muscular dystrophy.

  20. Red Palm Oil Attenuates Lead Acetate Induced Testicular Damage in Adult Male Sprague-Dawley Rats

    Directory of Open Access Journals (Sweden)

    A. I. Jegede

    2015-01-01

    Full Text Available To study the protective effect of Red Palm Oil (RPO on testicular damage induced by administration of lead acetate on male Sprague-Dawley rats, 28 rats divided into four groups of 7 animals each were used. They were administered orally with RPO (1 mL and 2 mL and lead acetate (i.p. 6 mg/kg body weight/day, respectively. Treatment was conducted for 8 weeks, and 24 hrs after the last treatment the rats were sacrificed using cervical dislocation. Sperms collected from epididymis were used for seminal fluid analyses; while the testes sample was used for ROS and oxidative enzyme activities assessment. Statistical analysis was carried out using GraphPad Prism 5.02 statistical analysis package. Administration of lead acetate increased generation of reactive oxygen species (ROS significantly (p<0.05 as evidenced by the elevated value of H2O2 and LPO and decreased GSH level. Also there was reduced epididymal sperm count, poor grade of sperm motility, and lower percentage of normal sperm morphology significantly. Coadministration with RPO, however, has a protective effect against lead toxicity by decreasing H2O2 production, increased GSH level, and increased sperm qualities especially. This shows that RPO has a potential to attenuate the toxic effect of lead on testicular cells preventing possible resultant male infertility.

  1. Red Palm Oil Attenuates Lead Acetate Induced Testicular Damage in Adult Male Sprague-Dawley Rats

    Science.gov (United States)

    Jegede, A. I.; Offor, U.; Azu, O. O.; Akinloye, O.

    2015-01-01

    To study the protective effect of Red Palm Oil (RPO) on testicular damage induced by administration of lead acetate on male Sprague-Dawley rats, 28 rats divided into four groups of 7 animals each were used. They were administered orally with RPO (1 mL and 2 mL) and lead acetate (i.p.) 6 mg/kg body weight/day, respectively. Treatment was conducted for 8 weeks, and 24 hrs after the last treatment the rats were sacrificed using cervical dislocation. Sperms collected from epididymis were used for seminal fluid analyses; while the testes sample was used for ROS and oxidative enzyme activities assessment. Statistical analysis was carried out using GraphPad Prism 5.02 statistical analysis package. Administration of lead acetate increased generation of reactive oxygen species (ROS) significantly (p < 0.05) as evidenced by the elevated value of H2O2 and LPO and decreased GSH level. Also there was reduced epididymal sperm count, poor grade of sperm motility, and lower percentage of normal sperm morphology significantly. Coadministration with RPO, however, has a protective effect against lead toxicity by decreasing H2O2 production, increased GSH level, and increased sperm qualities especially. This shows that RPO has a potential to attenuate the toxic effect of lead on testicular cells preventing possible resultant male infertility. PMID:26516332

  2. Effects of spaced learning in the water maze on development of dentate granule cells generated in adult mice.

    Science.gov (United States)

    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.

  3. Unusual Repertoire of Vocalizations in Adult BTBR T+tf/J Mice During Three Types of Social Encounters

    Science.gov (United States)

    Scattoni, Maria Luisa; Ricceri, Laura; Crawley, Jacqueline N.

    2010-01-01

    BTBR T+tf/J (BTBR) is an inbred mouse strain that displays social deficits and repetitive behaviors analogous to the first and third diagnostic symptoms of autism. We previously reported an unusual pattern of ultrasonic vocalizations in BTBR pups that may represent a behavioral homologue to the second diagnostic symptom of autism, impaired communication. The present study investigated the social and vocal repertoire in adult BTBR mice, to evaluate the role of ultrasonic vocalizations in multiple social situations at the adult stage of development. Three different social contexts were considered: male-female, male-male (resident-intruder) and female-female interactions. Behavioral responses and ultrasonic vocalizations were recorded for BTBR and for the highly social control strain C57BL/6J (B6). No episodes of overt fighting or mating were observed during the short durations of the three different experimental encounters. BTBR displayed lower levels of vocalizations and social investigation in all three social contexts as compared to B6. In addition, the correlation analyses between social investigation and USVs emission rate revealed that in B6 mice the two variables were positively correlated in all the three different social settings, whereas in BTBR mice the positive correlation was significant only in the male-female interactions. These findings strongly support the value of simultaneously recording two aspects of the mouse social repertoire, social motivation and bioacoustic communication. Moreover, our findings in adults are consistent with previous results in pups, showing an unusual vocal repertoire in BTBR as compared to B6. PMID:20618443

  4. Pubertal exposure to di-(2-ethylhexyl) phthalate influences social behavior and dopamine receptor D2 of adult female mice.

    Science.gov (United States)

    Wang, Ran; Xu, Xiaohong; Zhu, Qingjie

    2016-02-01

    DEHP, one of the most commonly phthalates used in plastics and many other products, is an environmental endocrine disruptor (EED). Puberty is another critical period for the brain development besides the neonatal period and is sensitive to EEDs. Social behavior is organized during puberty, so the present study is to investigate whether pubertal exposure to DEHP influenced social behavior of adult female mice. The results showed that pubertal exposure to DEHP for 2 weeks did not change the serum level of 17β-estradiol and the weight of uterus of adult females, but decreased the number of grid crossings and the frequency of rearing, and increased grooming in open field. DEHP reduced the open arm entries and the time spent in open arms in the elevated plus maze. DEHP reduced mutual sniffing and grooming between unfamiliar conspecifics in social play task and reduced the right chamber (containing unfamiliar female mouse) entries and the frequency of sniffing unfamiliar female mouse. DEHP at 1 mg kg(-1) d(-1) reduced the time spent in right chamber. Furthermore, Western blot analyses showed that DEHP decreased the levels of estrogen receptor β (ERβ), dopamine receptor D2, and the phosphorylation of ERKs in striatum. These results suggest that pubertal exposure to DEHP impaired social investigation and sociability and influenced anxiety-like state of adult female mice. The decreased activity of ERK1/2, and the down-regulated D2 and ERβ in striatum may be associated with the DEHP-induced changes of emotional and social behavior in mice. PMID:26524146

  5. Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21

    OpenAIRE

    Lees, Emma K.; Król, Elżbieta; Grant, Louise; Shearer, Kirsty; Wyse, Cathy; Moncur, Eleanor; Bykowska, Aleksandra S; Mody, Nimesh; Gettys, Thomas W.; Delibegovic, Mirela

    2014-01-01

    Methionine restriction (MR) decreases body weight and adiposity and improves glucose homeostasis in rodents. Similar to caloric restriction, MR extends lifespan, but is accompanied by increased food intake and energy expenditure. Most studies have examined MR in young animals; therefore, the aim of this study was to investigate the ability of MR to reverse age-induced obesity and insulin resistance in adult animals. Male C57BL/6J mice aged 2 and 12 months old were fed MR (0.172% methionine) o...

  6. Intrahepatic transplantation of CD34+ cord blood stem cells into newborn and adult NOD/SCID mice induce differential organ engraftment.

    Science.gov (United States)

    Wulf-Goldenberg, Annika; Keil, Marlen; Fichtner, Iduna; Eckert, Klaus

    2012-04-01

    In vivo studies concerning the function of human hematopoietic stem cells (HSC) are limited by relatively low levels of engraftment and the failure of the engrafted HSC preparations to differentiate into functional immune cells after systemic application. In the present paper we describe the effect of intrahepatically transplanted CD34(+) cells from cord blood into the liver of newborn or adult NOD/SCID mice on organ engraftment and differentiation. Analyzing the short and long term time dependency of human cell recruitment into mouse organs after cell transplantation in the liver of newborn and adult NOD/SCID mice by RT-PCR and FACS analysis, a significantly high engraftment was found after transplantation into liver of newborn NOD/SCID mice compared to adult mice, with the highest level of 35% human cells in bone marrow and 4.9% human cells in spleen at day 70. These human cells showed CD19 B-cell, CD34 and CD38 hematopoietic and CD33 myeloid cell differentiation, but lacked any T-cell differentiation. HSC transplantation into liver of adult NOD/SCID mice resulted in minor recruitment of human cells from mouse liver to other mouse organs. The results indicate the usefulness of the intrahepatic application route into the liver of newborn NOD/SCID mice for the investigation of hematopoietic differentiation potential of CD34(+) cord blood stem cell preparations.

  7. Environmental enrichment enhances episodic-like memory in association with a modified neuronal activation profile in adult mice.

    Directory of Open Access Journals (Sweden)

    Marianne Leger

    Full Text Available Although environmental enrichment is well known to improve learning and memory in rodents, the underlying neuronal networks' plasticity remains poorly described. Modifications of the brain activation pattern by enriched condition (EC, especially in the frontal cortex and the baso-lateral amygdala, have been reported during an aversive memory task in rodents. The aims of our study were to examine 1 whether EC modulates episodic-like memory in an object recognition task and 2 whether EC modulates the task-induced neuronal networks. To this end, adult male mice were housed either in standard condition (SC or in EC for three weeks before behavioral experiments (n = 12/group. Memory performances were examined in an object recognition task performed in a Y-maze with a 2-hour or 24-hour delay between presentation and test (inter-session intervals, ISI. To characterize the mechanisms underlying the promnesiant effect of EC, the brain activation profile was assessed after either the presentation or the test sessions using immunohistochemical techniques with c-Fos as a neuronal activation marker. EC did not modulate memory performances after a 2 h-ISI, but extended object recognition memory to a 24 h-ISI. In contrast, SC mice did not discriminate the novel object at this ISI. Compared to SC mice, no activation related to the presentation session was found in selected brain regions of EC mice (in particular, no effect was found in the hippocampus and the perirhinal cortex and a reduced activation was found in the baso-lateral amygdala. On the other hand, an activation of the hippocampus and the infralimbic cortex was observed after the test session for EC, but not SC mice. These results suggest that the persistence of object recognition memory in EC could be related to a reorganization of neuronal networks occurring as early as the memory encoding.

  8. Behavioural disturbances in adult CD-1 mice and absence of effects on their offspring upon SO{sub 2} exposure

    Energy Technology Data Exchange (ETDEWEB)

    Petruzzi, S. [Section of Behavioural Pathophysiology, Laboratorio di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Roma (Italy); Dell`Omo, G. [Section of Behavioural Pathophysiology, Laboratorio di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Roma (Italy); Fiore, M. [Section of Behavioural Pathophysiology, Laboratorio di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Roma (Italy); Chiarotti, F. [Section of Behavioural Pathophysiology, Laboratorio di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Roma (Italy); Bignami, G. [Section of Behavioural Pathophysiology, Laboratorio di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Roma (Italy); Alleva, E. [Section of Behavioural Pathophysiology, Laboratorio di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanita, Roma (Italy)

    1996-09-01

    Adult male and female CD-1 mice were exposed to different SO{sub 2} concentrations (0, 5, 12, or 30 ppm) for 24 days, from 9 days before the formation of breeding pairs to pregnancy day 12-14. This exposure was near-continuous, covering about 80% of the total time. The offspring of exposed dams were cross-fostered shortly after birth to dams not previously exposed. Videorecordings of the adult subjects` activities during the first hour after the start of exposure showed marked, acute transient behavioural effects such as increase of rearing and social interactions, which were more pronounced in males than in females. Subsequent activity tests on exposure days 3, 6, and 9 showed subacute effects including a dose-dependent decrease of grooming and an increase of digging as well as changes in chamber crossing and wall-rearing which were not dose-dependent; most of these effects were more pronounced in females than in males. Food and water consumption and body weight declined in a dose-dependent fashion only after the formation of breeding pairs, when consummatory responses were enhanced in the controls. Reproductive performance as well as postnatal somatic and neurobehavioural development of the offspring (the latter assessed by an observational test battery including eight reflexes and responses) were not affected by SO{sub 2}. Passive avoidance acquisition and retention at the young adult stage (60 days) and response changes produced by repeated apparatus exposure in non-reinforced animals (habituation) were similarly unaffected. The data indicate that SO{sub 2} produces transient, acute behavioural disturbances and more subtle subacute response changes in adult mice which may be due, at least partly, to a functional interference with olfactory modulation of mouse behaviour. The absence of effects on reproductive performance and neurobehavioural development of the offspring suggests that the risk to the developing organism from gestational SO{sub 2} exposure is low.

  9. Exposure to N-Ethyl-N-Nitrosourea in Adult Mice Alters Structural and Functional Integrity of Neurogenic Sites

    Science.gov (United States)

    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

  10. Chondrocyte-Specific Inhibition of β-Catenin Signaling Leads to Dysplasia of the Caudal Vertebrae in Mice

    OpenAIRE

    Shu, Bing; Li, Tian-Fang; Li, Xiao-Feng; Tang, De-Zhi; Zhang, Yejia; Shi, Qi; Wang, Yong-Jun; Chen, Di

    2013-01-01

    Study Design. To inhibit β-catenin specifically signaling in chondrocytes Col2-ICAT transgenic mice were generated. Anomalies in caudal vertebrae were detected during embryonic and postnatal stages of Col2-ICAT transgenic mice. Objective. To determine the role of canonical β-catenin signaling in caudal vertebral development. Summary of Background Data. β-catenin signaling plays a critical role in skeletal development. Col2-ICAT transgenic mice were generated to selectively block β-catenin sig...

  11. Comparison of local and systemic immunity after intratracheal, intraperitoneal and intravenous immunization of mice exposed to either aerosolized or ingested lead

    Energy Technology Data Exchange (ETDEWEB)

    Hillam, R.P.; Ozkan, A.N.

    1986-04-01

    The humoral immunity of newborn mice exposed for 28 days to 2.5 mg/m/sup 3/ aerosolized Pb(NO/sub 3/)/sub 2/ (Pb/sub 28-aero/) or of 2-week-old mice similarly exposed for 14 days (Pb/sub 14-aero/) was compared with that of both 2-week-old mice given 125 ..mu..g Pb(NO/sub 3/)/sub 2//day by gastric intubation for 14 days (Pb/sub 14-aero/) and of 4-week-old nonexposed controls. Mice from each group were immunized with 10/sup 8/ sheep red blood cells by intravenous (iv), intraperitoneal (ip), or intratracheal (it) routes of immunization. Immunity was assessed by both hemagglutination and the enumeration of antibody-forming cells from the spleen and thoracic lymph nodes. All treatment groups had decreased thymus/body weight and spleen/body weight ratios whereas only Pb/sub aero/ groups had enlarged livers. The most significant immunosuppression occurred in the ip-immunized Pb/sub 28-aero/ group. A significant suppression of humoral immunity was also observed in thoracic lymph node samples from Pb/sub aero/ groups immunized it or iv. There was no apparent immunosuppression in any treatment group after iv immunization. These results indicate that aerosolized lead is more immunosuppressive than equivalent amounts of ingested lead. This is most likely due to the greater absorption of inhaled lead and the subsequent cytotoxicity of lead for cells in the draining lymph nodes.

  12. Xylitol Affects the Intestinal Microbiota and Metabolism of Daidzein in Adult Male Mice

    OpenAIRE

    Motoi Tamura; Chigusa Hoshi; Sachiko Hori

    2013-01-01

    This study examined the effects of xylitol on mouse intestinal microbiota and urinary isoflavonoids. Xylitol is classified as a sugar alcohol and used as a food additive. The intestinal microbiota seems to play an important role in isoflavone metabolism. Xylitol feeding appears to affect the gut microbiota. We hypothesized that dietary xylitol changes intestinal microbiota and, therefore, the metabolism of isoflavonoids in mice. Male mice were randomly divided into two groups: those fed a 0....

  13. Disruption of NBS1 gene leads to early embryonic lethality in homozygous null mice and induces specific cancer in heterozygous mice

    Energy Technology Data Exchange (ETDEWEB)

    Kurimasa, Akihiro; Burma, Sandeep; Henrie, Melinda; Ouyang, Honghai; Osaki, Mitsuhiko; Ito, Hisao; Nagasawa, Hatsumi; Little, John B.; Oshimura, Mitsuo; Li, Gloria C.; Chen, David J.

    2002-04-15

    Nijmegen breakage syndrome (NBS) is a rare autosomal recessive chromosome instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition, with cellular features similar to that of ataxia telangiectasia (AT). NBS results from mutations in the mammalian gene Nbs1 that codes for a 95-kDa protein called nibrin, NBS1, or p95. To establish an animal model for NBS, we attempted to generate NBS1 knockout mice. However, NBS1 gene knockouts were lethal at an early embryonic stage. NBS1 homozygous(-/-) blastocyst cells cultured in vitro showed retarded growth and subsequently underwent growth arrest within 5 days of culture. Apoptosis, assayed by TUNEL staining, was observed in NBSI homozygous(-/-) blastocyst cells cultured for four days. NBSI heterozygous(+/-) mice were normal, and exhibited no specific phenotype for at least one year. However, fibroblast cells from NBSI heterozygous(+/-) mice displayed an enhanced frequency of spontaneous transformation to anchorage-independent growth as compared to NBS1 wild-type(+/+) cells. Furthermore, heterozygous(+/-) mice exhibited a high incidence of hepatocellular carcinoma after one year compared to wild-type mice, even though no significant differences in the incidence of other tumors such as lung adenocarcinoma and lymphoma were observed. Taken together, these results strongly suggest that NBS1 heterozygosity and reduced NBSI expression induces formation of specific tumors in mice.

  14. Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice.

    Directory of Open Access Journals (Sweden)

    Budd A Tucker

    Full Text Available This study was designed to determine whether adult mouse induced pluripotent stem cells (iPSCs, could be used to produce retinal precursors and subsequently photoreceptor cells for retinal transplantation to restore retinal function in degenerative hosts. iPSCs were generated using adult dsRed mouse dermal fibroblasts via retroviral induction of the transcription factors Oct4, Sox2, KLF4 and c-Myc. As with normal mouse ES cells, adult dsRed iPSCs expressed the pluripotency genes SSEA1, Oct4, Sox2, KLF4, c-Myc and Nanog. Following transplantation into the eye of immune-compromised retinal degenerative mice these cells proceeded to form teratomas containing tissue comprising all three germ layers. At 33 days post-differentiation a large proportion of the cells expressed the retinal progenitor cell marker Pax6 and went on to express the photoreceptor markers, CRX, recoverin, and rhodopsin. When tested using calcium imaging these cells were shown to exhibit characteristics of normal retinal physiology, responding to delivery of neurotransmitters. Following subretinal transplantation into degenerative hosts differentiated iPSCs took up residence in the retinal outer nuclear layer and gave rise to increased electro retinal function as determined by ERG and functional anatomy. As such, adult fibroblast-derived iPSCs provide a viable source for the production of retinal precursors to be used for transplantation and treatment of retinal degenerative disease.

  15. Protocol to isolate a large amount of functional oligodendrocyte precursor cells from the cerebral cortex of adult mice and humans.

    Directory of Open Access Journals (Sweden)

    Eva María Medina-Rodríguez

    Full Text Available 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.

  16. Hypoxia during pregnancy in rats leads to the changes of the cerebral white matter in adult offspring

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Lingxing; Cai, Ruowei [Department of Neurology, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian (China); Lv, Guorong, E-mail: lxingwan502@gmail.com [Department of Ultrasound, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian (China); Huang, Ziyang; Wang, Zhenhua [Department of Cardiology, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian (China)

    2010-05-28

    The aim of the present study is to evaluate the effect of reduced fetal oxygen supply on cerebral white matter in the adult offspring and further assess its susceptibility to postnatal hypoxia and high-fat diet. Based on a 3 x 2 full factorial design consisting of three factors of maternal hypoxia, postnatal high-fat diet, and postnatal hypoxia, the ultrastructure of myelin, axon and capillaries were observed, and the expression of myelin basic protein (MBP), neurofilament-H+L(NF-H+L), and glial fibrillary acidic protein (GFAP) was analyzed in periventricular white matter of 16-month-old offspring. Demyelination, injured axon and damaged microvasculars were observed in maternal hypoxia offspring. The main effect of maternal hypoxia lead to decreased expression of MBP or NF-H+L, and increased expression of GFAP (all P < 0.05). Moreover, there was positive three-way interaction among maternal hypoxia, high-fat diet and postnatal hypoxia on MBP, NF-H+L or GFAP expression (all P < 0.05). In summary, our results indicated that maternal hypoxia during pregnancy in rats lead to changes of periventricular white matter in adult offspring, including demyelination, damaged axon and proliferated astroglia. This effect was amplified by high-fat diet and postnatal hypoxia.

  17. Prenatal stress causes alterations in the morphology of microglia and the inflammatory response of the hippocampus of adult female mice

    Directory of Open Access Journals (Sweden)

    Diz-Chaves Yolanda

    2012-04-01

    Full Text Available Abstract Background Stress during fetal life increases the risk of affective and immune disorders later in life. The altered peripheral immune response caused by prenatal stress may impact on brain function by the modification of local inflammation. In this study we have explored whether prenatal stress results in alterations in the immune response in the hippocampus of female mice during adult life. Methods Pregnant C57BL/6 mice were subjected three times/day during 45 minutes to restraint stress from gestational Day 12 to delivery. Control non-stressed pregnant mice remained undisturbed. At four months of age, non-stressed and prenatally stressed females were ovariectomized. Fifteen days after surgery, mice received an i.p. injection of vehicle or of 5 mg/kg of lipopolysaccharide (LPS. Mice were sacrificed 20 hours later by decapitation and the brains were removed. Levels of interleukin-1β (IL1β, interleukin-6 (IL-6, tumor necrosis factor α (TNF-α, interferon γ-inducible protein 10 (IP10, and toll-like receptor 4 mRNA were assessed in the hippocampus by quantitative real-time polymerase chain reaction. Iba1 immunoreactivity was assessed by immunocytochemistry. Statistical significance was determined by one-way or two-way analysis of variance. Results Prenatal stress, per se, increased IL1β mRNA levels in the hippocampus, increased the total number of Iba1-immunoreactive microglial cells and increased the proportion of microglial cells with large somas and retracted cellular processes. In addition, prenatally stressed and non-stressed animals showed different responses to peripheral inflammation induced by systemic administration of LPS. LPS induced a significant increase in mRNA levels of IL-6, TNF-α and IP10 in the hippocampus of prenatally stressed mice but not of non-stressed animals. In addition, after LPS treatment, prenatally stressed animals showed a higher proportion of Iba1-immunoreactive cells in the hippocampus with

  18. Maternal nicotine exposure leads to higher liver oxidative stress and steatosis in adult rat offspring.

    Science.gov (United States)

    Conceição, E P; Peixoto-Silva, N; Pinheiro, C R; Oliveira, E; Moura, E G; Lisboa, P C

    2015-04-01

    Early nicotine exposure causes future obesity and insulin resistance. We evaluated the long-term effect of the maternal nicotine exposure during lactation in liver oxidative status, insulin sensitivity and morphology in adult offspring. Two days after birth, osmotic minipumps were implanted in the dams: nicotine (N), 6 mg/kg/day for 14 days or saline (C). Offspring were killed at 180 days. Protein content of superoxide dismutase, glutathione peroxidase, catalase, nitrotyrosine, 4HNE, IRS1, Akt1 and PPARs were measured. MDA, bound protein carbonyl content, SOD, GPx and catalase activities were determined in liver and plasma. Hepatic morphology and triglycerides content were evaluated. Albumin and bilirubin were determined. In plasma, N offspring had higher catalase activity, and SOD/GPx ratio, albumin and bilirubin levels but lower MDA content. In liver, they presented higher MDA and 4HNE levels, bound protein carbonyl content, SOD activity but lower GPx activity. N offspring presented an increase of lipid droplet, higher triglyceride content and a trend to lower PPARα in liver despite unchanged insulin signaling pathway. Early nicotine exposure causes oxidative stress in liver at adulthood, while protect against oxidative stress at plasma level. In addition, N offspring develop liver microsteatosis, which is related to oxidative stress but not to insulin resistance. PMID:25662863

  19. Delivery of human EV71 receptors by adeno-associated virus increases EV71 infection-induced local inflammation in adult mice.

    Science.gov (United States)

    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.

  20. Opposite-sex attraction in male mice requires testosterone-dependent regulation of adult olfactory bulb neurogenesis

    Science.gov (United States)

    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

  1. Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny

    Energy Technology Data Exchange (ETDEWEB)

    Haddad, Rami, E-mail: rami.haddad@mail.mcgill.ca [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2 (Canada); Kasneci, Amanda, E-mail: amanda.kasneci@mail.mcgill.ca [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); Mepham, Kathryn, E-mail: katherine.mepham@mail.mcgill.ca [Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2 (Canada); Sebag, Igal A., E-mail: igal.sebag@mcgill.ca [Division of Cardiology, Jewish General Hospital, 3755 chemin Cote Ste Catherine, Montréal, Québec, Canada H3T 1E2 (Canada); 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

  2. A Foxp2 Mutation Implicated in Human Speech Deficits Alters Sequencing of Ultrasonic Vocalizations in Adult Male Mice

    Science.gov (United States)

    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.

  3. Investigating the neurobiology of music: brain-derived neurotrophic factor modulation in the hippocampus of young adult mice.

    Science.gov (United States)

    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.

  4. Memory formation and retention are affected in adult miR-132/212 knockout mice.

    Science.gov (United States)

    Hernandez-Rapp, Julia; Smith, Pascal Y; Filali, Mohammed; Goupil, Claudia; Planel, Emmanuel; Magill, Stephen T; Goodman, Richard H; Hébert, Sébastien S

    2015-01-01

    The miR-132/212 family is thought to play an important role in neural function and plasticity, while its misregulation has been observed in various neurodegenerative disorders. In this study, we analyzed 6-month-old miR-132/212 knockout mice in a battery of cognitive and non-cognitive behavioral tests. No significant changes were observed in reflexes and basic sensorimotor functions as determined by the SHIRPA primary screen. Accordingly, miR-132/212 knockout mice did not differ from wild-type controls in general locomotor activity in an open-field test. Furthermore, no significant changes of anxiety were measured in an elevated plus maze task. However, the mutant mice showed retention phase defects in a novel object recognition test and in the T-water maze. Moreover, the learning and probe phases in the Barnes maze were clearly altered in knockout mice when compared to controls. Finally, changes in BDNF, CREB, and MeCP2 were identified in the miR-132/212-deficient mice, providing a potential mechanism for promoting memory loss. Taken together, these results further strengthen the role of miR-132/212 in memory formation and retention, and shed light on the potential consequences of its deregulation in neurodegenerative diseases.

  5. Protective effect of early prenatal stress on the induction of asthma in adult mice: Sex-specific differences.

    Science.gov (United States)

    Vargas, Mauro Henrique Moraes; Campos, Natália Evangelista; de Souza, Rodrigo Godinho; da Cunha, Aline Andrea; Nuñez, Nailê Karine; Pitrez, Paulo Márcio; Donadio, Márcio Vinícius Fagundes

    2016-10-15

    Adversities faced during the prenatal period can be related to the onset of diseases in adulthood. However, little is known about the effects on the respiratory system. This study aimed to evaluate the effects of prenatal stress in two different time-points during pregnancy on pulmonary function and on the inflammatory profile of mice exposed to an asthma model. Male and female BALB/c mice were divided into 3 groups: control (CON), prenatal stress from the second week of pregnancy (PNS1) and prenatal stress on the last week of pregnancy (PNS2). Both PNS1 and PNS2 pregnant females were submitted to restraint stress. As adults, fear/anxiety behaviors were assessed, and animals were subjected to an asthma model induced by ovalbumin. Pulmonary function, inflammatory parameters in bronchoalveolar lavage (BAL) and histology were evaluated. There was a significant decrease in the number of entries and time spent in the central quadrant on the open field test for the PNS1 animals. Females (PNS1) showed improved pulmonary function (airway resistance, tissue damping and pulmonary elastance), significant increase in the percentage of neutrophils and lymphocytes and a decrease in eosinophils when compared to controls. There was a significant decrease in inflammatory cytokines in BAL of both males (IL-5 and IL-13) and females (IL-4, IL-5 and IL-13) from PNS1 and PNS2 when compared to the CON group. Prenatal stress starting from the beginning of pregnancy reduces the impact of asthma development in adult female mice, showing an improved pulmonary function and a lower inflammatory response in the lungs.

  6. Protective effect of early prenatal stress on the induction of asthma in adult mice: Sex-specific differences.

    Science.gov (United States)

    Vargas, Mauro Henrique Moraes; Campos, Natália Evangelista; de Souza, Rodrigo Godinho; da Cunha, Aline Andrea; Nuñez, Nailê Karine; Pitrez, Paulo Márcio; Donadio, Márcio Vinícius Fagundes

    2016-10-15

    Adversities faced during the prenatal period can be related to the onset of diseases in adulthood. However, little is known about the effects on the respiratory system. This study aimed to evaluate the effects of prenatal stress in two different time-points during pregnancy on pulmonary function and on the inflammatory profile of mice exposed to an asthma model. Male and female BALB/c mice were divided into 3 groups: control (CON), prenatal stress from the second week of pregnancy (PNS1) and prenatal stress on the last week of pregnancy (PNS2). Both PNS1 and PNS2 pregnant females were submitted to restraint stress. As adults, fear/anxiety behaviors were assessed, and animals were subjected to an asthma model induced by ovalbumin. Pulmonary function, inflammatory parameters in bronchoalveolar lavage (BAL) and histology were evaluated. There was a significant decrease in the number of entries and time spent in the central quadrant on the open field test for the PNS1 animals. Females (PNS1) showed improved pulmonary function (airway resistance, tissue damping and pulmonary elastance), significant increase in the percentage of neutrophils and lymphocytes and a decrease in eosinophils when compared to controls. There was a significant decrease in inflammatory cytokines in BAL of both males (IL-5 and IL-13) and females (IL-4, IL-5 and IL-13) from PNS1 and PNS2 when compared to the CON group. Prenatal stress starting from the beginning of pregnancy reduces the impact of asthma development in adult female mice, showing an improved pulmonary function and a lower inflammatory response in the lungs. PMID:27568231

  7. Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1(G93A) Mice and Nonhuman Primates.

    Science.gov (United States)

    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 SOD1(G93A) 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 SOD1(G93A) transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1(G93A) 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

  8. Chronic treatment with fluoxetine for more than 6 weeks decreases neurogenesis in the subventricular zone of adult mice

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    Ohira Koji

    2011-03-01

    Full Text Available Abstract Background Recent studies indicate that chronic treatment with serotonergic antidepressants upregulates adult neurogenesis of the dentate gyrus (DG. In contrast, some studies claimed that there was very little alteration of neurogenesis in the subventricular zone (SVZ by the antidepressants. Since almost all of those studies treated animals with drugs for 2 to 4 weeks as chronic treatment models of antidepressants, it is possible that antidepressant treatments for longer periods would affect adult neurogenesis in the SVZ. Results In the present study, we examined the effects of long-term (up to 9 weeks administration of fluoxetine (FLX, a selective serotonin reuptake inhibitor, on cell proliferation and survival in the DG and the SVZ of adult mice. As reported previously, in the DG of mice treated with FLX for 3, 6, or 9 weeks that were also injected with 5-bromodeoxyuridine (BrdU in the last 3 days before perfusion, the numbers of Ki67- and BrdU-positive cells, which are cell proliferation markers, were significantly upregulated even at 3 weeks after the onset of the FLX treatments, and these increases were sustained in mice treated with FLX for 9 weeks. On the other hand, in the SVZ, we found a small, insignificant decrease in the numbers of Ki67- and BrdU-positive cells at 3 weeks, followed by highly significant decreases in the numbers of Ki67- and BrdU-positive cells at both 6 and 9 weeks. Furthermore, among olfactory newly generated cells that survived for 3 weeks after BrdU injection, the number of new cells was decreased at 9 weeks of FLX treatment. Conclusions These results demonstrate that long-term (more than 6 weeks treatment with FLX has the opposite effect on neurogenesis in the SVZ than it does in the DG. The results also suggest that the decrease in neurogenesis in the SVZ might be involved in some aspects of the drugs' therapeutic effects on depression. In addition, our findings raise the possibility that some of the

  9. Spectrographic analysis of the ultrasonic vocalisations of adult male and female BALB/c mice

    Science.gov (United States)

    Gourbal, Benjamin E. F.; Barthelemy, Mathieu; Petit, Gilles; Gabrion, Claude

    In this study, a spectrographic analysis was designed to improve the description of the shape, the modulations, the rate, length and frequencies of BALB/c mouse calls in different behavioural situations. Male and female calls emitted during investigation of cages with clean bedding, soiled with male or female bedding, and during same-sex encounters, were recorded and described. BALB/c male mice uttered different types of vocalisations both when investigating counterpart odour cues and when interacting with same-sex counterparts. BALB/c female mice vocalised solely during same-sex counterpart encounters and it appeared that calls were uttered mainly by the resident females. Male and female mice present a complex array of calls, which seem to be linked to particular behavioural situations. Further studies using this technology may help to improve our understanding of the role of vocal communication in natural rodent populations.

  10. The p38α MAPK function in osteoprecursors is required for bone formation and bone homeostasis in adult mice.

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    Edgardo Rodríguez-Carballo

    Full Text Available p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified.We evaluated osteoblast-specific deletion of p38α to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38α deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38α did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38α disruption after birth by removal of doxycycline. Deletion of p38α at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months.Our data demonstrates that, in addition to early skeletogenesis, p38α is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects.

  11. Deficiency of Lipoprotein Lipase in Neurons Decreases AMPA Receptor Phosphorylation and Leads to Neurobehavioral Abnormalities in Mice.

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    Tian Yu

    Full Text Available Alterations in lipid metabolism have been found in several neurodegenerative disorders, including Alzheimer's disease. Lipoprotein lipase (LPL hydrolyzes triacylglycerides in lipoproteins and regulates lipid metabolism in multiple organs and tissues, including the central nervous system (CNS. Though many brain regions express LPL, the functions of this lipase in the CNS remain largely unknown. We developed mice with neuron-specific LPL deficiency that became obese on chow by 16 wks in homozygous mutant mice (NEXLPL-/- and 10 mo in heterozygous mice (NEXLPL+/-. In the present study, we show that 21 mo NEXLPL+/- mice display substantial cognitive function decline including poorer learning and memory, and increased anxiety with no difference in general motor activities and exploratory behavior. These neurobehavioral abnormalities are associated with a reduction in the 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl propanoic acid (AMPA receptor subunit GluA1 and its phosphorylation, without any alterations in amyloid β accumulation. Importantly, a marked deficit in omega-3 and omega-6 polyunsaturated fatty acids (PUFA in the hippocampus precedes the development of the neurobehavioral phenotype of NEXLPL+/- mice. And, a diet supplemented with n-3 PUFA can improve the learning and memory of NEXLPL+/- mice at both 10 mo and 21 mo of age. We interpret these findings to indicate that LPL regulates the availability of PUFA in the CNS and, this in turn, impacts the strength of synaptic plasticity in the brain of aging mice through the modification of AMPA receptor and its phosphorylation.

  12. Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2.

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    Deepti Chugh

    Full Text Available Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age and tonic-clonic (3.5-4 months phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread.

  13. Comparison of apoptosis between adult worms of Schistosoma japonicum from susceptible (BALB/c mice) and less-susceptible (Wistar rats) hosts.

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    Wang, Tao; Guo, Xiaoyong; Hong, Yang; Han, Hongxiao; Cao, Xiaodan; Han, Yanhui; Zhang, Min; Wu, Miaoli; Fu, Zhiqiang; Lu, Ke; Li, Hao; Zhao, Zhixin; Lin, Jiaojiao

    2016-10-30

    Schistosomiasis remains a serious public health concern in China. BALB/c mice are susceptible to Schistosoma japonicum infection, whereas the Wistar rats are less susceptible. Apoptosis phenomenon was observed in 42d adult worms of S. japonicum from both rats and mice at the morphologic, DNA, cellular, and gene levels by transmission electron microscopy (TEM), fluorometric terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) analysis, fluorescein isothiocyanate-annexin-V/propidium iodide staining flow cytometry (FCM) analysis, and real-time PCR. The results showed that the apoptotic state in worms from two different susceptible hosts was diverse. Several classical hallmarks of apoptosis, including cell shrinkage, chromatin condensation and lunate marginalization, splitting of the nucleoli, nuclear shrinkage and apoptotic body formation were observed by TEM. TUNEL analysis showed that there were much more apoptosis spots in adult worms from rats than those from mice. Statistical analysis revealed that the degree of apoptosis and percentage of necrotic cells in adult worms from Wistar rats were significantly greater (Pworms from Wistar rats, as compared to those from BALB/c mice. The results obtained in this study collectively demonstrated that differential development of adult S. japonicum in less-susceptible rats and susceptible mice was significantly associated with apoptosis in the worm, and provided valuable information to guide further investigations of the mechanisms governing apoptosis and host interactions in schistosome infection.

  14. Co-transplantation of human fetal thymus, bone and CD34(+) cells into young adult immunodeficient NOD/SCID IL2Rγ(null) mice optimizes humanized mice that mount adaptive antibody responses.

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    Chung, Yun Shin; Son, Jin Kyung; Choi, Bongkum; Joo, Sung-Yeon; Lee, Yong-Soo; Park, Jae Berm; Moon, Hana; Kim, Tae Jin; Kim, Se Ho; Hong, Seokmann; Chang, Jun; Kang, Myung-Soo; Kim, Sung Joo

    2015-04-01

    Both the thymus (T) and bone (B) are necessary hematopoietic niches in adult humans. We previously showed that co-transplantation of human fetal T and B tissues into neonatal immunodeficient NOD/SCID IL2Rγ(null) (NSG, N) mice facilitated hematopoiesis. However, transplantation into neonatal mice resulted in high frequency of early death, making it unrealistic for repetitive experiments. In this study, young adult N mice were pre-engrafted with T and B, T alone, B alone or no tissues. The animals were irradiated and injected with autologous fetal liver (FL)-derived CD34(+) cells (34). The resultant mice were TB34N, T34N, B34N and 34N, respectively, and challenged with T cell dependent antigens (Ags). The humanized TB34N mice showed best performance of these mouse models in many aspects resembling the adult human Ag-experienced spleen. The TB34N mice exhibited better hematopoietic reconstitution; balanced development of T- and B-cell, and common progenitor cells; follicular lymphoid structures with a functional germinal center (GC) enriched with follicular dendritic cells (FDCs) and plasma cells (PCs); secretion of hIgG in the sera in response to Ags at comparable levels to those of human; derivations of hIgG mAb-secreting hybridoma clones. Collectively, the humanized TB34N mice could develop an adaptive immunity that was capable of producing Ag-specific hIgG at a significant level via class switching. This unprecedented TB34N platform in humanized mice would be useful in dissecting human immunity, for generating human Abs and clinical applications.

  15. Co-transplantation of human fetal thymus, bone and CD34(+) cells into young adult immunodeficient NOD/SCID IL2Rγ(null) mice optimizes humanized mice that mount adaptive antibody responses.

    Science.gov (United States)

    Chung, Yun Shin; Son, Jin Kyung; Choi, Bongkum; Joo, Sung-Yeon; Lee, Yong-Soo; Park, Jae Berm; Moon, Hana; Kim, Tae Jin; Kim, Se Ho; Hong, Seokmann; Chang, Jun; Kang, Myung-Soo; Kim, Sung Joo

    2015-04-01

    Both the thymus (T) and bone (B) are necessary hematopoietic niches in adult humans. We previously showed that co-transplantation of human fetal T and B tissues into neonatal immunodeficient NOD/SCID IL2Rγ(null) (NSG, N) mice facilitated hematopoiesis. However, transplantation into neonatal mice resulted in high frequency of early death, making it unrealistic for repetitive experiments. In this study, young adult N mice were pre-engrafted with T and B, T alone, B alone or no tissues. The animals were irradiated and injected with autologous fetal liver (FL)-derived CD34(+) cells (34). The resultant mice were TB34N, T34N, B34N and 34N, respectively, and challenged with T cell dependent antigens (Ags). The humanized TB34N mice showed best performance of these mouse models in many aspects resembling the adult human Ag-experienced spleen. The TB34N mice exhibited better hematopoietic reconstitution; balanced development of T- and B-cell, and common progenitor cells; follicular lymphoid structures with a functional germinal center (GC) enriched with follicular dendritic cells (FDCs) and plasma cells (PCs); secretion of hIgG in the sera in response to Ags at comparable levels to those of human; derivations of hIgG mAb-secreting hybridoma clones. Collectively, the humanized TB34N mice could develop an adaptive immunity that was capable of producing Ag-specific hIgG at a significant level via class switching. This unprecedented TB34N platform in humanized mice would be useful in dissecting human immunity, for generating human Abs and clinical applications. PMID:25725428

  16. Dido mutations trigger perinatal death and generate brain abnormalities and behavioral alterations in surviving adult mice.

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    Villares, Ricardo; Gutiérrez, Julio; Fütterer, Agnes; Trachana, Varvara; Gutiérrez del Burgo, Fernando; Martínez-A, Carlos

    2015-04-14

    Nearly all vertebrate cells have a single cilium protruding from their surface. This threadlike organelle, once considered vestigial, is now seen as a pivotal element for detection of extracellular signals that trigger crucial morphogenetic pathways. We recently proposed a role for Dido3, the main product of the death inducer-obliterator (dido) gene, in histone deacetylase 6 delivery to the primary cilium [Sánchez de Diego A, et al. (2014) Nat Commun 5:3500]. Here we used mice that express truncated forms of Dido proteins to determine the link with cilium-associated disorders. We describe dido mutant mice with high incidence of perinatal lethality and distinct neurodevelopmental, morphogenetic, and metabolic alterations. The anatomical abnormalities were related to brain and orofacial development, consistent with the known roles of primary cilia in brain patterning, hydrocephalus incidence, and cleft palate. Mutant mice that reached adulthood showed reduced life expectancy, brain malformations including hippocampus hypoplasia and agenesis of corpus callosum, as well as neuromuscular and behavioral alterations. These mice can be considered a model for the study of ciliopathies and provide information for assessing diagnosis and therapy of genetic disorders linked to the deregulation of primary cilia. PMID:25825751

  17. Zika Kills Vital Nervous System Cells in Adult Mice, Study Finds

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    ... effects of the Zika-related changes in neural stem cell numbers in mice. However, research with animals often doesn't translate to similar findings in humans. SOURCE: Cell Stem Cell , news release, Aug. 18, 2016 HealthDay Copyright ( ...

  18. Periostin deficiency increases bone damage and impairs injury response to fatigue loading in adult mice.

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    Bonnet, Nicolas; Gineyts, Evelyne; Ammann, Patrick; Conway, Simon J; Garnero, Patrick; Ferrari, Serge

    2013-01-01

    Bone damage removal and callus formation in response to fatigue loading are essential to prevent fractures. Periostin (Postn) is a matricellular protein that mediates adaptive response of cortical bone to loading. Whether and how periostin influences damage and the injury response to fatigue remains unknown. We investigated the skeletal response of Postn(-/-) and Postn(+/+) mice after fatigue stimulus by axial compression of their tibia. In Postn(+/+) mice, cracks number and surface (CsNb, CsS) increased 1h after fatigue, with a decrease in strength compared to non-fatigued tibia. At 15 days, CsNb had started to decline, while CtTV and CtBV increased in fatigued vs non-fatigued tibia, reflecting a woven bone response that was present in 75% of the fatigued bones. Cortical porosity and remodelling also prominently increased in the fatigued tibia of Postn(+/+) mice. At 30 days, paralleling a continuous removal of cortical damage, strength of the fatigued tibia was similar to the non-fatigue tibia. In Postn(-/-) mice, cracks were detectable even in the absence of fatigue, while the amount of collagen crosslinks and tissue hardness was decreased compared to Postn(+/+). Fatigue significantly increased CsNb and CsS in Postn(-/-), but was not associated with changes in CtTV and CtBV, as only 16% of the fatigued bones formed some woven bone. Cortical porosity and remodelling did not increase either after fatigue in Postn(-/-), and the level of damage remained high even after 30 days. As a result, strength remained compromised in Postn(-/-) mice. Contrary to Postn(+/+), which osteocytic lacunae showed a change in the degree of anisotropy (DA) after fatigue, Postn(-/-) showed no DA change. Hence periostin appears to influence bone materials properties, damage accumulation and repair, including local modeling/remodeling processes in response to fatigue. These observations suggest that the level of periostin expression could influence the propensity to fatigue fractures. PMID

  19. Periostin deficiency increases bone damage and impairs injury response to fatigue loading in adult mice.

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    Nicolas Bonnet

    Full Text Available Bone damage removal and callus formation in response to fatigue loading are essential to prevent fractures. Periostin (Postn is a matricellular protein that mediates adaptive response of cortical bone to loading. Whether and how periostin influences damage and the injury response to fatigue remains unknown. We investigated the skeletal response of Postn(-/- and Postn(+/+ mice after fatigue stimulus by axial compression of their tibia. In Postn(+/+ mice, cracks number and surface (CsNb, CsS increased 1h after fatigue, with a decrease in strength compared to non-fatigued tibia. At 15 days, CsNb had started to decline, while CtTV and CtBV increased in fatigued vs non-fatigued tibia, reflecting a woven bone response that was present in 75% of the fatigued bones. Cortical porosity and remodelling also prominently increased in the fatigued tibia of Postn(+/+ mice. At 30 days, paralleling a continuous removal of cortical damage, strength of the fatigued tibia was similar to the non-fatigue tibia. In Postn(-/- mice, cracks were detectable even in the absence of fatigue, while the amount of collagen crosslinks and tissue hardness was decreased compared to Postn(+/+. Fatigue significantly increased CsNb and CsS in Postn(-/-, but was not associated with changes in CtTV and CtBV, as only 16% of the fatigued bones formed some woven bone. Cortical porosity and remodelling did not increase either after fatigue in Postn(-/-, and the level of damage remained high even after 30 days. As a result, strength remained compromised in Postn(-/- mice. Contrary to Postn(+/+, which osteocytic lacunae showed a change in the degree of anisotropy (DA after fatigue, Postn(-/- showed no DA change. Hence periostin appears to influence bone materials properties, damage accumulation and repair, including local modeling/remodeling processes in response to fatigue. These observations suggest that the level of periostin expression could influence the propensity to fatigue fractures.

  20. Epidermal growth factor treatment of the adult brain subventricular zone leads to focal microglia/macrophage accumulation and angiogenesis.

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    Lindberg, Olle R; Brederlau, Anke; Kuhn, H Georg

    2014-04-01

    One of the major components of the subventricular zone (SVZ) neurogenic niche is the specialized vasculature. The SVZ vasculature is thought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF) is a mitogen with a wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion, dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis in the adult brain.

  1. Effects of aluminum sulfate on delta-aminolevulinate dehydratase from kidney, brain, and liver of adult mice

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    Schetinger M.R.C.

    1999-01-01

    Full Text Available The purpose of the present study was to investigate the in vitro and in vivo effects of aluminum sulfate on delta-aminolevulinic acid dehydratase (ALA-D activity from the brain, liver and kidney of adult mice (Swiss albine. In vitro experiments showed that the aluminum sulfate concentration needed to inhibit the enzyme activity was 1.0-5.0 mM (N = 3 in brain, 4.0-5.0 mM (N = 3 in liver and 0.0-5.0 mM (N = 3 in kidney. The in vivo experiments were performed on three groups for one month: 1 control animals (N = 8; 2 animals treated with 1 g% (34 mM sodium citrate (N = 8 and 3 animals treated with 1 g% (34 mM sodium citrate plus 3.3 g% (49.5 mM aluminum sulfate (N = 8. Exposure to aluminum sulfate in drinking water inhibited ALA-D activity in kidney (23.3 ± 3.7%, mean ± SEM, P<0.05 compared to control, but enhanced it in liver (31.2 ± 15.0%, mean ± SEM, P<0.05. The concentrations of aluminum in the brain, liver and kidney of adult mice were determined by graphite furnace atomic absorption spectrometry. The aluminum concentrations increased significantly in the liver (527 ± 3.9%, mean ± SEM, P<0.05 and kidney (283 ± 1.7%, mean ± SEM, P<0.05 but did not change in the brain of aluminum-exposed mice. One of the most important and striking observations was the increase in hepatic aluminum concentration in the mice treated only with 1 g% sodium citrate (34 mM (217 ± 1.5%, mean ± SEM, P<0.05 compared to control. These results show that aluminum interferes with delta-aminolevulinate dehydratase activity in vitro and in vivo. The accumulation of this element was in the order: liver > kidney > brain. Furthermore, aluminum had only inhibitory properties in vitro, while in vivo it inhibited or stimulated the enzyme depending on the organ studied.

  2. Heterozygous Hfe gene deletion leads to impaired glucose homeostasis, but not liver injury in mice fed a high-calorie diet.

    Science.gov (United States)

    Britton, Laurence; Jaskowski, Lesley; Bridle, Kim; Santrampurwala, Nishreen; Reiling, Janske; Musgrave, Nick; Subramaniam, V Nathan; Crawford, Darrell

    2016-06-01

    Heterozygous mutations of the Hfe gene have been proposed as cofactors in the development and progression of nonalcoholic fatty liver disease (NAFLD). Homozygous Hfe deletion previously has been shown to lead to dysregulated hepatic lipid metabolism and accentuated liver injury in a dietary mouse model of NAFLD We sought to establish whether heterozygous deletion of Hfe is sufficient to promote liver injury when mice are exposed to a high-calorie diet (HCD). Eight-week-old wild-type and Hfe(+/-) mice received 8 weeks of a control diet or HCD Liver histology and pathways of lipid and iron metabolism were analyzed. Liver histology demonstrated that mice fed a HCD had increased NAFLD activity score (NAS), steatosis, and hepatocyte ballooning. However, liver injury was unaffected by Hfe genotype. Hepatic iron concentration (HIC) was increased in Hfe(+/-) mice of both dietary groups. HCD resulted in a hepcidin-independent reduction in HIC Hfe(+/-) mice demonstrated raised fasting serum glucose concentrations and HOMA-IR score, despite unaltered serum adiponectin concentrations. Downstream regulators of hepatic de novo lipogenesis (pAKT, SREBP-1, Fas, Scd1) and fatty acid oxidation (AdipoR2, Pparα, Cpt1) were largely unaffected by genotype. In summary, heterozygous Hfe gene deletion is associated with impaired iron and glucose metabolism. However, unlike homozygous Hfe deletion, heterozygous gene deletion did not affect lipid metabolism pathways or liver injury in this model. PMID:27354540

  3. CX3 chemokine receptor 1 defciency leads to reduced dendritic complexity and delayed maturation of newborn neurons in the adult mouse hippocampus

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    Feng Xiao

    2015-01-01

    Full Text Available Previous studies have shown that microglia impact the proliferation and differentiation of neurons during hippocampal neurogenesis via the fractalkine/CX3 chemokine receptor 1 (CX3CR1 signaling pathway. However, whether microglia can influence the maturation and dendritic growth of newborn neurons during hippocampal neurogenesis remains unclear. In the present study, we found that the number of doublecortin-positive cells in the hippocampus was decreased, and the dendritic length and number of intersections in newborn neurons in the hippocampus were reduced in transgenic adult mice with CX3CR1 deficiency (CX3CR1GFP/GFP. Furthermore, after experimental seizures were induced with kainic acid in these CX3CR1-deficient mice, the expression of c-fos, a marker of neuronal activity, was reduced compared with wild-type mice. Collectively, the experimental findings indicate that the functional maturation of newborn neurons during hippocampal neurogenesis in adult mice is delayed by CX3CR1 deficiency.

  4. CX3 chemokine receptor 1 deficiency leads to reduced dendritic complexity and delayed maturation of newborn neurons in the adult mouse hippocampus

    Institute of Scientific and Technical Information of China (English)

    Feng Xiao; Jun-mei Xu; Xing-hua Jiang

    2015-01-01

    Previous studies have shown that microglia impact the proliferation and differentiation of neu-rons during hippocampal neurogenesisvia the fractalkine/CX3 chemokine receptor 1 (CX3CR1) signaling pathway. However, whether microglia can influence the maturation and dendritic growth of newborn neurons during hippocampal neurogenesis remains unclear. In the present study, we found that the number of doublecortin-positive cells in the hippocampus was decreased, and the dendritic length and number of intersections in newborn neurons in the hippocampus were reduced in transgenic adult mice with CX3CR1 deifciency (CX3CR1GFP/GFP). Furthermore, after experimental seizures were induced with kainic acid in these CX3CR1-deifcient mice, the expression of c-fos, a marker of neuronal activity, was reduced compared with wild-type mice. Collectively, the experimental ifndings indicate that the functional maturation of newborn neu-rons during hippocampal neurogenesis in adult mice is delayed by CX3CR1 deifciency.

  5. Loss of CD24 in Mice Leads to Metabolic Dysfunctions and a Reduction in White Adipocyte Tissue.

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    Nicholas A Fairbridge

    Full Text Available CD24 is a glycophosphatidylinositol (GPI-linked cell surface receptor that is involved in regulating the survival or differentiation of several different cell types. CD24 has been used to identify pre-adipocytes that are able to reconstitute white adipose tissue (WAT in vivo. Moreover, we recently found that the dynamic upregulation of CD24 in vitro during early phases of adipogenesis is necessary for mature adipocyte development. To determine the role of CD24 in adipocyte development in vivo, we evaluated the development of the inguinal and interscapular subcutaneous WAT and the epididymal visceral WAT in mice with a homozygous deletion of CD24 (CD24KO. We observed a significant decrease in WAT mass of 40% to 74% in WAT mass from both visceral and subcutaneous depots in male mice, with no significant effect in female mice, compared to wild-type (WT sex- and age-matched controls. We also found that CD24KO mice had increased fasting glucose and free fatty acids, decreased fasting insulin, and plasma leptin. No major differences were observed in the sensitivity to insulin or glucose, or in circulating triglycerides, total cholesterol, HDL-cholesterol, or LDL-cholesterol levels between WT and CD24KO mice. Challenging the CD24KO mice with either high sucrose (35% or high fat (45% diets that promote increased adiposity, increased WAT mass and fasting insulin, adiponectin and leptin levels, as well as reduced the sensitivity to insulin and glucose, to the levels of WT mice on the same diets. The CD24-mediated reduction in fat pad size was due to a reduction in adipocyte cell size in all depots with no significant reduction pre-adipocyte or adipocyte cell number. Thus, we have clearly demonstrated that the global absence of CD24 affects adipocyte cell size in vivo in a sex- and diet-dependent manner, as well as causing metabolic disturbances in glucose homeostasis and free fatty acid levels.

  6. ATP differentially upregulates fibroblast growth factor 2 and transforming growth factor α in neonatal and adult mice: effect on neuroproliferation.

    Science.gov (United States)

    Jia, C; Cussen, A R; Hegg, C C

    2011-03-17

    Multiple neurotrophic factors play a role in proliferation, differentiation and survival in the olfactory epithelium (OE); however, the signaling cascade has not been fully elucidated. We tested the hypotheses that ATP induces the synthesis and secretion of two neurotrophic factors, fibroblast growth factor 2 (FGF2) and transforming growth factor alpha (TGFα), and that these neurotrophic factors have a role in inducing proliferation. Protein levels of FGF2 and TGFα were increased 20 h post-intranasal instillation of ATP compared to vehicle control in adult Swiss Webster mice. Pre-intranasal treatment with purinergic receptor antagonist pyridoxal-phosphate-6-azophenyl-20,40-disulfonic acid (PPADS) significantly blocked this ATP-induced increase, indicating that upregulation of FGF2 and TGFα expression is mediated by purinergic receptor activation. However, in neonatal mouse, intranasal instillation of ATP significantly increased the protein levels of FGF2, but not TGFα. Likewise, ATP evoked the secretion of FGF2, but not TGFα, from neonatal mouse olfactory epithelial slices and PPADS significantly blocked ATP-evoked FGF2 release. To determine the role of FGF2 and TGFα in inducing proliferation, 5-bromo-2-deoxyuridine (BrdU) incorporation was examined in adult olfactory epithelium. Intranasal treatment with FGF receptor inhibitor PD173074 or epidermal growth factor receptor inhibitor AG1478 following ATP instillation significantly blocked ATP-induced BrdU incorporation. Collectively, these data demonstrate that ATP induces proliferation in adult mouse olfactory epithelium by promoting FGF2 and TGFα synthesis and activation of their receptors. These data suggest that different mechanisms regulate neurogenesis in neonatal and adult OE, and FGF2 and TGFα may have different roles throughout development. PMID:21187124

  7. ATP differentially upregulates growth factors FGF2 and TGFα in neonatal and adult mice: Effect on neuroproliferation

    Science.gov (United States)

    Jia, Cuihong; Cussen, Amber R.; Hegg, Colleen Cosgrove

    2011-01-01

    Multiple neurotrophic factors play a role in proliferation, differentiation and survival in the olfactory epithelium; however, the signaling cascade has not been fully elucidated. We tested the hypotheses that ATP induces the synthesis and secretion of two neurotrophic factors, fibroblast growth factor 2 (FGF2) and transforming growth factor alpha (TGFα), and that these neurotrophic factors have a role in inducing proliferation. Protein levels of FGF2 and TGFα were increased 20 h post-intranasal instillation of ATP compared to vehicle control in adult Swiss Webster mice. Pre-intranasal treatment with purinergic receptor antagonist pyridoxalphosphate-6-azophenyl-20,40-disulfonic acid (PPADS) significantly blocked this ATP-induced increase, indicating that upregulation of FGF2 and TGFα expression is mediated by purinergic receptor activation. However, in neonatal mouse, intranasal instillation of ATP significantly increased the protein levels of FGF2, but not TGFα. Likewise, ATP evoked the secretion of FGF2, but not TGFα, from neonatal mouse olfactory epithelial slices and PPADS significantly blocked ATP-evoked FGF2 release. To determine the role of FGF2 and TGFα in inducing proliferation, 5-bromo-2-deoxyuridine (BrdU) incorporation was examined in adult olfactory epithelium. Intranasal treatment with FGF receptor inhibitor PD173074 or epidermal growth factor receptor inhibitor AG1478 following ATP instillation significantly blocked ATP-induced BrdU incorporation. Collectively, these data demonstrate that ATP induces proliferation in adult mouse olfactory epithelium by promoting FGF2 and TGFα synthesis and activation of their receptors. These data suggest that different mechanisms regulate neurogenesis in neonatal and adult OE, and FGF2 and TGFα may have different roles throughout development. PMID:21187124

  8. Effect of nitrofurazone on the reproductive organs in adult male mice

    Institute of Scientific and Technical Information of China (English)

    Shio Kumar Singh; Sumana Chakravarty

    2001-01-01

    To study the effect of 5-nitro-2-furaldehyde semicarbazone (nitrofurazone), a derivative of nitrofuran, on male reproductive organs of Parkes (P) strain mice. Methods: Mice were given nitrofurazone orally at a dose of 64mg/kg body weight per day, for 10 and 20 days, and were killed 24 h and/or 56 days after the last treatment. Histological appearance of testis, motility and number of spermatozoa in cauda epididymidis, and biochemical indices in epididymis and seminal vesicle were evaluated. Results: Histologically, testis showed marked regressive changes in the seminiferous tubules in mice treated with nitrofurazone. Ten days after treatment, there was much depletion of germ cells in the seminiferous tubules, and the germinal epithelium was lined mainly with Sertoli cells, spermatogonia, spermatocytes, and a few round spermatids; intraepithelial vacuoles and multinucleated giant cells were also observed in tubules. By 20 days, regressive changes in the seminiferous tubules were further pronounced, and pachytene spermatocytes were the most advanced germ cells noticed in the tubules. In severe cases, the tubules were lined with a thin layer of Sertoli cells and spennatogonia. The treatment also caused marked reductions in the motility and number of spermatozoa in the cauda epididymidis, in weight and the level of fructose in the seminal vesicle, and in sialic acid level in the epididymis. Fifty six days after drug withdrawal, the alterations induced in the reproductive organs returned to control levels. Conclusion: Our results suggest that nitrofurazone treatment in P mice induces marked alterations in the male reproductive organs, and that the alterations are reversible following cessation of treatment.

  9. Aberrant Neural Stem Cell Proliferation and Increased Adult Neurogenesis in Mice Lacking Chromatin Protein HMGB2

    OpenAIRE

    Abraham, Ariel B; Robert Bronstein; Avanish S Reddy; Mirjana Maletic-Savatic; Adan Aguirre; Tsirka, Stella E.

    2013-01-01

    Neural stem and progenitor cells (NSCs/NPCs) are distinct groups of cells found in the mammalian central nervous system (CNS). Previously we determined that members of the High Mobility Group (HMG) B family of chromatin structural proteins modulate NSC proliferation and self-renewal. Among them HMGB2 was found to be dynamically expressed in proliferating and differentiating NSCs, suggesting that it may regulate NSC maintenance. We report now that Hmgb2(-/-) mice exhibit SVZ hyperproliferation...

  10. Repopulation of adult and neonatal mice with human hepatocytes: A chimeric animal model

    OpenAIRE

    Bissig, Karl-Dimiter; Le, Tam T.; Woods, Niels-Bjarne; Verma, Inder M.

    2007-01-01

    We report the successful transplantation of human hepatocytes in immunodeficient, fumarylacetoacetate hydrolase-deficient (fah−/−) mice. Engraftment occurs over the entire liver acinus upon transplantation. A few weeks after transplantation, increasing concentrations of human proteins (e.g., human albumin and human C3a) can be measured in the blood of the recipient mouse. No fusion between mouse and human hepatocytes can be detected. Three months after transplantation, up to 20% of the mouse ...

  11. Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus.

    Science.gov (United States)

    Nomura, Toshihiro; Oyamada, Yoshihiro; Fernandes, Herman B; Remmers, Christine L; Xu, Jian; Meltzer, Herbert Y; Contractor, Anis

    2016-01-01

    Repeated administration of non-competitive N-methyl-d-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) to rodents causes long-lasting deficits in cognition and memory, and has effects on behaviors that have been suggested to be models of the cognitive impairment associated with schizophrenia (CIAS). Despite this being a widely studied animal model, little is known about the long lasting changes in synapses and circuits that underlie the altered behaviors. Here we examined synaptic transmission ex-vivo in the hippocampus of mice after a subchronic PCP (scPCP) administration regime. We found that after at least one week of drug free washout period when mice have impaired cognitive function, the threshold for long-term potentiation (LTP) of CA1 excitatory synapses was elevated. This elevated LTP threshold was directly related to increased inhibitory input to CA1 pyramidal cells through increased activity of GABAergic neurons. These results suggest repeated PCP administration causes a long-lasting metaplastic change in the inhibitory circuits in the hippocampus that results in impaired LTP, and could contribute to the deficits in hippocampal-dependent memory in PCP-treated mice. Changes in GABA signaling have been described in patients with schizophrenia, therefore our results support using scPCP as a model of CIAS. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'. PMID:25937215

  12. CXC receptor knockout mice: characterization of skeletal features and membranous bone healing in the adult mouse.

    Science.gov (United States)

    Bischoff, David S; Sakamoto, Taylor; Ishida, Kenji; Makhijani, Nalini S; Gruber, Helen E; Yamaguchi, Dean T

    2011-02-01

    The potential role of CXC chemokines bearing the glu-leu-arg (ELR) motif in bone repair was studied using a cranial defect (CD) model in mice lacking the CXC receptor (mCXCR(-/-) knockout mice), which is homologous to knockout of the human CXC receptor 2 (CXCR2) gene. During the inflammatory stage of bone repair, ELR CXC chemokines are released by inflammatory cells and serve as chemotactic and angiogenic factors. mCXCR(-/-) mice were smaller in weight and length from base of tail to nose tip, compared to WT littermates. DEXA analysis indicated that bone mineral density (BMD), bone mineral content (BMC), total area (TA), bone area (BA), and total tissue mass (TTM) were decreased in the mCXCR(-/-) mice at 6, 12, and 18 weeks of age. Trabecular bone characteristics in mCXCR(-/-) (% bone, connectivity, number, and thickness) were reduced, and trabecular spacing was increased as evidenced by μCT. There was no difference in bone formation or resorption indices measured by bone histomorphometry. Trabecular BMD was not altered. Cortical bone volume, BMD, and thickness were reduced; whereas, bone marrow volume was increased in mCXCR(-/-). Decreased polar moment of inertia (J) in the tibias/femurs suggested that the mCXCR(-/-) long bones are weaker. This was confirmed by three-point bending testing of the femurs. CDs created in 6-week-old male mCXCR(-/-) and WT littermates were not completely healed at 12 weeks; WT animals, however, had significantly more bone in-growth than mCXCR(-/-). New bone sites were identified using polarized light and assessed for numbers of osteocyte (OCy) lacunae and blood vessels (BlV) around the original CD. In new bone, the number of BlV in WT was >2× that seen in mCXCR(-/-). Bone histomorphometry parameters in the cranial defect did not show any difference in bone formation or resorption markers. In summary, studies showed that mCXCR(-/-) mice have (1) reduced weight and size; (2) decreased BMD and BMC; (3) decreased amounts of trabecular

  13. Overexpression of MyrAkt1 in endothelial cells leads to erythropoietin- and BMP4-independent splenic erythropoiesis in mice.

    Directory of Open Access Journals (Sweden)

    Rebekah K O'Donnell

    Full Text Available Under steady state conditions, erythropoiesis occurs in the bone marrow. However, in mice, stress or tissue hypoxia results in increased erythropoiesis in the spleen. There is increasing evidence that the hematopoietic microenvironment, including endothelial cells, plays an important role in regulating erythropoiesis. Here, we show that short-term expression of constitutively active Akt in the endothelium of mice results in non-anemic stress erythropoiesis in the spleen. The initiation of this stress response was independent of erythropoietin and BMP4, and was observed in endothelial myrAkt1 mice reconstituted with wild-type bone marrow. Together, these data suggest that endothelial cell hyperactivation is a potentially novel pathway of inducing red cell production under stress.

  14. Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation.

    Science.gov (United States)

    López-Armas, Gabriela; Flores-Soto, Mario Eduardo; Chaparro-Huerta, Verónica; Jave-Suarez, Luis Felipe; Soto-Rodríguez, Sofía; Rusanova, Iryna; Acuña-Castroviejo, Dario; González-Perez, Oscar; González-Castañeda, Rocío Elizabeth

    2016-01-01

    Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD. PMID:27579149

  15. Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation

    Science.gov (United States)

    Flores-Soto, Mario Eduardo; Chaparro-Huerta, Verónica; Soto-Rodríguez, Sofía; González-Perez, Oscar

    2016-01-01

    Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P < 0.021). The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD.

  16. The refinement of ipsilateral eye retinotopic maps is increased by removing the dominant contralateral eye in adult mice.

    Directory of Open Access Journals (Sweden)

    Spencer L Smith

    Full Text Available BACKGROUND: Shortly after eye opening, initially disorganized visual cortex circuitry is rapidly refined to form smooth retinotopic maps. This process asymptotes long before adulthood, but it is unknown whether further refinement is possible. Prior work from our lab has shown that the retinotopic map of the non-dominant ipsilateral eye develops faster when the dominant contralateral eye is removed. We examined whether input from the contralateral eye might also limit the ultimate refinement of the ipsilateral eye retinotopic map in adults. In addition, we examined whether the increased refinement involved the recruitment of adjacent cortical area. METHODOLOGY/PRINCIPAL FINDINGS: By surgically implanting a chronic optical window over visual cortex in mice, we repeatedly measured the degree of retinotopic map refinement using quantitative intrinsic signal optical imaging over four weeks. We removed the contralateral eye and observed that the retinotopic map for the ipsilateral eye was further refined and the maximum magnitude of response increased. However, these changes were not accompanied by an increase in the area of responsive cortex. CONCLUSIONS/SIGNIFICANCE: Since the retinotopic map was functionally refined to a greater degree without taking over adjacent cortical area, we conclude that input from the contralateral eye limits the normal refinement of visual cortical circuitry in mice. These findings suggest that the refinement capacity of cortical circuitry is normally saturated.

  17. Effects of spaced learning in the water maze on development of dentate granule cells generated in adult mice.

    Science.gov (United States)

    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. PMID:25740272

  18. Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation

    Science.gov (United States)

    Flores-Soto, Mario Eduardo; Chaparro-Huerta, Verónica; Soto-Rodríguez, Sofía; González-Perez, Oscar

    2016-01-01

    Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P < 0.021). The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD. PMID:27579149

  19. Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation.

    Science.gov (United States)

    López-Armas, Gabriela; Flores-Soto, Mario Eduardo; Chaparro-Huerta, Verónica; Jave-Suarez, Luis Felipe; Soto-Rodríguez, Sofía; Rusanova, Iryna; Acuña-Castroviejo, Dario; González-Perez, Oscar; González-Castañeda, Rocío Elizabeth

    2016-01-01

    Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD.

  20. Proliferation of Estrogen Receptor alpha Positive Mammary Epithelial Cells is Restrained by TGFbeta1 in Adult Mice

    Energy Technology Data Exchange (ETDEWEB)

    Ewan, Kenneth B.R.; Oketch-Rabah, Hellen A.; Ravani, Shraddha A.; Shyamala, G.; Moses, Harold L.; Barcellos-Hoff, Mary Helen

    2005-03-03

    Transforming growth factor {beta}1 (TGF{beta}1) is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor {alpha} (ER{alpha}) cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF{beta}1 is necessary for the quiescence of ER{alpha}-positive population, we examined mouse mammary epithelial gland at estrus. Approximately 35% of cells showed TGF{beta}1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF{beta} signaling is autocrine. Furthermore, nuclear Smad co-localized with nuclear ER{alpha}. To test whether TGF{beta} was functional, we examined genetically engineered mice with different levels of TGF{beta}1. ER{alpha} co-localization with markers of proliferation (i.e. Ki-67 or BrdU) at estrus was significantly increased in the mammary glands of Tgf{beta}1 C57/bl/129SV heterozygote mice. This relationship was maintained following pregnancy, but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF{beta}1 via the MMTV promoter suppressed proliferation of ER{alpha} positive cells. Thus, TGF{beta}1 activation functionally restrains ER{alpha} positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF{beta}1 dysregulation may promote proliferation of ER{alpha} positive cells associated with breast cancer risk in humans.

  1. Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation

    Directory of Open Access Journals (Sweden)

    Gabriela López-Armas

    2016-01-01

    Full Text Available Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1 control, (2 REMSD, (3 melatonin (10 mg/kg plus REMSD, (4 melatonin and intraperitoneal luzindole (once a day at 5 mg/kg plus REMSD, and (5 luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P<0.021. The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD.

  2. Effect of intermittent exposure to ethanol and MDMA during adolescence on learning and memory in adult mice

    Directory of Open Access Journals (Sweden)

    Vidal-Infer Antonio

    2012-06-01

    Full Text Available Abstract Background Heavy binge drinking is increasingly frequent among adolescents, and consumption of 3,4-methylenedioxymethamphetamine (MDMA is often combined with ethanol (EtOH. The long-lasting effects of intermittent exposure to EtOH and MDMA during adolescence on learning and memory were evaluated in adult mice using the Hebb-Williams maze. Methods Adolescent OF1 mice were exposed to EtOH (1.25 g/kg on two consecutive days at 48-h intervals over a 14-day period (from PD 29 to 42. MDMA (10 or 20 mg/kg was injected twice daily at 4-h intervals over two consecutive days, and this schedule was repeated six days later (PD 33, 34, 41 and 42, resulting in a total of eight injections. Animals were initiated in the Hebb-Williams maze on PND 64. The concentration of brain monoamines in the striatum and hippocampus was then measured. Results At the doses employed, both EtOH and MDMA, administered alone or together, impaired learning in the Hebb-Williams maze, as treated animals required more time to reach the goal than their saline-treated counterparts. The groups treated during adolescence with EtOH, alone or plus MDMA, also presented longer latency scores and needed more trials to reach the acquisition criterion score. MDMA induced a decrease in striatal DA concentration, an effect that was augmented by the co-administration of EtOH. All the treatment groups displayed an imbalance in the interaction DA/serotonin. Conclusions The present findings indicate that the developing brain is highly vulnerable to the damaging effects of EtOH and/or MDMA, since mice receiving these drugs in a binge pattern during adolescence exhibit impaired learning and memory in adulthood.

  3. Commentary to Krishna et al. (2014): brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water.

    Science.gov (United States)

    Kumasaka, Mayuko Y; Yajima, Ichiro; Ohgami, Nobutaka; Naito, Hisao; Omata, Yasuhiro; Kato, Masashi

    2014-05-01

    Krishna et al. (Arch Toxicol 88(1):47-64, 2014) recently published the results of a study in which adult C57BL/6 mice were subchronically exposed to 400,000 μg/L manganese (Mn) using manganese chloride via drinking water for 8 weeks and examined the neurotoxic effects. After 5 weeks of Mn exposure, significant deposition of Mn in all of the brain regions examined by magnetic resonance imaging was detected. After 6 weeks of Mn exposure, neurobehavioral deficits in an open field test, a grip strength test, and a forced swim test were observed. Eight weeks of Mn exposure increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) levels, but did not alter the levels of striatal dopamine, its metabolites and serotonin. Krishna et al. also reported significant increases in mRNA levels of GFAP (an astrocyte activation marker), HO-1 (an oxidative stress marker) and NOS2 (a nitrosative stress marker), and in protein expression level of GFAP in the substantia nigra pars reticulata after 8 weeks of Mn exposure. These results suggest that 400,000 μg/L Mn exposure via drinking water in mice induces neurobehavioral deficits, serotonergic imbalance, and glial activation accompanied by an increase in brain Mn deposition. The report by Krishna et al. is interesting because the studies on the neurobehavioral effect of Mn exposure by drinking water in mice are very limited. However, Mn concentrations previously reported in well drinking water (Agusa et al. in Vietnam Environ Pollut 139(1):95-106, 2006; Buschmann et al. in Environ Int 34(6):756-764, 2008; Hafeman et al. in Environ Health Perspect 115(7):1107-1112, 2007; Wasserman et al. in Bangladesh Environ Health Perspect 114(1):124-129, 2006) were lower than 400,000 μg/L.

  4. Increased adipogenesis in cultured embryonic chondrocytes and in adult bone marrow of dominant negative Erg transgenic mice.

    Directory of Open Access Journals (Sweden)

    Sébastien Flajollet

    Full Text Available In monolayer culture, primary articular chondrocytes have an intrinsic tendency to lose their phenotype during expansion. The molecular events underlying this chondrocyte dedifferentiation are still largely unknown. Several transcription factors are important for chondrocyte differentiation. The Ets transcription factor family may be involved in skeletal development. One family member, the Erg gene, is mainly expressed during cartilage formation. To further investigate the potential role of Erg in the maintenance of the chondrocyte phenotype, we isolated and cultured chondrocytes from the rib cartilage of embryos of transgenic mice that express a dominant negative form of Erg (DN-Erg during cartilage formation. DN-Erg expression in chondrocytes cultured for up to 20 days did not affect the early dedifferentiation usually observed in cultured chondrocytes. However, lipid droplets accumulated in DN-Erg chondrocytes, suggesting adipocyte emergence. Transcriptomic analysis using a DNA microarray, validated by quantitative RT-PCR, revealed strong differential gene expression, with a decrease in chondrogenesis-related markers and an increase in adipogenesis-related gene expression in cultured DN-Erg chondrocytes. These results indicate that Erg is involved in either maintaining the chondrogenic phenotype in vitro or in cell fate orientation. Along with the in vitro studies, we compared adipocyte presence in wild-type and transgenic mice skeletons. Histological investigations revealed an increase in the number of adipocytes in the bone marrow of adult DN-Erg mice even though no adipocytes were detected in embryonic cartilage or bone. These findings suggest that the Ets transcription factor family may contribute to the homeostatic balance in skeleton cell plasticity.

  5. Overexpression of human low density lipoprotein receptors leads to accelerated catabolism of Lp(a) lipoprotein in transgenic mice.

    OpenAIRE

    Hofmann, S L; Eaton, D L; Brown, M. S.; McConathy, W J; Goldstein, J L; Hammer, R. E.

    1990-01-01

    Lp(a) lipoprotein purified from human plasma bound with high affinity to isolated bovine LDL receptors on nitrocellulose blots and in a solid-phase assay. Lp(a) also competed with 125I-LDL for binding to human LDL receptors in intact fibroblasts. Binding led to cellular uptake of Lp(a) with subsequent stimulation of cholesterol esterification. After intravenous injection, human Lp(a) was cleared slowly from the plasma of normal mice. The clearance was markedly accelerated in transgenic mice t...

  6. Dermal dysplasia, hypotrichosis, and dorsal skin ulcers in adult NMRI-mice after X-irradiation in utero

    International Nuclear Information System (INIS)

    Prenatal X-irradiation in mice leads to a marked incidence of hypotrichosis and alopecia in offspring, when irradiation occurs during the stage of late organogenesis (day 11-13 p.c.). In addition, severe ulcerative dermatitis occurs in offspring starting at 2 months of age, with marked preference for those animals which have been irradiated at least during days 11-13 p.c. This occurs without any dose dependence; application of doses between 2.4 Gy and 7.2 Gy results in approximately similar incidence rates of skin ulcers (range between 39.1 and 48.0%). There is no sex preference and no dependence on housing. At autopsy no special abnormalities were found in the internal organs with the exception of frequent signs of amyloidosis. This disease pattern could also be produced in germ-free animals. The intracutanous administration of skin extracts from affected animals into unirradiated mice leads to a marked infiltration of leukocytes. It is therefore suggested that prenatal X-irradiation induces a distinct dysplasia of the epidermis, which is followed by an endogenous leukotactic activity. (orig.)

  7. Multiple phenotypes in adult mice following inactivation of the Coxsackievirus and Adenovirus Receptor (Car gene.

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    Ahmad Pazirandeh

    Full Text Available To determine the normal function of the Coxsackievirus and Adenovirus Receptor (CAR, a protein found in tight junctions and other intercellular complexes, we constructed a mouse line in which the CAR gene could be disrupted at any chosen time point in a broad spectrum of cell types and tissues. All knockouts examined displayed a dilated intestinal tract and atrophy of the exocrine pancreas with appearance of tubular complexes characteristic of acinar-to-ductal metaplasia. The mice also exhibited a complete atrio-ventricular block and abnormal thymopoiesis. These results demonstrate that CAR exerts important functions in the physiology of several organs in vivo.

  8. Cytogenetic damage in adult and newborn mice exposed to Elf magnetic fields

    Energy Technology Data Exchange (ETDEWEB)

    Ieradi, L.A. [Istituto per lo Studio degli Ecosistemi, CNR, Rome (Italy); Udroiu, I.; Chiuchiarelli, G.; Migliorini, D.; Cristaldi, M. [Universite La Sapienza, Dipt. di Biologia Animale e dell' Uomo, Rome (Italy); Tanzarella, C. [Roma Univ., Dipt. di Biologia (Italy)

    2006-07-01

    Data obtained in newborn mice show that the chronic exposure during intra-uterine life to a 50 Hz, 650 {mu}T E.L.F. magnetic field induce a genetic damage. Nevertheless, the increase of DNA strand break in brain and in micronuclei frequency in peripheral blood and liver disagree with the data obtained by Abramsson-Zetterberg and Grawe (13) which did not find any genetic alterations in mice exposed to extremely low frequency (E.L.F.) magnetic field. In any case, along with other dissimilarities in the experimental design, the intensity of the field (14 {mu}T) and the time of sampling (35 days) were different. It is important to underline the four-fold increase in C.R.E.S.T.+ micronuclei frequency in circulating erythrocytes in the exposed group in comparison with the control group. Even though this value is quite low, it could indicate that E.L.F. magnetic fields may have different properties to damage the genome integrity. This stresses the need for further investigation on the possible link between electromagnetic fields and aneuploidy in order to elucidate the relationship with carcinogenesis. Preliminary data obtained with sperm abnormality assay show a significant increase of sperm abnormalities in mice exposed to E.L.F. magnetic fields and suggest a possible alteration to the spermatogenic process after exposure. This data agrees with data obtained by Tablado et al. (1998), in mice exposed continually for 35 days to a field of 1 T. Regarding the palatal ridges alterations assay, the results obtained show that the development of the secondary palate is not affected by E.L.F. magnetic field (50 Hz, 0,65 T). Nevertheless further studies at different frequency and intensity should be carried out to detect the possible epigenetic damage induced by E.L.F. exposure (Migliorini, 2005). With regard to the mechanism of action, it is generally believed that the damage induced by the magnetic field is an oxidative damage and that free radicals are involved. Some authors

  9. Estrogen deficiency leads to telomerase inhibition,telomere shortening and reduced cell proliferation in the adrenal gland of mice

    Institute of Scientific and Technical Information of China (English)

    Sharyn Bayne; Margaret EE Jones; He Li; Alex R Pinto; Evan R Simpson; Jun-Ping Liu

    2008-01-01

    Estrogen deficiency mediates aging, but the underlying mechanism remains to be fully determined. We report here that estrogen deficiency caused by targeted disruption of aromatase in mice results in significant inhibition oftelomerase activity in the adrenal gland in vivo. Gene expression analysis showed that, in the absence of estrogen, telomerase reverse transcriptase (TERT) gene expression is reduced in association with compromised cell proliferation in the adrenal gland cortex and adrenal atrophy. Stem cells positive in c-kit are identified to populate in the parenchyma of adrenal cortex. Analysis of telomeres revealed that estrogen deficiency results in significantly shorter telomeres in the adrenal cortex than that in wild-type (WT) control mice. To further establish the causal effects of estrogen, we conducted an estrogen replacement therapy in these estrogen-deficient animals. Administration of estrogen for 3 weeks restores TERT gene expression, telomerase activity and cell proliferation in estrogen-deficient mice. Thus, our data show for the first time that estrogen deficiency causes inhibitions of TERT gene expression, telomerase activity, telomere maintenance, and cell proliferation in the adrenal gland of mice in vivo, suggesting that telomerase inhibition and telomere shortening may mediate cell proliferation arrest in the adrenal gland, thus contributing to estrogen deficiency-induced aging under physiological conditions.

  10. Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice

    International Nuclear Information System (INIS)

    TET2 (Ten Eleven Translocation 2) is a dioxygenase that converts methylcytosine (mC) to hydroxymethylcytosine (hmC). TET2 loss-of-function mutations are highly frequent in subtypes of T-cell lymphoma that harbor follicular helper T (Tfh)-cell-like features, such as angioimmunoblastic T-cell lymphoma (30–83%) or peripheral T-cell lymphoma, not otherwise specified (10–49%), as well as myeloid malignancies. Here, we show that middle-aged Tet2 knockdown (Tet2gt/gt) mice exhibit Tfh-like cell overproduction in the spleen compared with control mice. The Tet2 knockdown mice eventually develop T-cell lymphoma with Tfh-like features after a long latency (median 67 weeks). Transcriptome analysis revealed that these lymphoma cells had Tfh-like gene expression patterns when compared with splenic CD4-positive cells of wild-type mice. The lymphoma cells showed lower hmC densities around the transcription start site (TSS) and higher mC densities at the regions of the TSS, gene body and CpG islands. These epigenetic changes, seen in Tet2 insufficiency-triggered lymphoma, possibly contributed to predated outgrowth of Tfh-like cells and subsequent lymphomagenesis. The mouse model described here suggests that TET2 mutations play a major role in the development of T-cell lymphoma with Tfh-like features in humans

  11. Dysfunctional HDL containing L159R apoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice

    Science.gov (United States)

    In this study, the effect of the mutation L159R apoA-I or apoA-IL159R (FIN) was assessed. apoA-IL159R (FIN) is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Transgenic mice lines were created through strategic mati...

  12. Enhanced dopamine D1 and BDNF signaling in the adult dorsal striatum but not nucleus accumbens of prenatal cocaine treated mice

    Directory of Open Access Journals (Sweden)

    Thomas F. Tropea

    2011-12-01

    Full Text Available Previous work from our group and others utilizing animal models have demonstrated long lasting structural and functional alterations in the meso-cortico-striatal dopamine pathway following prenatal cocaine treatment. We have shown that prenatal cocaine treatment results in augmented D1 -induced cyclic AMP (cAMP and cocaine-induced immediate-early gene expression in the striatum of adult mice. In this study we further examined basal as well as cocaine or D1-induced activation of a set of molecules known to be mediators of neuronal plasticity following psychostimulant treatment, with emphasis in the dorsal striatum (Str and nucleus accumbens (NAc of adult mice exposed to cocaine in utero. Basally, in the striatum of prenatal cocaine treated (PCOC mice there were significantly higher levels of a number of the transcription factors studied. Following acute administration of cocaine (15 mg/kg, i.p. or D1 agonist (SKF 82958; 1 mg/kg, i.p. there were significantly higher levels of Ser133 P-CREB, Thr34 P-DARPP-32, and Thr202/Tyr204 P-ERK2 in the Str, that were significantly augmented in PCOC mice. In sharp contrast, in the NAc of those mice, we found increased P-CREB and P-ERK2 in PSAL mice, a response that was not evident in PCOC mice. Examination of Ser 845 P-GluA1 revealed increased levels in PSAL mice, but significantly decreased levels in PCOC mice in both the Str and NAc following acute administration of cocaine or D1 agonist. We also found significantly higher levels of the BDNF precursor, pro-BDNF and one of its receptors, TrkB in the Str of PCOC mice. These results suggest a persistent up-regulation of molecules critical to D1 and BDNF signaling in the Str of adult mice exposed to cocaine in utero. These molecular adaptations may underlie components of the behavioral deficits evident in exposed animals and a subset of exposed humans, and may represent a therapeutic target for ameliorating aspects of the prenatal cocaine-induced phenotype.

  13. Human-derived neural progenitors functionally replace astrocytes in adult mice

    OpenAIRE

    Chen, Hong; Qian, Kun; Chen, Wei; Hu, Baoyang; Blackbourn, Lisle W.; Du, Zhongwei; Ma, Lixiang; Liu, Huisheng; Knobel, Karla M.; Ayala, Melvin; Zhang, Su-Chun

    2015-01-01

    Astrocytes are integral components of the homeostatic neural network as well as active participants in pathogenesis of and recovery from nearly all neurological conditions. Evolutionarily, compared with lower vertebrates and nonhuman primates, humans have an increased astrocyte-to-neuron ratio; however, a lack of effective models has hindered the study of the complex roles of human astrocytes in intact adult animals. Here, we demonstrated that after transplantation into the cervical spinal co...

  14. Maternal antioxidant blocks programmed cardiovascular and behavioural stress responses in adult mice

    OpenAIRE

    Roghair, Robert D.; Wemmie, John A.; Volk, Kenneth A.; Scholz, Thomas D.; Lamb, Fred S.; Jeffrey L. Segar

    2011-01-01

    Intra-uterine growth restriction is an independent risk factor for adult psychiatric and cardiovascular diseases. In humans, intra-uterine growth restriction is associated with increased placental and fetal oxidative stress, as well as down-regulation of placental 11β-HSD (11β-hydroxysteroid dehydrogenase). Decreased placental 11β-HSD activity increases fetal exposure to maternal glucocorticoids, further increasing fetal oxidative stress. To explore the developmental origins of co-morbid hype...

  15. Aniracetam does not alter cognitive and affective behavior in adult C57BL/6J mice.

    Directory of Open Access Journals (Sweden)

    Thomas W Elston

    Full Text Available There is a growing community of individuals who self-administer the nootropic aniracetam for its purported cognitive enhancing effects. Aniracetam is believed to be therapeutically useful for enhancing cognition, alleviating anxiety, and treating various neurodegenerative conditions. Physiologically, aniracetam enhances both glutamatergic neurotransmission and long-term potentiation. Previous studies of aniracetam have demonstrated the cognition-restoring effects of acute administration in different models of disease. No previous studies have explored the effects of aniracetam in healthy subjects. We investigated whether daily 50 mg/kg oral administration improves cognitive performance in naïve C57BL/6J mice in a variety of aspects of cognitive behavior. We measured spatial learning in the Morris water maze test; associative learning in the fear conditioning test; motor learning in the accelerating rotarod test; and odor discrimination. We also measured locomotion in the open field test, anxiety through the elevated plus maze test and by measuring time in the center of the open field test. We measured repetitive behavior through the marble burying test. We detected no significant differences between the naive, placebo, and experimental groups across all measures. Despite several studies demonstrating efficacy in impaired subjects, our findings suggest that aniracetam does not alter behavior in normal healthy mice. This study is timely in light of the growing community of healthy humans self-administering nootropic drugs.

  16. Xylitol Affects the Intestinal Microbiota and Metabolism of Daidzein in Adult Male Mice

    Directory of Open Access Journals (Sweden)

    Motoi Tamura

    2013-12-01

    Full Text Available This study examined the effects of xylitol on mouse intestinal microbiota and urinary isoflavonoids. Xylitol is classified as a sugar alcohol and used as a food additive. The intestinal microbiota seems to play an important role in isoflavone metabolism. Xylitol feeding appears to affect the gut microbiota. We hypothesized that dietary xylitol changes intestinal microbiota and, therefore, the metabolism of isoflavonoids in mice. Male mice were randomly divided into two groups: those fed a 0.05% daidzein with 5% xylitol diet (XD group and those fed a 0.05% daidzein-containing control diet (CD group for 28 days. Plasma total cholesterol concentrations were significantly lower in the XD group than in the CD group (p < 0.05. Urinary amounts of equol were significantly higher in the XD group than in the CD group (p < 0.05. The fecal lipid contents (% dry weight were significantly greater in the XD group than in the CD group (p < 0.01. The cecal microbiota differed between the two dietary groups. The occupation ratios of Bacteroides were significantly greater in the CD than in the XD group (p < 0.05. This study suggests that xylitol has the potential to affect the metabolism of daidzein by altering the metabolic activity of the intestinal microbiota and/or gut environment. Given that equol affects bone health, dietary xylitol plus isoflavonoids may exert a favorable effect on bone health.

  17. Xylitol Affects the Intestinal Microbiota and Metabolism of Daidzein in Adult Male Mice

    Science.gov (United States)

    Tamura, Motoi; Hoshi, Chigusa; Hori, Sachiko

    2013-01-01

    This study examined the effects of xylitol on mouse intestinal microbiota and urinary isoflavonoids. Xylitol is classified as a sugar alcohol and used as a food additive. The intestinal microbiota seems to play an important role in isoflavone metabolism. Xylitol feeding appears to affect the gut microbiota. We hypothesized that dietary xylitol changes intestinal microbiota and, therefore, the metabolism of isoflavonoids in mice. Male mice were randomly divided into two groups: those fed a 0.05% daidzein with 5% xylitol diet (XD group) and those fed a 0.05% daidzein-containing control diet (CD group) for 28 days. Plasma total cholesterol concentrations were significantly lower in the XD group than in the CD group (p < 0.05). Urinary amounts of equol were significantly higher in the XD group than in the CD group (p < 0.05). The fecal lipid contents (% dry weight) were significantly greater in the XD group than in the CD group (p < 0.01). The cecal microbiota differed between the two dietary groups. The occupation ratios of Bacteroides were significantly greater in the CD than in the XD group (p < 0.05). This study suggests that xylitol has the potential to affect the metabolism of daidzein by altering the metabolic activity of the intestinal microbiota and/or gut environment. Given that equol affects bone health, dietary xylitol plus isoflavonoids may exert a favorable effect on bone health. PMID:24336061

  18. Aniracetam does not alter cognitive and affective behavior in adult C57BL/6J mice.

    Science.gov (United States)

    Elston, Thomas W; Pandian, Ashvini; Smith, Gregory D; Holley, Andrew J; Gao, Nanjing; Lugo, Joaquin N

    2014-01-01

    There is a growing community of individuals who self-administer the nootropic aniracetam for its purported cognitive enhancing effects. Aniracetam is believed to be therapeutically useful for enhancing cognition, alleviating anxiety, and treating various neurodegenerative conditions. Physiologically, aniracetam enhances both glutamatergic neurotransmission and long-term potentiation. Previous studies of aniracetam have demonstrated the cognition-restoring effects of acute administration in different models of disease. No previous studies have explored the effects of aniracetam in healthy subjects. We investigated whether daily 50 mg/kg oral administration improves cognitive performance in naïve C57BL/6J mice in a variety of aspects of cognitive behavior. We measured spatial learning in the Morris water maze test; associative learning in the fear conditioning test; motor learning in the accelerating rotarod test; and odor discrimination. We also measured locomotion in the open field test, anxiety through the elevated plus maze test and by measuring time in the center of the open field test. We measured repetitive behavior through the marble burying test. We detected no significant differences between the naive, placebo, and experimental groups across all measures. Despite several studies demonstrating efficacy in impaired subjects, our findings suggest that aniracetam does not alter behavior in normal healthy mice. This study is timely in light of the growing community of healthy humans self-administering nootropic drugs. PMID:25099639

  19. Newly generated cells are increased in hippocampus of adult mice lacking a serine protease inhibitor

    Directory of Open Access Journals (Sweden)

    Sticker Melanie

    2010-06-01

    Full Text Available Abstract Background Neurogenesis in the hippocampal dentate gyrus and the subventricular zone occurs throughout the life of mammals and newly generated neurons can integrate functionally into established neuronal circuits. Neurogenesis levels in the dentate gyrus are modulated by changes in the environment (enrichment, exercise, hippocampal-dependent tasks, NMDA receptor (NMDAR activity, sonic hedgehog (SHH and/or other factors. Results previously, we showed that Protease Nexin-1 (PN-1, a potent serine protease inhibitor, regulates the NMDAR availability and activity as well as SHH signaling. Compared with wild-type (WT, we detected a significant increase in BrdU-labeled cells in the dentate gyrus of mice lacking PN-1 (PN-1 -/- both in controls and after running exercise. Patched homologue 1 (Ptc1 and Gli1 mRNA levels were higher and Gli3 down-regulated in mutant mice under standard conditions and to a lesser extent after running exercise. However, the number of surviving BrdU-positive cells did not differ between WT and PN-1 -/- animals. NMDAR availability was altered in the hippocampus of mutant animals after exercise. Conclusion All together our results indicate that PN-1 controls progenitors proliferation through an effect on the SHH pathway and suggest an influence of the serpin on the survival of newly generated neurons through modulation of NMDAR availability.

  20. Functional analysis of neurovascular adaptations to exercise in the dentate gyrus of young adult mice associated with cognitive gain.

    Science.gov (United States)

    Clark, Peter J; Brzezinska, Weronika J; Puchalski, Emily K; Krone, David A; Rhodes, Justin S

    2009-10-01

    The discovery that aerobic exercise increases adult hippocampal neurogenesis and can enhance cognitive performance holds promise as a model for regenerative medicine. This study adds two new pieces of information to the rapidly growing field. First, we tested whether exercise increases vascular density in the granular layer of the dentate gyrus, whole hippocampus, and striatum in C57BL/6J mice known to display procognitive effects of exercise. Second, we determined the extent to which new neurons from exercise participate in the acute neuronal response to high levels of running in B6D2F1/J (F1 hybrid of C57BL/6J female by DBA/2J male). Mice were housed with or without a running wheel for 50 days (runner vs. sedentary). The first 10 days, they received daily injections of BrdU to label dividing cells. The last 10 days, mice were tested for performance on the Morris water maze and rotarod and then euthanized to measure neurogenesis, c-Fos induction from running and vascular density. In C57BL/6J, exercise increased neurogenesis, density of blood vessels in the dentate gyrus and striatum (but not whole hippocampus), and enhanced performance on the water maze and rotarod. In B6D2F1/J, exercise also increased hippocampal neurogenesis but not vascular density in the granular layer. Improvement on the water maze from exercise was marginal, and no gain was seen for rotarod, possibly because of a ceiling effect. Running increased the number of c-Fos positive neurons in the granular layer by fivefold, and level of running was strongly correlated with c-Fos within 90 min before euthanasia. In runners, approximately 3.3% (+/-0.008 S.E.) of BrdU-positive neurons in the middle of the granule layer displayed c-Fos when compared with 0.8% (+/-0.001) of BrdU-negative neurons. Results suggest that procognitive effects of exercise are associated with increased vascular density in the dentate gyrus and striatum in C57BL/6J mice, and that new neurons from exercise preferentially

  1. Epidermal Growth Factor Treatment of the Adult Brain Subventricular Zone Leads to Focal Microglia/Macrophage Accumulation and Angiogenesis

    Directory of Open Access Journals (Sweden)

    Olle R. Lindberg

    2014-04-01

    Full Text Available One of the major components of the subventricular zone (SVZ neurogenic niche is the specialized vasculature. The SVZ vasculature is thought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF is a mitogen with a wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion, dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis in the adult brain.

  2. Trypanosoma brucei gambiense Infections in Mice Lead to Tropism to the Reproductive Organs, and Horizontal and Vertical Transmission.

    Science.gov (United States)

    Biteau, Nicolas; Asencio, Corinne; Izotte, Julien; Rousseau, Benoit; Fèvre, Muriel; Pillay, Davita; Baltz, Théo

    2016-01-01

    Trypanosoma brucei gambiense, transmitted by the tsetse fly, is the main causative agent of Human African trypanosomosis in West Africa and poses a significant health risk to 70 million people. Disease progression varies depending on host immunity, but usually begins with a haemo-lymphatic phase, followed by parasite invasion of the central nervous system. In the current study, the tropism of T. b. gambiense 1135, causing a low level chronic 'silent' infection, was monitored in a murine model using bioluminescence imaging and PCR. A tropism to the reproductive organs, in addition to the central nervous system, after 12-18 months of infection was observed. Bioluminescent analysis of healthy females crossed with infected males showed that 50%, 62.5% and 37.5% of the female mice were subsequently positive for parasites in their ovaries, uteri and brain respectively. Although PCR confirmed the presence of parasites in the uterus of one of these mice, the blood of all mice was negative by PCR and LAMP. Subsequently, bioluminescent imaging of the offspring of infected female mice crossed with healthy males indicated parasites were present in the reproductive organs of both male (80%) and female (60%) offspring. These findings imply that transmission of T. b. gambiense 1135 occurs horizontally, most probably via sexual contact, and vertically in a murine model, which raises the possibility of a similar transmission in humans. This has wide reaching implications. Firstly, the observations made in this study are likely to be valid for wild animals acting as a reservoir for T. b. gambiense. Also, the reproductive organs may act as a refuge for parasites during drug treatment in a similar manner to the central nervous system. This could leave patients at risk of a relapse, ultimately allowing them to act as a reservoir for subsequent transmission by tsetse and possibly, horizontally and vertically. PMID:26735855

  3. Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron-deficient anemia.

    Science.gov (United States)

    Rishi, Gautam; Secondes, Eriza S; Wallace, Daniel F; Subramaniam, V Nathan

    2016-08-01

    Iron metabolism and erythropoiesis are inherently interlinked physiological processes. Regulation of iron metabolism is mediated by the iron-regulatory hormone hepcidin. Hepcidin limits the amount of iron released into the blood by binding to and causing the internalization of the iron exporter, ferroportin. A number of molecules and physiological stimuli, including erythropoiesis, are known to regulate hepcidin. An increase in erythropoietic demand decreases hepcidin, resulting in increased bioavailable iron in the blood. Transferrin receptor 2 (TFR2) is involved in the systemic regulation of iron metabolism. Patients and mice with mutations in TFR2 develop hemochromatosis due to inappropriate hepcidin levels relative to body iron. Recent studies from our laboratory and others have suggested an additional role for TFR2 in response to iron-restricted erythropoiesis. These studies used mouse models with perturbed systemic iron metabolism: anemic mice lacking matriptase-2 and Tfr2, or bone marrow transplants from iron-loaded Tfr2 null mice. We developed a novel transgenic mouse model which lacks Tfr2 in the hematopoietic compartment, enabling the delineation of the role of Tfr2 in erythroid development without interfering with its role in systemic iron metabolism. We show that in the absence of hematopoietic Tfr2 immature polychromatic erythroblasts accumulate with a concordant reduction in the percentage of mature erythroid cells in the spleen and bone marrow of anemic mice. These results demonstrate that erythroid Tfr2 is essential for an appropriate erythropoietic response in iron-deficient anemia. These findings may be of relevance in clinical situations in which an immediate and efficient erythropoietic response is required. Am. J. Hematol. 91:812-818, 2016. © 2016 Wiley Periodicals, Inc. PMID:27169626

  4. Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice.

    Directory of Open Access Journals (Sweden)

    Sanjeev K Bhardwaj

    2015-03-01

    Full Text Available The expression of dysbindin-1, a protein coded by the risk gene dtnbp1, is reduced in the brains of schizophrenia patients. Evidence indicates a role of dysbindin-1 in dopaminergic and glutamatergic transmission. Glutamatergic transmission and plasticity at excitatory synapses is critically regulated by G-protein coupled metabotropic glutamate receptor (mGluR family members, that have been implicated in schizophrenia. Here, we report a role of dysbindin-1 in hippocampal group 1 mGluR (mGluRI function in mice. In hippocampal synaptoneurosomal preparations from sandy (sdy mice, that have a loss of function mutation in dysbindin-1 gene, we observed a striking reduction in mGluRI agonist [(S-3,5-dihydroxyphenylglycine] (DHPG-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2. This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5 or in another mGluRI signaling pathway, i.e., protein kinase C (PKC. Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD at CA1 excitatory synapses was significantly reduced. Behavioral data suggest that the mGluRI hypofunction may underlie some of the cognitive abnormalities described in sdy mice as the administration of CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide, a positive allosteric modulator of mGluR5, rescued short-term object recognition and spatial learning and memory deficits in these mice. Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

  5. High-fat diet leads to tissue-specific changes reflecting risk factors for diseases in DBA/2J mice.

    Science.gov (United States)

    Hageman, Rachael S; Wagener, Asja; Hantschel, Claudia; Svenson, Karen L; Churchill, Gary A; Brockmann, Gudrun A

    2010-06-01

    The aim of this study was to characterize the responses of individual tissues to high-fat feeding as a function of mass, fat composition, and transcript abundance. We examined a panel of eight tissues [5 white adipose tissues (WAT), brown adipose tissue (BAT), liver, muscle] obtained from DBA/2J mice on either a standard breeding diet (SBD) or a high-fat diet (HFD). HFD led to weight gain, decreased insulin sensitivity, and tissue-specific responses, including inflammation, in these mice. The dietary fatty acids were partially metabolized and converted in both liver and fat tissues. Saturated fatty acids (SFA) were converted in the liver to monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), and oleic acid (C18:1) was the preferred MUFA for storage of excess energy in all tissues of HFD-fed mice. Transcriptional changes largely reflected the tissue-specific fat deposition. SFA were negatively correlated with genes in the collagen family and processes involving the extracellular matrix. We propose a novel role of the tryptophan hydroxylase 2 (Tph2) gene in adipose tissues of diet-induced obesity. Tissue-specific responses to HFD were identified. Liver steatosis was evident in HFD-fed mice. Gonadal, retroperitoneal and subcutaneous adipose tissue and BAT exhibited severe inflammatory and immune responses. Mesenteric adipose tissue was the most metabolically active adipose tissue. Gluteal adipose tissue had the highest mass gain but was sluggish in its metabolism. In HFD conditions, BAT functioned largely like WAT in its role as a depot for excess energy, whereas WAT played a role in thermogenesis.

  6. Pronounced susceptibility to infection by Salmonella enterica serovar Typhimurium in mice chronically exposed to lead correlates with a shift to Th2-type immune responses

    International Nuclear Information System (INIS)

    Persistent exposure to inorganic lead (Pb) is known to adversely affect the immune system. In the present study, we assessed the effect of chronic Pb exposure on susceptibility to infection by the facultative intracellular pathogen Salmonella enterica serovar Typhimurium. Mice were exposed to 10 mM Pb-acetate in drinking water for ∼ 16 weeks, resulting in a significant level of Pb in the blood (106.2 ± 8.9 μg/dl). Pb exposure rendered mice susceptible to Salmonella infection, manifested by increased bacterial burden in target organs and heightened mortality. Flow cytometric analysis of the splenic cellular composition in normal and Pb-exposed mice revealed no gross alteration in the ratios of B and T lymphocytes or myeloid cells. Similarly, the capacity of B and T cells to upregulate the expression of activation antigens in response to mitogenic or inflammatory stimuli was not hindered by Pb exposure. Analysis of the ability of ex vivo-cultured splenocytes to secrete cytokines demonstrated a marked reduction in IFN-γ and IL-12p40 production associated with Pb exposure. In contrast, secretion of IL-4 by splenocytes of Pb-treated mice was 3- to 3.6-fold higher than in normal mice. The increased capacity to produce IL-4 correlated with a shift in the in vivo anti-Salmonella antibody response from the protective IgG2a isotype to the Th2-induced IgG1 isotype. We conclude that chronic exposure to high levels of Pb results in a state of immunodeficiency which is not due to an overt cytotoxic or immunosuppressive mechanism, but rather is largely caused by a shift in immune responsiveness to Th2-type reactions

  7. The effect of the anabolic steroid, nandrolone, in conditioned place preference and D1 dopamine receptor expression in adolescent and adult mice.

    Science.gov (United States)

    Martínez-Rivera, Freddyson J; Natal-Albelo, Eduardo J; Martínez, Namyr A; Orozco-Vega, Roberto A; Muñiz-Seda, Oscar A; Barreto-Estrada, Jennifer L

    2015-04-01

    Adolescents and adults engage in anabolic-androgenic steroid (AAS) misuse seeking their anabolic effects, even though later on, many could develop neuropsychological dependence. Previously, we have shown that nandrolone induces conditioned place preference (CPP) in adult male mice. However, whether nandrolone induces CPP during adolescence remains unknown. In this study, the CPP test was used to determine the rewarding properties of nandrolone (7.5 mg/kg) in adolescent mice. In addition, since D1 dopamine receptors (D1DR) are critical for reward-related processes, the effect of nandrolone on the expression of D1DR in the nucleus accumbens (NAc) was investigated by Western blot analysis. Similar to our previous results, nandrolone induced CPP in adults. However, in adolescents, nandrolone failed to produce place preference. At the molecular level, nandrolone decreased D1DR expression in the NAc only in adult mice. Our data suggest that nandrolone may not be rewarding in adolescents at least during short-term use. The lack of nandrolone rewarding effects in adolescents may be due, in part to differences in D1DR expression during development.

  8. Effect of a lead-expelling food on lead poisoning in mice%排铅食品对铅中毒小鼠的排铅作用及对矿物质的影响

    Institute of Scientific and Technical Information of China (English)

    李瑞; 陈玉柱; 张惠英

    2011-01-01

    Objective To evaluate the effectiveness of a lead-expelling food on expelling mineral matters and expelling lead from lead poisoning mice induced by acetate lead. Methods Seventy-five Kuming male mice weighted 18 - 22 g were randomly divided into five groups: negative control group, lead poisoning model group and three intervention groups fed with low, medium and high dosage of lead-expelling food. Deionized water was provided for the negative control group and 1.00 g/L lead acetate solution was provided for the lead-poisoning model group and three intervention groups freely. The lead-expelling food for the low, medium and high dose intervention groups was administrated intragastrically with 5-, 10- or 20-fold of the recommended dosage for human use (0. 60 g/kg BW). The general situation and body weight changes were observed in 30 days. The content of lead, calcium, iron, zinc and copper in blood, liver, femur, kidney and brain were determined. Results The lead content of liver, kidney and brain in low, medium and high-dose intervention groups were lower than those in the lead-poisoning model group (P < 0. 05 or P < 0. 01 ). The lead content of blood and femur in medium and high-dose intervention group were lower than those in lead-poisoning model group ( P < 0. 05 or P < 0. 01 ). The calcium of liver, zinc of brain, copper of kidney in low-, medium- and high-dose intervention group were higher than those in the lead-poisoning model group (P <0. 05or P < 0. 01 ). The calcium of blood, kidney and brain, the iron, zinc and copper of blood, the blood and copper of brain in middle- and high-dose intervention groups were higher than those in lead-poisoning model group (P < 0. 05 or P < 0. 01 ). Iron of femur in high-dose intervention group was higher than that in lead-poisoning model group ( P < 0. 05 ). Conclusion The lead-expelling food plays a role in promoting lead elimination from mice, and can improve calcium, iron, zinc and copper metabolism

  9. Seipin knockout in mice impairs stem cell proliferation and progenitor cell differentiation in the adult hippocampal dentate gyrus via reduced levels of PPARγ

    Directory of Open Access Journals (Sweden)

    Guoxi Li

    2015-12-01

    Full Text Available The seipin gene (BSCL2 was originally identified in humans as a loss-of-function gene associated with congenital generalized lipodystrophy type 2 (CGL2. Neuronal seipin-knockout (seipin-nKO mice display a depression-like phenotype with a reduced level of hippocampal peroxisome proliferator-activated receptor gamma (PPARγ. The present study investigated the influence of seipin deficiency on adult neurogenesis in the hippocampal dentate gyrus (DG and the underlying mechanisms of the effects. We show that the proliferative capability of stem cells in seipin-nKO mice was substantially reduced compared to in wild-type (WT mice, and that this could be rescued by the PPARγ agonist rosiglitazone (rosi. In seipin-nKO mice, neuronal differentiation of progenitor cells was inhibited, with the enhancement of astrogliogenesis; both of these effects were recovered by rosi treatment during early stages of progenitor cell differentiation. In addition, rosi treatment could correct the decline in hippocampal ERK2 phosphorylation and cyclin A mRNA level in seipin-nKO mice. The MEK inhibitor U0126 abolished the rosi-rescued cell proliferation and cyclin A expression in seipin-nKO mice. In seipin-nKO mice, the hippocampal Wnt3 protein level was less than that in WT mice, and there was a reduction of neurogenin 1 (Neurog1 and neurogenic differentiation 1 (NeuroD1 mRNA, levels of which were corrected by rosi treatment. STAT3 phosphorylation (Tyr705 was enhanced in seipin-nKO mice, and was further elevated by rosi treatment. Finally, rosi treatment for 10 days could alleviate the depression-like phenotype in seipin-nKO mice, and this alleviation was blocked by the MEK inhibitor U0126. The results indicate that, by reducing PPARγ, seipin deficiency impairs proliferation and differentiation of neural stem and progenitor cells, respectively, in the adult DG, which might be responsible for the production of the depression-like phenotype in seipin-nKO mice.

  10. Temporal and spatial patterns of transgene expression in aging adult mice provide insights about the origins, organization, and differentiation of the intestinal epithelium.

    OpenAIRE

    Cohn, S. M.; Roth, K A; Birkenmeier, E H; Gordon, J I

    1991-01-01

    We have used liver fatty acid-binding protein/human growth hormone (L-FABP/hGH) fusion genes to explore the temporal and spatial differentiation of intestinal epithelial cells in 1- to 12-month-old transgenic mice. The intact, endogenous L-FABP gene (Fabpl) was not expressed in the colon at any time. Young adult transgenic mice containing nucleotides -596 to +21 of the rat L-FABP gene linked to the hGH gene (minus its 5' nontranscribed domain) demonstrated inappropriate expression of hGH in e...

  11. High Fetal Estrogen Concentrations: Correlation with Increased Adult Sexual Activity and Decreased Aggression in Male Mice

    Science.gov (United States)

    Vom Saal, Frederick S.; Grant, William M.; McMullen, Carol W.; Laves, Kurt S.

    1983-06-01

    In the house mouse (Mus musculus), fetuses may develop in utero next to siblings of the same or opposite sex. The amniotic fluid of the female fetuses contains higher concentrations of estradiol than that of male fetuses. Male fetuses that developed in utero between female fetuses had higher concentrations of estradiol in their amniotic fluid than males that were located between other male fetusesw during intrauterine development. They were also more sexually active as adults, less aggressive, and had smaller seminal vesicles than males that had developed between other male fetuses in utero. These findings raise the possibility that during fetal life circulating estrogens may interact with circulating androgens both in regulating the development of sex differences between males and females and in producing variation in phenotype among males and among females.

  12. Anxiety- and Depression-Like States Lead to Pronounced Olfactory Deficits and Impaired Adult Neurogenesis in Mice.

    OpenAIRE

    Siopi, Eleni; Denizet, Marie; Gabellec, Marie-Madeleine; De Chaumont, Fabrice; Olivo-Marin, Jean-Christophe; Guilloux, Jean-Philippe; Lledo, Pierre-Marie; Lazarini, Françoise

    2016-01-01

    International audience Numerous clinical reports underscore the frequency of olfactory impairments in patients suffering from major depressive disorders (MDDs), yet the underlying physiopathological mechanisms remain poorly understood. We hypothesized that one key link between olfactory deficits and MDD lies in hypercortisolemia, a cardinal symptom of MDD. Corticosterone (CORT) is known to negatively correlate with hippocampal neurogenesis, yet its effects on olfactory neurogenesis and olf...

  13. Lead Poisoning

    Science.gov (United States)

    ... has also been associated with juvenile delinquency and criminal behavior. In adults, lead can increase blood pressure ... and-forth manner, but rather from left to right (or vise-versa), or from the top of ...

  14. Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF

    OpenAIRE

    Worm, Jesper; Stenvang, Jan; Petri, Andreas; Frederiksen, Klaus Stensgaard; Obad, Susanna; Elmén, Joacim; Hedtjärn, Maj; Straarup, Ellen Marie; Hansen, Jens Bo; Kauppinen, Sakari

    2009-01-01

    microRNA-155 (miR-155) has been implicated as a central regulator of the immune system, but its function during acute inflammatory responses is still poorly understood. Here we show that exposure of cultured macrophages and mice to lipopolysaccharide (LPS) leads to up-regulation of miR-155 and that the transcription factor c/ebp Beta is a direct target of miR-155. Interestingly, expression profiling of LPS-stimulated macrophages combined with overexpression and silencing of miR-155 in murine ...

  15. Periowave demonstrates bactericidal activity against periopathogens and leads to improved clinical outcomes in the treatment of adult periodontitis

    Science.gov (United States)

    Street, Cale N.; Andersen, Roger; Loebel, Nicolas G.

    2009-02-01

    Periodontitis affects half of the U.S. population over 50, and is the leading cause of tooth loss after 35. It is believed to be caused by growth of complex bacterial biofilms on the tooth surface below the gumline. Photodynamic therapy, a technology used commonly in antitumor applications, has more recently been shown to exhibit antimicrobial efficacy. We have demonstrated eradication of the periopathogens Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans in vitro using PeriowaveTM; a commercial photodisinfection system. In addition, several clinical studies have now demonstrated the efficacy of this treatment. A pilot study in the U.S. showed that 68% of patients treated with PeriowaveTM adjunctively to scaling and root planing (SRP) showed clinical attachment level increase of >1 mm, as opposed to 30% with SRP alone. In a subsequent larger study, a second PeriowaveTM treatment 6 weeks after initial treatment led to pocket depth improvements of >1.5 mm in 89% of patients. Finally, in the most recent multicenter, randomized, examiner-blinded study conducted on 121 subjects in Canada, PeriowaveTM treatment produced highly significant gains in attachment level (0.88 mm vs. 0.57 mm; p=0.003) and pocket depth (0.87 mm vs. 0.63 mm; p=0.01) as compared to SRP alone. In summary, PeriowaveTM demonstrated strong bactericidal activity against known periopathogens, and treatment of periodontitis using this system produced significantly better clinical outcomes than SRP alone. This, along with the absence of any adverse events in patients treated to date demonstrates that PDT is a safe and effective treatment for adult chronic periodontitis.

  16. Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice.

    Science.gov (United States)

    Nuber, Silke; Franck, Thomas; Wolburg, Hartwig; Schumann, Ulrike; Casadei, Nicolas; Fischer, Kristina; Calaminus, Carsten; Pichler, Bernd J; Chanarat, Sittinan; Teismann, Peter; Schulz, Jörg B; Luft, Andreas R; Tomiuk, Jürgen; Wilbertz, Johannes; Bornemann, Antje; Krüger, Rejko; Riess, Olaf

    2010-02-01

    Synphilin-1 has been identified as an interacting protein of alpha-synuclein, Parkin, and LRRK2, proteins which are mutated in familial forms of Parkinson disease (PD). Subsequently, synphilin-1 has also been shown to be an intrinsic component of Lewy bodies in sporadic PD. In order to elucidate the role of synphilin-1 in the pathogenesis of PD, we generated transgenic mice overexpressing wild-type and mutant (R621C) synphilin-1 driven by a mouse prion protein promoter. Transgenic expression of both wild-type and the R621C variant synphilin-1 resulted in increased dopamine levels of the nigrostriatal system in 3-month-old mice. Furthermore, we found pathological ubiquitin-positive inclusions in cerebellar sections and dark-cell degeneration of Purkinje cells. Both transgenic mouse lines showed significant reduction of motor skill learning and motor performance. These findings suggest a pathological role of overexpressed synphilin-1 in vivo and will help to further elucidate the mechanisms of protein aggregation and neuronal cell death. PMID:19760259

  17. Expression profiling reveals novel hypoxic biomarkers in peripheral blood of adult mice exposed to chronic hypoxia.

    Directory of Open Access Journals (Sweden)

    Matias Mosqueira

    Full Text Available Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX, exposed for two weeks to normobaric chronic hypoxia (CH or two weeks of CH followed by two weeks of normoxic recovery (REC. Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off, 230 genes were identified and separated into four distinct temporal categories. Class I contained 1 transcript up-regulated in both CH and REC; Class II contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III contained 9 transcripts down-regulated both in CH and REC; Class IV contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1 by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia.

  18. Activation of the Wnt/{beta}-catenin signaling pathway is associated with glial proliferation in the adult spinal cord of ALS transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yanchun [Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong (China); Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong (China); Guan, Yingjun, E-mail: guanyj@wfmc.edu.cn [Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong (China); Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong (China); Liu, Huancai [Department of Orthopedic, Affiliated Hospital, Weifang Medical University, Weifang, Shandong (China); Wu, Xin; Yu, Li; Wang, Shanshan; Zhao, Chunyan; Du, Hongmei [Department of Histology and Embryology, Weifang Medical University, Weifang, Shandong (China); Wang, Xin, E-mail: xwang@rics.bwh.harvard.edu [Department of Neurosurgery, Brigham and Women' s Hospital, Harvard Medical School, Boston, MA (United States)

    2012-04-06

    Highlights: Black-Right-Pointing-Pointer Wnt3a and Cyclin D1 were upregulated in the spinal cord of the ALS mice. Black-Right-Pointing-Pointer {beta}-catenin translocated from the cell membrane to the nucleus in the ALS mice. Black-Right-Pointing-Pointer Wnt3a, {beta}-catenin and Cyclin D1 co-localized for astrocytes were all increased. Black-Right-Pointing-Pointer BrdU/Cyclin D1 double-positive cells were increased in the spinal cord of ALS mice. Black-Right-Pointing-Pointer BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. -- Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive and fatal loss of motor neurons. In ALS, there is a significant cell proliferation in response to neurodegeneration; however, the exact molecular mechanisms of cell proliferation and differentiation are unclear. The Wnt signaling pathway has been shown to be involved in neurodegenerative processes. Wnt3a, {beta}-catenin, and Cyclin D1 are three key signaling molecules of the Wnt/{beta}-catenin signaling pathway. We determined the expression of Wnt3a, {beta}-catenin, and Cyclin D1 in the adult spinal cord of SOD1{sup G93A} ALS transgenic mice at different stages by RT-PCR, Western blot, and immunofluorescence labeling techniques. We found that the mRNA and protein of Wnt3a and Cyclin D1 in the spinal cord of the ALS mice were upregulated compared to those in wild-type mice. In addition, {beta}-catenin translocated from the cell membrane to the nucleus and subsequently activated transcription of the target gene, Cyclin D1. BrdU and Cyclin D1 double-positive cells were increased in the spinal cord of these mice. Moreover, Wnt3a, {beta}-catenin, and Cyclin D1 were also expressed in both neurons and astrocytes. The expression of Wnt3a, {beta}-catenin or Cyclin D1 in mature GFAP{sup +} astrocytes increased. Moreover, BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. Our findings suggest that

  19. A comparison of osteoclast-rich and osteoclast-poor osteopetrosis in adult mice sheds light on the role of the osteoclast in coupling bone resorption and bone formation.

    Science.gov (United States)

    Thudium, Christian S; Moscatelli, Ilana; Flores, Carmen; Thomsen, Jesper S; Brüel, Annemarie; Gudmann, Natasja Stæhr; Hauge, Ellen-Margrethe; Karsdal, Morten A; Richter, Johan; Henriksen, Kim

    2014-07-01

    Osteopetrosis due to lack of acid secretion by osteoclasts is characterized by abolished bone resorption, increased osteoclast numbers, but normal or even increased bone formation. In contrast, osteoclast-poor osteopetrosis appears to have less osteoblasts and reduced bone formation, indicating that osteoclasts are important for regulating osteoblast activity. To illuminate the role of the osteoclast in controlling bone remodeling, we transplanted irradiated skeletally mature 3-month old wild-type mice with hematopoietic stem cells (HSCs) to generate either an osteoclast-rich or osteoclast-poor adult osteopetrosis model. We used fetal liver HSCs from (1) oc/oc mice, (2) RANK KO mice, and (3) compared these to wt control cells. TRAP5b activity, a marker of osteoclast number and size, was increased in the oc/oc recipients, while a significant reduction was seen in the RANK KO recipients. In contrast, the bone resorption marker CTX-I was similarly decreased in both groups. Both oc/oc and Rank KO recipients developed a mild osteopetrotic phenotype. However, the osteoclast-rich oc/oc recipients showed higher trabecular bone volume (40 %), increased bone strength (66 %), and increased bone formation rate (54 %) in trabecular bone, while RANK KO recipients showed only minor trends compared to control recipients. We here show that maintaining non-resorbing osteoclasts, as opposed to reducing the osteoclasts, leads to increased bone formation, bone volume, and ultimately higher bone strength in vivo, which indicates that osteoclasts are sources of anabolic molecules for the osteoblasts.

  20. Increases in the numerical density of GAT-1 positive puncta in the barrel cortex of adult mice after fear conditioning.

    Directory of Open Access Journals (Sweden)

    Ewa Siucinska

    Full Text Available Three days of fear conditioning that combines tactile stimulation of a row of facial vibrissae (conditioned stimulus, CS with a tail shock (unconditioned stimulus, UCS expands the representation of "trained" vibrissae, which can be demonstrated by labeling with 2-deoxyglucose in layer IV of the barrel cortex. We have also shown that functional reorganization of the primary somatosensory cortex (S1 increases GABAergic markers in the hollows of "trained" barrels of the adult mouse. This study investigated how whisker-shock conditioning (CS+UCS affected the expression of puncta of a high-affinity GABA plasma membrane transporter GAT-1 in the barrel cortex of mice 24 h after associative learning paradigm. We found that whisker-shock conditioning (CS+UCS led to increase expression of neuronal and astroglial GAT-1 puncta in the "trained" row compared to controls: Pseudoconditioned, CS-only, UCS-only and Naïve animals. These findings suggest that fear conditioning specifically induces activation of systems regulating cellular levels of the inhibitory neurotransmitter GABA.

  1. Impact of Environmental Microbes on the Composition of the Gut Microbiota of Adult BALB/c Mice

    Science.gov (United States)

    Li, Na; Bai, Zhiyu; Zhang, Liling; Xue, Zhencheng; Jiang, Haitao; Song, Yuan; Zhou, Dongrui

    2016-01-01

    To investigate the impact of microbes within the living environment on the gut microbiota of adults, we raised three groups of BALB/c mice from 3–4 weeks age in the same specific-pathogen-free animal room for 8 weeks. The control group lived in cages with sterilized bedding (pelletized cardboard), the probiotics group had three probiotics added to the sterilized bedding, and the intestinal microbes (IM) group had the intestinal microbes of a healthy goat added to the bedding. All other variables such as diet, age, genetic background, physiological status, original gut microbiota, and living room were controlled. Using high-throughput sequencing of the 16S rRNA gene, we observed that the control and probiotics groups had similar diversity and richness of gut microbiota. The two groups had significantly lower diversity than the IM group. We also observed that the IM group had a specific structure of gut microbial community compared with the control and probiotics groups. However, the dominate bacteria changed slightly upon exposure to intestinal microbes, and the abundance of the non-dominate species changed significantly. In addition, exposure to intestinal microbes inhibited DNFB-induced elevation of serum IgE levels. Our results provide new evidence in support of the microflora and hygiene hypotheses. PMID:27518814

  2. Impact of Environmental Microbes on the Composition of the Gut Microbiota of Adult BALB/c Mice.

    Science.gov (United States)

    Bai, Zhimao; Zhang, Honglin; Li, Na; Bai, Zhiyu; Zhang, Liling; Xue, Zhencheng; Jiang, Haitao; Song, Yuan; Zhou, Dongrui

    2016-01-01

    To investigate the impact of microbes within the living environment on the gut microbiota of adults, we raised three groups of BALB/c mice from 3-4 weeks age in the same specific-pathogen-free animal room for 8 weeks. The control group lived in cages with sterilized bedding (pelletized cardboard), the probiotics group had three probiotics added to the sterilized bedding, and the intestinal microbes (IM) group had the intestinal microbes of a healthy goat added to the bedding. All other variables such as diet, age, genetic background, physiological status, original gut microbiota, and living room were controlled. Using high-throughput sequencing of the 16S rRNA gene, we observed that the control and probiotics groups had similar diversity and richness of gut microbiota. The two groups had significantly lower diversity than the IM group. We also observed that the IM group had a specific structure of gut microbial community compared with the control and probiotics groups. However, the dominate bacteria changed slightly upon exposure to intestinal microbes, and the abundance of the non-dominate species changed significantly. In addition, exposure to intestinal microbes inhibited DNFB-induced elevation of serum IgE levels. Our results provide new evidence in support of the microflora and hygiene hypotheses.

  3. Impact of Environmental Microbes on the Composition of the Gut Microbiota of Adult BALB/c Mice.

    Science.gov (United States)

    Bai, Zhimao; Zhang, Honglin; Li, Na; Bai, Zhiyu; Zhang, Liling; Xue, Zhencheng; Jiang, Haitao; Song, Yuan; Zhou, Dongrui

    2016-01-01

    To investigate the impact of microbes within the living environment on the gut microbiota of adults, we raised three groups of BALB/c mice from 3-4 weeks age in the same specific-pathogen-free animal room for 8 weeks. The control group lived in cages with sterilized bedding (pelletized cardboard), the probiotics group had three probiotics added to the sterilized bedding, and the intestinal microbes (IM) group had the intestinal microbes of a healthy goat added to the bedding. All other variables such as diet, age, genetic background, physiological status, original gut microbiota, and living room were controlled. Using high-throughput sequencing of the 16S rRNA gene, we observed that the control and probiotics groups had similar diversity and richness of gut microbiota. The two groups had significantly lower diversity than the IM group. We also observed that the IM group had a specific structure of gut microbial community compared with the control and probiotics groups. However, the dominate bacteria changed slightly upon exposure to intestinal microbes, and the abundance of the non-dominate species changed significantly. In addition, exposure to intestinal microbes inhibited DNFB-induced elevation of serum IgE levels. Our results provide new evidence in support of the microflora and hygiene hypotheses. PMID:27518814

  4. Exercise prevents high-fat diet-induced impairment of flexible memory expression in the water maze and modulates adult hippocampal neurogenesis in mice.

    Science.gov (United States)

    Klein, C; Jonas, W; Iggena, D; Empl, L; Rivalan, M; Wiedmer, P; Spranger, J; Hellweg, R; Winter, Y; Steiner, B

    2016-05-01

    Obesity is currently one of the most serious threats to human health in the western civilization. A growing body of evidence suggests that obesity is associated with cognitive dysfunction. Physical exercise not only improves fitness but it has also been shown in human and animal studies to increase hippocampus-dependent learning and memory. High-fat diet (HFD)-induced obesity and physical exercise both modulate adult hippocampal neurogenesis. Adult neurogenesis has been demonstrated to play a role in hippocampus-dependent learning and memory, particularly flexible memory expression. Here, we investigated the effects of twelve weeks of HFD vs. control diet (CD) and voluntary physical activity (wheel running; -R) vs. inactivity (sedentary; -S) on hippocampal neurogenesis and spatial learning and flexible memory function in female C57Bl/6 mice assessed in the Morris water maze. HFD was initiated either in adolescent mice combined with long-term concurrent exercise (preventive approach) or in young adult mice with 14days of subsequent exercise (therapeutic approach). HFD resulted in impaired flexible memory expression only when initiated in adolescent (HFD-S) but not in young adult mice, which was successfully prevented by concurrent exercise (HFD-R). Histological analysis revealed a reduction of immature neurons in the hippocampus of the memory-impaired HFD-S mice of the preventive approach. Long-term physical exercise also led to accelerated spatial learning during the acquisition period, which was accompanied by increased numbers of newborn mature neurons (HFD-R and CD-R). Short-term exercise of 14days in the therapeutic group was not effective in improving spatial learning or memory. We show that (1) alterations in learning and flexible memory expression are accompanied by changes in the number of neuronal cells at different maturation stages; (2) these neuronal cells are in turn differently affected by HFD; (3) adolescent mice are specifically susceptible to the

  5. Exercise prevents high-fat diet-induced impairment of flexible memory expression in the water maze and modulates adult hippocampal neurogenesis in mice.

    Science.gov (United States)

    Klein, C; Jonas, W; Iggena, D; Empl, L; Rivalan, M; Wiedmer, P; Spranger, J; Hellweg, R; Winter, Y; Steiner, B

    2016-05-01

    Obesity is currently one of the most serious threats to human health in the western civilization. A growing body of evidence suggests that obesity is associated with cognitive dysfunction. Physical exercise not only improves fitness but it has also been shown in human and animal studies to increase hippocampus-dependent learning and memory. High-fat diet (HFD)-induced obesity and physical exercise both modulate adult hippocampal neurogenesis. Adult neurogenesis has been demonstrated to play a role in hippocampus-dependent learning and memory, particularly flexible memory expression. Here, we investigated the effects of twelve weeks of HFD vs. control diet (CD) and voluntary physical activity (wheel running; -R) vs. inactivity (sedentary; -S) on hippocampal neurogenesis and spatial learning and flexible memory function in female C57Bl/6 mice assessed in the Morris water maze. HFD was initiated either in adolescent mice combined with long-term concurrent exercise (preventive approach) or in young adult mice with 14days of subsequent exercise (therapeutic approach). HFD resulted in impaired flexible memory expression only when initiated in adolescent (HFD-S) but not in young adult mice, which was successfully prevented by concurrent exercise (HFD-R). Histological analysis revealed a reduction of immature neurons in the hippocampus of the memory-impaired HFD-S mice of the preventive approach. Long-term physical exercise also led to accelerated spatial learning during the acquisition period, which was accompanied by increased numbers of newborn mature neurons (HFD-R and CD-R). Short-term exercise of 14days in the therapeutic group was not effective in improving spatial learning or memory. We show that (1) alterations in learning and flexible memory expression are accompanied by changes in the number of neuronal cells at different maturation stages; (2) these neuronal cells are in turn differently affected by HFD; (3) adolescent mice are specifically susceptible to the

  6. Effect of lead-excretion glycan on removing lead and essential metal elements in mice%排铅聚糖对染铅小鼠的驱铅作用及对必需元素的影响

    Institute of Scientific and Technical Information of China (English)

    冯国昌; 朱振平; 刘萍

    2012-01-01

    目的 观察排铅聚糖对醋酸铅染毒小鼠的驱铅作用及对体内必需元素的影响.方法 以昆明种小鼠为实验对象,按体质量随机分为阴性对照组,醋酸铅模型组,排铅聚糖高(1 600 mg/kg)、中(800 mg/kg)、低(400 mg/kg)剂量组,除阴性对照组外均腹腔注射醋酸铅溶液染毒造成中毒模型,后各剂量组用不同剂量排铅聚糖灌胃,阴性对照组及醋酸铅模型组用生理盐水灌胃.实验结束后取小鼠的血液、肝、肾、骨、脑组织进行消解,采用原子吸收分光光度法检测血液及各组织中铅及钙、镁、铁、锌、铜、锰的含量.结果 血液及各组织脏器中铅的含量,排铅聚糖各剂量组均低于醋酸铅模型组(P<0.05).排铅聚糖高剂量组血液、骨中镁的含量低于阴性对照组(P<0.05),肝铁含量中、高剂量组高于醋酸铅模型组(P<0.05),而与阴性对照组比较差异无统计学意义(P>0.05),排铅聚糖各剂量组中钙、铜、锌、锰与阴性对照组相比,在肝、肾、骨、脑中含量差异大部分无统计学意义(P>0.05).结论 排铅聚糖能有效地排出血液、肝、肾、骨、脑中的铅,但没有明显的剂量-效应关系.用排铅聚糖排出小鼠体内的铅时,除高剂量对血镁、骨镁有促排作用外,对机体内其他必需元素基本无损失,同时中、高剂量对肝内的铁有保护作用.%Objective To study the effect of lead-excretion glycan on lead-poisoned mice. Methods 50 healthy mice of Kunming strain (25 males and 25 females) were randomly divided into 5 groups according to their body weights; the negative control group, lead acetate, the lead acetate, model group, the high-dose group( 1 600 mg/kg), the medium-dose group(800mg/kg), and the low-dose group(400mg/kg). Pb(Ac)2 solutions were given to the groups except the negative control group to form lead-poisoned models in mice, then the low-dose group, the medium-dose group and the high-dose group were given

  7. 羊睾丸提取液对铅损伤小鼠精子顶体形成的影响%Effect of caprine testicular extract on acrosome formation of spermatids of lead-injured mice

    Institute of Scientific and Technical Information of China (English)

    田洪艳; 李质馨; 王弘珺; 朱辛为; 潘晓燕; 刘忠平; 林冬静

    2012-01-01

    目的 观察羊睾丸提取液对铅损伤小鼠精子顶体形成的影响.方法 成年健康清洁级ICR雄性小鼠30只,随机分为对照组、模型组和给药组,每组l0只.模型组采用醋酸铅(30mg/kg)灌胃建立睾丸损伤模型,给药组在醋酸铅灌胃的同时腹腔注射羊睾丸提取液0.5ml,对照组采用等体积蒸馏水灌胃及腹腔注射,每天1次,共21d.经心脏行甲醛灌流固定,制备睾丸标本,PAS染色,光镜下观察圆形精子细胞期顶体的形态学变化.结果 与对照组相比,模型组精子顶体形成障碍,顶体囊泡不完整,膜皱缩,较粗糙,结构模糊;给药组精子顶体形成接近对照组,顶体囊泡形状较规则,膜平滑.结论 羊睾丸提取液可保护小鼠精子顶体在形成过程中免受铅的损害,从而维持其正常的结构及功能.%Objective To investigate the effect of caprine testicular extract on the acrosomal formation of spermatids of lead-treated mice, and find a theoretical and experimental basis for further research on the effects of caprine testicular extract on the reproductive system. Methods The study was carried out on thirty male adult ICR mice, which were randomly assigned into control group, model group and treatment group (10 each). The testis-injury model was reproduced by intragastric administration of lead acetate (30mg/kg, 0.1ml/10g). Animals in treatment group received intragastric administration of lead acetate and intraabdominal injection of 0.5ml caprine testicular extract at the same time for 21days, and the mice in control group received the same amount of distilled water by intragastric administration and 0.5ml distilled water by intraabdominal injection. By the end of the experimental period, the mice were sacrificed. The testes were fixed by cardiac perfusion and processed for light microscopic examination. The acrosomal formation in round spermatids was observed by PAS staining. Results Compared with the control group, the acrosomal

  8. Lessons from Hepatocyte-Specific Cyp51 Knockout Mice: Impaired Cholesterol Synthesis Leads to Oval Cell-Driven Liver Injury

    Science.gov (United States)

    Lorbek, Gregor; Perše, Martina; Jeruc, Jera; Juvan, Peter; Gutierrez-Mariscal, Francisco M.; Lewinska, Monika; Gebhardt, Rolf; Keber, Rok; Horvat, Simon; Björkhem, Ingemar; Rozman, Damjana

    2015-03-01

    We demonstrate unequivocally that defective cholesterol synthesis is an independent determinant of liver inflammation and fibrosis. We prepared a mouse hepatocyte-specific knockout (LKO) of lanosterol 14α-demethylase (CYP51) from the part of cholesterol synthesis that is already committed to cholesterol. LKO mice developed hepatomegaly with oval cell proliferation, fibrosis and inflammation, but without steatosis. The key trigger was reduced cholesterol esters that provoked cell cycle arrest, senescence-associated secretory phenotype and ultimately the oval cell response, while elevated CYP51 substrates promoted the integrated stress response. In spite of the oval cell-driven fibrosis being histologically similar in both sexes, data indicates a female-biased down-regulation of primary metabolism pathways and a stronger immune response in males. Liver injury was ameliorated by dietary fats predominantly in females, whereas dietary cholesterol rectified fibrosis in both sexes. Our data place defective cholesterol synthesis as a focus of sex-dependent liver pathologies.

  9. Restoration of Cocaine Stimulation and Reward by Reintroducing Wild Type Dopamine Transporter in Adult Knock-in Mice with a Cocaine-Insensitive Dopamine Transporter

    Science.gov (United States)

    Wu, Haiyin; O’Neill, Brian; Han, Dawn D.; Thirtamara-Rajamani, Keerthi; Wang, Yanlin; Gu, Howard H.

    2014-01-01

    In previous studies, we generated knock-in mice with a cocaine-insensitive dopamine transporter (DAT-CI mice) and found cocaine does not stimulate locomotion or produce reward in these mice, indicating DAT inhibition is necessary for cocaine stimulation and reward. However, DAT uptake is reduced in DAT-CI mice and thus the lack of cocaine responses could be due to adaptive changes. To test this, we used adeno-associated virus (AAV) to reintroduce the cocaine-sensitive wild type DAT (AAV-DATwt) back into adult DAT-CI mice, which restores cocaine inhibition of DAT in affected brain regions but does not reverse the adaptive changes. In an earlier study we showed that AAV-DATwt injections in regions covering the lateral nucleus accumbens (NAc) and lateral caudate-putamen (CPu) restored cocaine stimulation but not cocaine reward. In the current study, we expanded the AAV-DATwt infected areas to cover the olfactory tubercle (Tu) and the ventral midbrain (vMB) containing the ventral tegmental area (VTA) and substantia nigra (SN) in addition to CPu and NAc with multiple injections. These mice displayed the restoration of both locomotor stimulation and cocaine reward. We further found that AAV-DATwt injection in the vMB alone was sufficient to restore both cocaine stimulation and reward in DAT-CI mice. AAV injected in the VTA and SN resulted in DATwt expression and distribution to the DA terminal regions. In summary, cocaine induced locomotion and reward can be restored in fully developed DAT-CI mice, and cocaine inhibition of DAT expressed in dopaminergic neurons originated from the ventral midbrain mediates cocaine reward and stimulation. PMID:24835281

  10. CCRL1/ACKR4 is expressed in key thymic microenvironments but is dispensable for T lymphopoiesis at steady state in adult mice

    DEFF Research Database (Denmark)

    Lucas, Beth; White, Andrea J.; Ulvmar, Maria H.;

    2015-01-01

    Thymus colonisation and thymocyte positioning are regulated by interactions between CCR7 and CCR9, and their respective ligands, CCL19/CCL21 and CCL25. The ligands of CCR7 and CCR9 also interact with the atypical receptor CCRL1 (also known as ACKR4), which is expressed in the thymus and has...... in mice. Interestingly, CCRL1 is also expressed by stromal cells which surround the pericytes of vessels at the corticomedullary junction, the site for progenitor cell entry and mature thymocyte egress from the thymus. We show that CCRL1 suppresses thymocyte progenitor entry into the thymus, however......, the thymus size and cellularity are the same in adult WT and CCRL1-/- mice. Moreover, CCRL1-/- mice have no major perturbations in T-cell populations at different stages of thymic differentiation and development, and have a similar rate of thymocyte migration into the blood. Collectively, our findings argue...

  11. High-protein diet in lactation leads to a sudden infant death-like syndrome in mice.

    Directory of Open Access Journals (Sweden)

    Thomas Walther

    Full Text Available BACKGROUND: It is well accepted that reduced foetal growth and development resulting from maternal malnutrition are associated with a number of chronic conditions in later life. On the other hand such generation-transcending effects of over-nutrition and of high-protein consumption in pregnancy and lactation, a proven fact in all developed societies, are widely unknown. Thus, we intended to describe the generation-transcending effects of a high-protein diet, covering most relevant topics of human life like embryonic mortality, infant death, and physical health in later life. METHODS: Female mice received control food (21% protein or were fed a high protein diet (42% protein during mating. After fertilisation, females stayed on their respective diet until weaning. At birth, pups were put to foster mothers who were fed with standard food or with HP diet. After weaning, control diet was fed to all mice. All offspring were monitored up to 360 days after birth. We determined glucose-tolerance and measured cardiovascular parameters using a tip-catheter. Finally, abdominal fat amount was measured. RESULTS AND CONCLUSIONS: We identified a worried impact of high-protein diet during pregnancy on dams' body weight gain, body weight of newborns, number of offspring, and also survival in later life. Even more important is the discovery that high-protein diet during lactation caused a more than eight-fold increase in offspring mortality. The observed higher newborn mortality during lactation is a hitherto non-described, unique link to the still incompletely understood human sudden infant death syndrome (SIDS. Thus, although offspring of lactating mothers on high-protein diet might have the advantage of lower abdominal fat within the second half of life, this benefit seems not to compensate the immense risk of an early sudden death during lactation. Our data may implicate that both pregnant women and lactating mothers should not follow classical high

  12. Protective Effects of Royal Jelly and Vitamin C against Experimental Hemolytic Anemia on Sex Hormones and Histochemical Testicle Tissue Histochemistry of Adult Mice

    OpenAIRE

    H Anbara; R Shahrooz; H Malekinejad; S Saadati

    2016-01-01

    Introduction: Phenylhydrazine (PHZ) is a well-known hemolytic compound inducing intoxication in erythrocytes. Therefore, the present study aimed to evaluate the protective effects of royal jelly and vitamin C against phenylhydrazine-induced damages in mouse testicles. Methods: In this study, 64 adult male mice were randomly and equally assigned to eight groups. The first group received normal saline (0.1ml) intraperitoneally. The second group received PHZ (6 mg/100 gr) intraperitoneally i...

  13. Epigallocatechin-3-gallate rescues LPS-impaired adult hippocampal neurogenesis through suppressing the TLR4-NF-κB signaling pathway in mice.

    Science.gov (United States)

    Seong, Kyung-Joo; Lee, Hyun-Gwan; Kook, Min Suk; Ko, Hyun-Mi; Jung, Ji-Yeon; Kim, Won-Jae

    2016-01-01

    Adult hippocampal dentate granule neurons are generated from neural stem cells (NSCs) in the mammalian brain, and the fate specification of adult NSCs is precisely controlled by the local niches and environment, such as the subventricular zone (SVZ), dentate gyrus (DG), and Toll-like receptors (TLRs). Epigallocatechin-3-gallate (EGCG) is the main polyphenolic flavonoid in green tea that has neuroprotective activities, but there is no clear understanding of the role of EGCG in adult neurogenesis in the DG after neuroinflammation. Here, we investigate the effect and the mechanism of EGCG on adult neurogenesis impaired by lipopolysaccharides (LPS). LPS-induced neuroinflammation inhibited adult neurogenesis by suppressing the proliferation and differentiation of neural stem cells in the DG, which was indicated by the decreased number of Bromodeoxyuridine (BrdU)-, Doublecortin (DCX)- and Neuronal Nuclei (NeuN)-positive cells. In addition, microglia were recruited with activatingTLR4-NF-κB signaling in the adult hippocampus by LPS injection. Treating LPS-injured mice with EGCG restored the proliferation and differentiation of NSCs in the DG, which were decreased by LPS, and EGCG treatment also ameliorated the apoptosis of NSCs. Moreover, pro-inflammatory cytokine production induced by LPS was attenuated by EGCG treatment through modulating the TLR4-NF-κB pathway. These results illustrate that EGCG has a beneficial effect on impaired adult neurogenesis caused by LPSinduced neuroinflammation, and it may be applicable as a therapeutic agent against neurodegenerative disorders caused by inflammation. PMID:26807022

  14. Improved function and proliferation of adult human beta cells engrafted in diabetic immunodeficient NOD-scid IL2rγnull mice treated with alogliptin

    Directory of Open Access Journals (Sweden)

    Jurczyk A

    2013-12-01

    Full Text Available Agata Jurczyk,1 Philip diIorio,1 Dean Brostowin,1 Linda Leehy,1 Chaoxing Yang,1 Fumihiko Urano,2 David M Harlan,3 Leonard D Shultz,4 Dale L Greiner,1 Rita Bortell1 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 2Department of Medicine, Washington University School of Medicine, St Louis, MO, 3Department of Medicine, University of Massachusetts Medical School, Worcester, MA, 4The Jackson Laboratory, Bar Harbor, ME, USA Purpose: Dipeptidyl-peptidase-4 (DPP-4 inhibitors are known to increase insulin secretion and beta cell proliferation in rodents. To investigate the effects on human beta cells in vivo, we utilize immunodeficient mice transplanted with human islets. The study goal was to determine the efficacy of alogliptin, a DPP-4 inhibitor, to enhance human beta cell function and proliferation in an in vivo context using diabetic immunodeficient mice engrafted with human pancreatic islets. Methods: Streptozotocin-induced diabetic NOD-scid IL2rγnull (NSG mice were transplanted with adult human islets in three separate trials. Transplanted mice were treated daily by gavage with alogliptin (30 mg/kg/day or vehicle control. Islet graft function was compared using glucose tolerance tests and non-fasting plasma levels of human insulin and C-peptide; beta cell proliferation was determined by bromodeoxyuridine (BrdU incorporation. Results: Glucose tolerance tests were significantly improved by alogliptin treatment for mice transplanted with islets from two of the three human islet donors. Islet-engrafted mice treated with alogliptin also had significantly higher plasma levels of human insulin and C-peptide compared to vehicle controls. The percentage of insulin+BrdU+ cells in human islet grafts from alogliptin-treated mice was approximately 10-fold more than from vehicle control mice, consistent with a significant increase in human beta cell proliferation. Conclusion: Human islet-engrafted immunodeficient mice

  15. Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female, but not male mice.

    Science.gov (United States)

    Philpot, Rex M; Ficken, Melissa; Wecker, Lynn

    2016-07-01

    Self-reports of chemotherapy-related cognitive deficits (CRCDs) are more prevalent among women than men, suggesting that women may be more vulnerable to the cognitive-impairing effects of chemotherapy. However, there have been no direct comparisons of females and males using objective measures of cognitive function either during or following exposure to the same chemotherapeutic regimen. The present study used an animal model, and a prospective longitudinal design, to assess sex differences in the manifestation and persistence of spatial memory deficits resulting from exposure to doxorubicin (DOX) and cyclophosphamide (CYP), commonly used anticancer drugs. The spatial memory of female and male BALB/C mice was assessed using the Morris water maze prior to, during and following 4 weekly intravenous injections of DOX (2.5mg/kg) and CYP (25mg/kg) or vehicle. Females receiving DOX+CYP experienced significant deficits in spatial memory during and following injections when compared to baseline or females receiving vehicle. These deficits persisted for at least 34 days following the final injection. In contrast, males receiving DOX+CYP injections did not exhibit alterations in spatial memory relative to baseline or males receiving vehicle. These findings indicate that females may be more vulnerable than males to the cognitive-impairing effects of DOX+CYP and demonstrate that deficits in females persist for at least several weeks following drug exposure. Preclinical studies of CRCDs should parallel clinical work by including females and examine sex specific factors as potential mechanisms. PMID:27083301

  16. Adult glucocorticoid exposure leads to transcriptional and DNA methylation changes in nuclear steroid receptors in the hippocampus and kidney of mouse male offspring.

    Science.gov (United States)

    Petropoulos, Sophie; Matthews, Stephen G; Szyf, Moshe

    2014-02-01

    Synthetic glucocorticoids (sGCs) are commonly prescribed for the management of inflammatory and endocrine disorders. However, nothing is known regarding the effects of sGC on adult germline methylome and whether these effects can be transmitted to the next generation. We hypothesized that administration of sGC to adult male mice alters DNA methylation in mature sperm and modifies the transcription and methylation of steroid receptors in male F1 offspring. Adult C57BL/6 males (n = 10/group) were injected on five consecutive days with 1 mg/kg sGC (i.e., dexamethasone) or vehicle and euthanized 35 or 60 days after initial treatment or bred with control females (60 days postinitial treatment; n = 5/group). A significant increase in global non-CpG methylation was observed in F0 sperm 60 days following sGC treatment. In the hippocampus and kidney of Postnatal Day 50 (PND50) and PND240 male offspring derived from fathers exposed to sGC, significant differences in mineralocorticoid receptor (Nr3c2; Mr), estrogen alpha receptor (Nr3a1; Ers1), and glucocorticoid receptor (Nr3c1; Gr) expression were observed. Furthermore, significant demethylation in regulatory regions of Mr, Gr, and Esr1 was observed in the PND50 kidney derived from fathers exposed to sGC. This is the first demonstration that paternal pharmacological exposure to sGC can alter the expression and DNA methylation of nuclear steroid receptors in brain and somatic tissues of offspring. These findings provide proof of principle that adult male exposure to sGC can affect DNA methylation and gene expression in offspring, indicating the possibility that adult experiences that evoke increases in endogenous glucocorticoid (i.e., stress) might have similar effects.

  17. Calcium/calmodulin-dependent kinase IV contributes to translation-dependent early synaptic potentiation in the anterior cingulate cortex of adult mice

    Directory of Open Access Journals (Sweden)

    Toyoda Hiroki

    2010-09-01

    Full Text Available Abstract Calcium/calmodulin-dependent kinase IV (CaMKIV phosphorylates the major transcription factor, cyclic AMP-responsive element binding protein (CREB, which plays key roles in synaptic plasticity and memory consolidation. Our previous study showed that long-term potentiation (LTP in the anterior cingulate cortex (ACC was significantly enhanced in transgenic mice overexpressing CaMKIV. Considering that the CaMKIV-CREB pathway plays a central role in the protein synthesis-dependent LTP, it is possible that upregulation of CaMKIV contributes to enhancement of LTP by promoting protein synthesis. To test this possibility, we examined the effects of transcription and translation inhibitors on synaptic potentiation induced by pairing of synaptic activity with postsynaptic depolarization (paired training in ACC pyramidal neurons of wild-type and CaMKIV transgenic mice. We found that synaptic potentiation induced by paired training was partially inhibited by transcription or translation inhibitors both in wild-type and CaMKIV transgenic mice; the extent of inhibition was markedly larger in the CaMKIV transgenic mice than in the wild-type mice. Biochemical and immunohistochemical studies revealed that CaMKIV was distributed in the membrane, cytosol and nucleus of ACC neurons. Our results reveal in the first time a transcription- and translation-dependent component of early synaptic LTP in adult ACC synapses, and demonstrate that CaMKIV enhances early synaptic potentiation by activating new protein synthesis.

  18. The Intrauterine and Nursing Period Is a Window of Susceptibility for Development of Obesity and Intestinal Tumorigenesis by a High Fat Diet in Min/+ Mice as Adults

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    Ha Thi Ngo

    2015-01-01

    Full Text Available We studied how obesogenic conditions during various life periods affected obesity and intestinal tumorigenesis in adult C57BL/6J-Min (multiple intestinal neoplasia/+ mice. The mice were given a 10% fat diet throughout life (negative control or a 45% fat diet in utero, during nursing, during both in utero and nursing, during adult life, or during their whole life-span, and terminated at 11 weeks for tumorigenesis (Min/+ or 23 weeks for obesogenic effect (wild-type. Body weight at 11 weeks was increased after a 45% fat diet during nursing, during both in utero and nursing, and throughout life, but had normalized at 23 weeks. In the glucose tolerance test, the early exposure to a 45% fat diet in utero, during nursing, or during both in utero and nursing, did not affect blood glucose, whereas a 45% fat diet given to adults or throughout life did. However, a 45% fat diet during nursing or during in utero and nursing increased the number of small intestinal tumors. So did exposures to a 45% fat diet in adult life or throughout life, but without increasing the tumor numbers further. The intrauterine and nursing period is a window of susceptibility for dietary fat-induced obesity and intestinal tumor development.

  19. Dietary early-life exposure to contaminated eels does not impair spatial cognitive performances in adult offspring mice as assessed in the Y-maze and the Morris water maze.

    Science.gov (United States)

    Dridi, Imen; Leroy, Delphine; Guignard, Cédric; Scholl, Georges; Bohn, Torsten; Landoulsi, Ahmed; Thomé, Jean-Pierre; Eppe, Gauthier; Soulimani, Rachid; Bouayed, Jaouad

    2014-12-01

    Many environmental contaminants are introduced via the diet and may act as neurotoxins and endocrine disrupters, especially influencing growing organisms in early life. The purpose of this study was to examine whether dietary exposure of dams to fish naturally contaminated with xenobiotics, especially with polychlorinated biphenyls (PCBs) and heavy metals (e.g., mercury and lead), resulted in cognitive function deficits in adult offspring mice. Daily, four groups of dams (n = 10/group) ingested standard diet plus paste with/without eels, during gestation and lactation, from gestational day (GD) six until post natal day (PND) 21 (weaning). Dams orally ingested a standardized amount of eel (0.8 mg kg(-1) d(-1)) containing the six non-dioxin-like (NDL) PCBs (Σ6 NDL-PCBs: 28, 52, 101, 138, 153, and 180) at 0, 85, 216, and 400 ng kg(-1) d(-1). Results showed that early-life exposure to contaminated eels did not (compared to non-exposed controls) impair immediate working memory in the Y-maze in the offspring assessed at PND 38. Furthermore, it did not significantly impact spatial learning and retention memory as measured in the Morris water maze in adult offspring mice (PND 120-123). Our results suggest that perinatal exposure to contaminated eels does not affect spatial cognitive performances, as assessed by the Y-maze and Morris water maze at adult age. Adverse effects of xenobiotics reported earlier might be camouflaged by beneficial eel constituents, such as n-3 fatty acids. However, additional studies are needed to differentiate between potential positive and negative effects following consumption of food items both rich in nutrients and contaminants.

  20. Adolescent and adult responsiveness to the incentive value of cocaine reward in mice: role of neuronal nitric oxide synthase (nNOS) gene.

    Science.gov (United States)

    Balda, Mara A; Anderson, Karen L; Itzhak, Yossef

    2006-08-01

    A major concern in adolescent psychostimulant abuse is the long-term consequence of this practice, because early drug exposure may cause long-term adaptations, which render the organism more susceptible to drug abuse later in life. The incentive value of drug and natural reward in rodents is commonly assessed by the conditioned place preference (CPP) paradigm, which involves Pavlovian learning. The aims of the present study were to investigate: a) the acquisition, expression, maintenance and reinstatement of cocaine CPP from periadolescence (PD24-45) through adulthood (PD70); b) potential sexual dimorphism in adolescence and adulthood in response to cocaine-induced CPP; and c) the role of the neuronal nitric oxide synthase (nNOS) gene in long-term neural plasticity underlying responsiveness to cocaine and cocaine-associated cues. Adolescent wild type (WT) mice acquired significant cocaine (20 mg/kg) CPP that was maintained from PD24 through PD43. Upon extinction, CPP was reinstated in adulthood (PD70) following a priming injection of cocaine (5 mg/kg). In contrast, cocaine CPP acquired between PD26 and PD31 in adolescent nNOS knockout (KO) mice, was neither maintained nor reinstated by cocaine. There was no sexual dimorphism in adolescent WT and KO mice. Genotype differences and sexual dimorphism were observed in adult mice. Cocaine CPP in adult WT males (PD89-94) was maintained for 4 weeks post training, and subsequently reinstated by cocaine priming; the magnitude of CPP in adult WT males was lower than in female counterparts. CPP in adult KO males (PD88-93) was neither maintained nor reinstated by cocaine priming; in contrast, CPP in adult KO females was not significantly different from adult WT females. Results suggest that the nNOS gene is essential during adolescence of both sexes for the development of long-term neural plasticity underlying responsiveness to the incentive value of cocaine reward. Sexual dimorphism in response to cocaine CPP emerges in

  1. Depletion of nucleus accumbens dopamine leads to impaired reward and aversion processing in mice: Relevance to motivation pathologies.

    Science.gov (United States)

    Bergamini, Giorgio; Sigrist, Hannes; Ferger, Boris; Singewald, Nicolas; Seifritz, Erich; Pryce, Christopher R

    2016-10-01

    Dopamine (DA) neurotransmission, particularly the ventral tegmental area-nucleus accumbens (VTA-NAcc) projection, underlies reward and aversion processing, and deficient DA function could underlie motivational impairments in psychiatric disorders. 6-hydroxydopamine (6-OHDA) injection is an established method for chronic DA depletion, principally applied in rat to study NAcc DA regulation of reward motivation. Given the increasing focus on studying environmental and genetic regulation of DA function in mouse models, it is important to establish the effects of 6-OHDA DA depletion in mice, in terms of reward and aversion processing. This mouse study investigated effects of 6-OHDA-induced NAcc DA depletion using the operant behavioural test battery of progressive ratio schedule (PRS), learned non-reward (LNR), learned helplessness (LH), treadmill, and in addition Pavlovian fear conditioning. 6-OHDA NAcc DA depletion, confirmed by ex vivo HPLC-ED, reduced operant responding: for gustatory reward under effortful conditions in the PRS test; to a stimulus recently associated with gustatory non-reward in the LNR test; to escape footshock recently experienced as uncontrollable in the LH test; and to avoid footshock by physical effort in the treadmill test. Evidence for specificity of effects to NAcc DA was provided by lack of effect of medial prefrontal cortex DA depletion in the LNR and LH tests. These findings add significantly to the evidence that NAcc DA is a major regulator of behavioural responding, particularly at the motivational level, to both reward and aversion. They demonstrate the suitability of mouse models for translational study of causation and reversal of pathophysiological DA function underlying motivation psychopathologies. PMID:27036890

  2. Pituitary-specific overexpression of porcine follicle-stimulating hormone leads to improvement of female fecundity in BAC transgenic mice.

    Directory of Open Access Journals (Sweden)

    Mingjun Bi

    Full Text Available Follicle-stimulating hormone (FSH is a pituitary glycoprotein that, together with luteinizing hormone, plays a crucial role in ovarian folliculogenesis and female fertility. We previously found that FSH beta is a major gene controlling high prolificacy of Chinese Erhualian pigs. To directly study the biological effects on reproductive function of porcine FSH (pFSH for polyovulatory species, we generated a novel gain-of-function mouse model using a bacterial artificial chromosome (BAC system to jointly introduce 92 kb and 165 kb genomic fragments comprising the pFSH α- and β-subunit genes. These directed the physiological expression of pFSH with the same temporal and spatial pattern as endogenous FSH in female transgenic (TG mice. Serum levels of biologically active pFSH heterodimers in independent TG lines ranged from 6.36 to 19.83 IU/L. High basal pFSH activity led to a significant reduction of serum LH and testosterone levels in TG females compared to wild-type (WT littermates, yet endogenous FSH and estradiol levels were significantly elevated. Interestingly, ovarian histology showed that the number of corpora lutea was significantly higher at 14 and 28 weeks of age in TG females and breeding curves revealed that mean litter sizes of TG females were obviously larger than for WT littermates before 52 weeks of age. These findings indicate that pituitary-specific overexpression of pFSH within physiological boundaries can increase ovulation rate and litter size, but it does not cause reproductive defects. Therefore, our TG mouse model provides exciting insights for investigating the actions of pFSH in vivo.

  3. Mapping of fluorescent protein-expressing neurons and axon pathways in adult and developing Thy1-eYFP-H transgenic mice.

    Science.gov (United States)

    Porrero, Cesar; Rubio-Garrido, Pablo; Avendaño, Carlos; Clascá, Francisco

    2010-07-23

    Transgenic mouse lines in which a fluorescent protein is constitutively expressed under the Thy1 gene promoter have become important models in cell biology and pathology studies of specific neuronal populations. As a result of positional insertion and/or copy number effects on the transgene, the populations expressing the fluorescent protein (eYFP+) vary markedly among the different mice lines. However, identification of the eYFP+ subpopulations has remained sketchy and fragmentary even for the most widely used lines such as Thy1-eYFP-H mice (Feng, G., Mellor, R.H., Bernstein, M., Keller-Peck, C., Nguyen, Q.T., Wallace, M., Nerbonne, J.M., Lichtman and J.W., Sanes. J.R. 2000. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41-51). Here, we provide a comprehensive mapping of labeled cell types throughout the central nervous system in adult and postnatal (P0-P30) Thy1-eYFP-H mice. Cell type identification was based on somatodendritic morphology, axon trajectories, and, for cortical cells, retrograde labeling with Fast Blue to distinguish between subpopulations with different axonal targets. In the neocortex, eYFP+ cells are layers 5 and 6 pyramidal neurons, whose abundance and sublaminar distribution varies markedly between areas. Labeling is particularly prevalent in the corticospinal cells; as a result, the pyramidal pathway axons are conspicuously labeled down to the spinal cord. Large populations of hippocampal, subicular and amygdaloid projection neurons are eYFP+ as well. Additional eYFP+ cell groups are located in specific brainstem nuclei. Present results provide a comprehensive reference dataset for adult and developmental studies using the Thy1-eYFP-H mice strain, and show that this animal model may be particularly suitable for studies on the cell biology of corticospinal neurons.

  4. Prenatal nicotine exposure enhances Cx43 and Panx1 unopposed channel activity in brain cells of adult offspring mice fed a high-fat/cholesterol diet

    Directory of Open Access Journals (Sweden)

    Juan Andrés Orellana

    2014-12-01

    Full Text Available Nicotine, the most important neuroteratogen of tobacco smoke, can reproduce brain and cognitive disturbances per se when administered prenatally. However, it is still unknown if paracrine signaling among brain cells participates in prenatal nicotine-induced brain impairment of adult offspring. Paracrine signaling is partly mediated by unopposed channels formed by connexins (hemichannels and pannexins serving as aqueous pores permeable to ions and small signaling molecules, allowing exchange between the intra- and extracellular milieus. Our aim was to address whether prenatal nicotine exposure changes the activity of those channels in adult mice offspring under control conditions or subjected to a second challenge during young ages: high-fat/cholesterol (HFC diet. To induce prenatal exposure to nicotine, osmotic minipumps were implanted in CF1 pregnant mice at gestational day 5 to deliver nicotine bitartrate or saline (control solutions. After weaning, offspring of nicotine-treated or untreated pregnant mice were fed ad libitum with chow or HFC diets for 8 weeks. The functional state of Cx43 and Panx1 unopposed channels was evaluated by dye uptake experiments in hippocampal slices from 11-week-old mice. We found that prenatal nicotine increased the opening of Cx43 hemichannels in astrocytes, and Panx1 channels in microglia and neurons only if offspring mice were fed with HFC diet. Blockade of iNOS, COX2 and EP1, P2X7 and NMDA receptors, showed differential inhibition of prenatal nicotine-induced channel opening in glial cells and neurons. Importantly, inhibition of the above mentioned enzymes and receptors, or blockade of Cx43 and Panx1 unopposed channels greatly reduced ATP and glutamate release from hippocampal slices of prenatally nicotine-exposed offspring. We propose that unregulated gliotransmitter release through Cx43 and Panx1 unopposed channels may participate in brain alterations observed in offspring of mothers exposed to tobacco smoke

  5. Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF.

    Science.gov (United States)

    Worm, Jesper; Stenvang, Jan; Petri, Andreas; Frederiksen, Klaus Stensgaard; Obad, Susanna; Elmén, Joacim; Hedtjärn, Maj; Straarup, Ellen Marie; Hansen, Jens Bo; Kauppinen, Sakari

    2009-09-01

    microRNA-155 (miR-155) has been implicated as a central regulator of the immune system, but its function during acute inflammatory responses is still poorly understood. Here we show that exposure of cultured macrophages and mice to lipopolysaccharide (LPS) leads to up-regulation of miR-155 and that the transcription factor c/ebp Beta is a direct target of miR-155. Interestingly, expression profiling of LPS-stimulated macrophages combined with overexpression and silencing of miR-155 in murine macrophages and human monocytic cells uncovered marked changes in the expression of granulocyte colony-stimulating factor (G-CSF), a central regulator of granulopoiesis during inflammatory responses. Consistent with these data, we show that silencing of miR-155 in LPS-treated mice by systemically administered LNA-antimiR results in derepression of the c/ebp Beta isoforms and down-regulation of G-CSF expression in mouse splenocytes. Finally, we report for the first time on miR-155 silencing in vivo in a mouse inflammation model, which underscores the potential of miR-155 antagonists in the development of novel therapeutics for treatment of chronic inflammatory diseases. PMID:19596814

  6. Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality

    DEFF Research Database (Denmark)

    Buchou, Thierry; Vernet, Muriel; Blond, Olivier;

    2003-01-01

    . Attempts to generate homozygous embryonic stem (ES) cells failed. By using a conditional knockout approach, we show that lack of CK2beta is deleterious for mouse ES cells and primary embryonic fibroblasts. This is in contrast to what occurs with yeast cells, which can survive without functional CK2beta...... in mice leads to postimplantation lethality. Mutant embryos were reduced in size at embryonic day 6.5 (E6.5). They did not exhibit signs of apoptosis but did show reduced cell proliferation. Mutant embryos were resorbed at E7.5. In vitro, CK2beta(-/-) morula development stopped after the blastocyst stage......Protein kinase CK2 is a ubiquitous protein kinase implicated in proliferation and cell survival. Its regulatory beta subunit, CK2beta, which is encoded by a single gene in mammals, has been suspected of regulating other protein kinases. In this work, we show that knockout of the CK2beta gene...

  7. Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice.

    Science.gov (United States)

    Miyazaki, Satsuki; Tashiro, Fumi; Miyazaki, Jun-Ichi

    2016-01-01

    A promising approach to new diabetes therapies is to generate β cells from other differentiated pancreatic cells in vivo. Because the acinar cells represent the most abundant cell type in the pancreas, an attractive possibility is to reprogram acinar cells into β cells. The transcription factor Pdx1 (Pancreas/duodenum homeobox protein 1) is essential for pancreatic development and cell lineage determination. Our objective is to examine whether exogenous expression of Pdx1 in acinar cells of adult mice might induce reprogramming of acinar cells into β cells. We established a transgenic mouse line in which Pdx1 and EGFP (enhanced green fluorescent protein) could be inducibly expressed in the acinar cells. After induction of Pdx1, we followed the acinar cells for their expression of exocrine and endocrine markers using cell-lineage tracing with EGFP. The acinar cell-specific expression of Pdx1 in adult mice reprogrammed the acinar cells as endocrine precursor cells, which migrated into the pancreatic islets and differentiated into insulin-, somatostatin-, or PP (pancreatic polypeptide)-producing endocrine cells, but not into glucagon-producing cells. When the mice undergoing such pancreatic reprogramming were treated with streptozotocin (STZ), the newly generated insulin-producing cells were able to ameliorate STZ-induced diabetes. This paradigm of in vivo reprogramming indicates that acinar cells hold promise as a source for new islet cells in regenerative therapies for diabetes. PMID:27526291

  8. Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice

    Science.gov (United States)

    Miyazaki, Satsuki; Tashiro, Fumi; Miyazaki, Jun-ichi

    2016-01-01

    A promising approach to new diabetes therapies is to generate β cells from other differentiated pancreatic cells in vivo. Because the acinar cells represent the most abundant cell type in the pancreas, an attractive possibility is to reprogram acinar cells into β cells. The transcription factor Pdx1 (Pancreas/duodenum homeobox protein 1) is essential for pancreatic development and cell lineage determination. Our objective is to examine whether exogenous expression of Pdx1 in acinar cells of adult mice might induce reprogramming of acinar cells into β cells. We established a transgenic mouse line in which Pdx1 and EGFP (enhanced green fluorescent protein) could be inducibly expressed in the acinar cells. After induction of Pdx1, we followed the acinar cells for their expression of exocrine and endocrine markers using cell-lineage tracing with EGFP. The acinar cell-specific expression of Pdx1 in adult mice reprogrammed the acinar cells as endocrine precursor cells, which migrated into the pancreatic islets and differentiated into insulin-, somatostatin-, or PP (pancreatic polypeptide)-producing endocrine cells, but not into glucagon-producing cells. When the mice undergoing such pancreatic reprogramming were treated with streptozotocin (STZ), the newly generated insulin-producing cells were able to ameliorate STZ-induced diabetes. This paradigm of in vivo reprogramming indicates that acinar cells hold promise as a source for new islet cells in regenerative therapies for diabetes. PMID:27526291

  9. Beta-amyloid precursor protein cleavage enzyme-1 expression in adult rat retinal neurons in the early period after lead exposure

    Institute of Scientific and Technical Information of China (English)

    Jufang Huang; Kai Huang; Lei Shang; Hui Wang; Xiaoxin Yan; Kun Xiong

    2011-01-01

    Previous studies have reported that non-human primates and rodents exposed to lead during brain development may become dependent on the deposition of pre-determined β-amyloid protein (Aβ), and exhibit upregulation of β-site amyloid precursor protein expression in old age. However, further evidence is required to elucidate the precise relationship and molecular mechanisms underlying the effects of early lead exposure on excessive Aβ production in adult mammals. The present study investigated the effects of lead exposure on expression of β-amyloid precursor protein cleavage enzyme-1 (BACE-1) in the rat retina and the production of Aβ in early development, using the retina as a window for studying Alzheimer's disease. Adult rats were intraocularly injected with different doses of lead acetate (10 μmol/L, 100 μmol/L, 1 mmol/L, 10 mmol/L and 100 mmol/L). The results revealed that retinal lead concentration, BACE-1 and its cleavage products β-C-terminal fragment and retina Aβ1-40 were all significantly increased in almost all of the lead exposure groups 48 hours later in a dose-dependent manner. The only exception was the 10 μmol/L group. The distribution of BACE-1 in the retina did not exhibit obvious changes, and no distinctive increase in the activation of retinal microglia was apparent. Similarly, retinal synaptophysin expression did not exhibit any clear changes. These data suggest that lead exposure can result in the upregulation of retinal neuron BACE-1 expression in the early period of development and further increase the overproduction of Aβ1-40 in the retina. Our results provided novel insight into the molecular mechanisms underlying environmentally-induced Alzheimer's disease.

  10. Activation of the central histaminergic system is involved in hypoxia-induced stroke tolerance in adult mice.

    Science.gov (United States)

    Fan, Yan-ying; Hu, Wei-wei; Dai, Hai-bin; Zhang, Jian-xiang; Zhang, Lu-yi; He, Ping; Shen, Yao; Ohtsu, Hiroshi; Wei, Er-qing; Chen, Zhong

    2011-01-01

    We hypothesized that activation of the central histaminergic system is required for neuroprotection induced by hypoxic preconditioning. Wild-type (WT) and histidine decarboxylase knockout (HDC-KO) mice were preconditioned by 3 hours of hypoxia (8% O(2)) and, 48 hours later, subjected to 30 minutes of middle cerebral artery (MCA) occlusion, followed by 24 hours of reperfusion. Hypoxic preconditioning improved neurologic function and decreased infarct volume in WT or HDC-KO mice treated with histamine, but not in HDC-KO or WT mice treated with α-fluoromethylhistidine (α-FMH, an inhibitor of HDC). Laser-Doppler flowmetry analysis showed that hypoxic preconditioning ameliorated cerebral blood flow (CBF) in the periphery of the MCA territory during ischemia in WT mice but not in HDC-KO mice. Histamine decreased in the cortex of WT mice after 2, 3, and 4 hours of hypoxia, and HDC activity increased after 3 hours of hypoxia. Vascular endothelial growth factor (VEGF) mRNA and protein expressions showed a greater increase after hypoxia than those in HDC-KO or α-FMH-treated WT mice. In addition, the VEGF receptor-2 antagonist SU1498 prevented the protective effect of hypoxic preconditioning in infarct volume and reversed increased peripheral CBF in WT mice. Therefore, endogenous histamine is an essential mediator of hypoxic preconditioning. It may function by enhancing hypoxia-induced VEGF expression.

  11. Exposure to music in the perinatal period enhances learning performance and alters BDNF/TrkB signaling in mice as adults.

    Science.gov (United States)

    Chikahisa, Sachiko; Sei, Hiroyoshi; Morishima, Masaki; Sano, Atsuko; Kitaoka, Kazuyoshi; Nakaya, Yutaka; Morita, Yusuke

    2006-05-15

    Music has been suggested to have a beneficial effect on various types of performance in humans. However, the physiological and molecular mechanism of this effect remains unclear. We examined the effect of music exposure during the perinatal period on learning behavior in adult mice, and measured the levels of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), which play critical roles in synaptic plasticity. In addition, we measured the levels of 3-phosphoinositide-dependent protein kinase-1 (PDK1) and mitogen-activated protein kinase (MAPK), downstream targets of two main pathways in BDNF/TrkB signaling. Music-exposed mice completed a maze learning task with fewer errors than the white noise-exposed mice and had lower levels of BDNF and higher levels of TrkB and PDK1 in the cortex. MAPK levels were unchanged. Furthermore, TrkB and PDK1 protein levels in the cortex showed a significant negative correlation with the number of errors on the maze. These results suggest that perinatal exposure of mice to music has an influence on BDNF/TrkB signaling and its intracellular signaling pathway targets, including PDK1, and thus may induce improved learning and memory functions.

  12. Signals leading to the activation of NF-kappa B transcription factor are stronger in neonatal than adult T lymphocytes.

    Science.gov (United States)

    Kilpinen, S; Henttinen, T; Lahdenpohja, N; Hulkkonen, J; Hurme, M

    1996-07-01

    The molecular background of the defects in the immune reactivity of human neonates has not been fully elucidated. As the NF-kappa B transcription factor has a central role in the control of transcription of several genes involved in immune and inflammatory responses, the authors have analysed the activation of NF-kappa B in human umbilical cord T lymphocytes. The activity was tested by quantitating the nuclear proteins binding to an oligonucleotide containing the consensus kappa B binding sequence (electrophoretic mobility shift assay). The data obtained demonstrate that phorbol dibutyrate/calcium ionophore A23187 (PDBu/iono) combination induced a clearly higher nuclear translocation of NF-kappa B in neonatal than adult T cells. This higher NF-kappa B activity was restricted to the CD4+ T-cell subset. Analysis of the nuclear extracts with antibodies directed against the major components of NF-kappa B the p50 and RelA (p65) proteins, indicated that the composition of NF-kappa B was similar in neonatal and adult cells. These results suggest that neonatal T cells are exposed to oxidative stress-inducing signals during delivery and/or are inherently more sensitive to NF-kappa B activating signals than adult T cells. PMID:8693296

  13. Protective effect of royal jelly on the sperm parameters and testosterone level and lipid peroxidation in adult mice treated with oxymetholone

    Directory of Open Access Journals (Sweden)

    Ensieh Zahmatkesh

    2014-01-01

    Full Text Available Objectives: The aim of the present study was to evaluate protective effect of royal jelly on sperm parameters, testosterone level, and malondialdehyde (MDA production in mice. Materials and Methods: Thirty-two adult male NMRI mice weighing 30±2 g were used. All the animals were divided into 4 groups. Control group: received saline 0.1 ml/mouse/day orally for 30 days. Royal Jelly group (RJ: received royal jelly at dose of 100 mg/kg daily for 30 days orally. Oxymetholone group: the received Oxymetholone (OX at dose of 5 mg/kg daily for 30 days orally. Royal Jelly+Oxymetholone group: received royal jelly at dose of 100 mg/kg/day orally concomitant with OX administration. Sperm count, sperm motility, viability, maturity, and DNA integrity were analyzed. Furthermore, serum testosterone and MDA concentrations were determined. Results: In Oxymetholone group, sperm count, motility as well as testosterone concentration reduced significantly (p

  14. Cardiac and non-cardiac causes of T-wave inversion in the precordial leads in adult subjects: A Dutch case series and review of the literature

    Institute of Scientific and Technical Information of China (English)

    Salah; AM; Said; Rene; Bloo; Ramon; de; Nooijer; Andries; Slootweg

    2015-01-01

    AIM: To describe the electrocardiographic(ECG) phenomena characterized by T-wave inversion in the precordial leads in adults and to highlight its differential diagnosis. METHODS: A retrospective chart review of 8 adult patients who were admitted with ECG T-wave inversion in the anterior chest leads with or without prolongation of corrected QT(QTc) interval. They had different clinical conditions. Each patient underwent appropriate clinical assessment including investigation for myocardial involvement. Single and multimodality noninvasive, semi-invasive and invasive diagnostic approach were used to ascertain the diagnosis. The diagnostic assessment included biochemical investigation, cardiac and abdominal ultrasound, cerebral and chest computed tomography, nuclear medicine and coronary angiography.RESULTS: Eight adult subjects(5 females) with a mean age of 66 years(range 51 to 82) are analyzed. The etiology of T-wave inversion in the precordial leads were diverse. On admission, all patients had normal blood pressure and the ECG showed sinus rhythm. Five patients showed marked prolongation of the QTc interval. The longest QTc interval(639 ms) was found in the patient with pheochromocytoma. Giant T-wave inversion(≥ 10 mm) was found in pheochromocytoma followed by electroconvulsive therapy and finally ischemic heart disease. The deepest T-wave was measured in lead V3(5 ×). In 3 patients presented with mild T-wave inversion(patients 1, 5 and 4 mm), the QTc interval was not prolonged(432, 409 and 424 msec), respectively.CONCLUSION: T-wave inversion associated with or without QTc prolongation requires meticulous history taking, physical examination and tailored diagnostic modalities to reach rapid and correct diagnosis to establish appropriate therapeutic intervention.

  15. Effects of Duloxetine Treatment on Cognitive Flexibility and BDNF Expression in the mPFC of Adult Male Mice Exposed to Social Stress during Adolescence

    Science.gov (United States)

    Xu, Hang; Zhang, Yu; Zhang, Fan; Yuan, San-na; Shao, Feng; Wang, Weiwen

    2016-01-01

    Early stress is a significant risk factor for the onset of mood disorders such as depression during adulthood. Impairments in cognitive flexibility mediated by prefrontal cortex (PFC) dysfunction are increasingly recognized as important etiological and pathological factors in the development of depression. Our previous study demonstrated that social defeat stress during early adolescence produced delayed deficits in cognitive flexibility in adult mice. The potential molecular mechanisms underlying these long-term consequences remain unclear. One candidate molecule is brain-derived neurotrophic factor (BDNF), which plays a vital role in neural development and synaptic plasticity. In this study, we initially examined the effects of adolescent social stress on cognitive flexibility and PFC BDNF expression within a week after the last stress exposure and 6 weeks later during adulthood. Adolescent (PND 28) male mice were subjected to stress or control manipulation for 10 days. The attentional set-shifting task (AST) was used to assess cognitive flexibility. Levels of BDNF mRNA and protein in the PFC were examined after behavioral testing. The results demonstrated that previously stressed mice exhibited delayed extra-dimensional set-shifting deficits in AST when tested as adults but not when tested as adolescents. Consistent with the cognitive alterations, adolescent stress induced dynamic alterations in BDNF expression in the medial PFC (mPFC), with a transient increase observed shortly after the stress, followed by a decrease 6 weeks later during adulthood. Next, we further determined the effects of chronic treatment with the antidepressant duloxetine during early adulthood on cognitive and molecular alterations induced by adolescent stress. Compared with the controls, duloxetine treatment reversed the cognitive deficits and increased the BDNF protein expression in the mPFC during adulthood in previously stressed mice. These findings demonstrated that BDNF expression

  16. Exposure to hypergravity during specific developmental periods differentially affects metabolism and vestibular reactions in adult C57BL /6j mice.

    Science.gov (United States)

    Bojados, Mickael; Jamon, Marc

    2011-12-01

    The development of the posturo-motor control of movement is conditioned by Earth's gravity. Missing or altered gravity during the critical periods of development delays development and induces durable changes in the vestibular, cerebellar, or muscular structures, but these are not consistently mirrored at a functional level. The differences in the time schedule of vestibular and motor development could contribute to this inconstancy. To investigate the influence of gravity on the development of vestibular and locomotor functions, we analysed the performance of adult mice subjected to hypergravity during the time covering either the vestibular or locomotor development. The mice were centrifuged at 2 g from embryonic day (E) 0 to postnatal day (P) 10 (PRE), from P10 to P30 (POST), from E0 to P30 (FULL), and from E7 to P21. Their muscular force, anxiety level, vestibular reactions, and aerobic capacity during treadmill training were then evaluated at the age of 2 and 6 months. The performance of young adults varied in relation to the period of exposure to hypergravity. The mice that acquired locomotion in hypergravity (POST and FULL) showed a lower forelimb force and delayed vestibular reactions. The mice centrifuged from conception to P10 (PRE) showed a higher aerobic capacity during treadmill training. The differences in muscular force and vestibular reactions regressed with age, but the metabolic changes persisted. These results confirmed that early exposure to hypergravity induces qualitative changes depending on the period of exposure. They validated, at a functional level, the existence of several critical periods for adaptation to gravity. PMID:22122506

  17. Adult hippocampal neurogenesis and mRNA expression are altered by perinatal arsenic exposure in mice and restored by brief exposure to enrichment.

    Directory of Open Access Journals (Sweden)

    Christina R Tyler

    Full Text Available Arsenic is a common and pervasive environmental contaminant found in drinking water in varying concentrations depending on region. Exposure to arsenic induces behavioral and cognitive deficits in both human populations and in rodent models. The Environmental Protection Agency (EPA standard for the allotment of arsenic in drinking water is in the parts-per-billion range, yet our lab has shown that 50 ppb arsenic exposure during development can have far-reaching consequences into adulthood, including deficits in learning and memory, which have been linked to altered adult neurogenesis. Given that the morphological impact of developmental arsenic exposure on the hippocampus is unknown, we sought to evaluate proliferation and differentiation of adult neural progenitor cells in the dentate gyrus after 50 ppb arsenic exposure throughout the perinatal period of development in mice (equivalent to all three trimesters in humans using a BrdU pulse-chase assay. Proliferation of the neural progenitor population was decreased by 13% in arsenic-exposed mice, but was not significant. However, the number of differentiated cells was significantly decreased by 41% in arsenic-exposed mice compared to controls. Brief, daily exposure to environmental enrichment significantly increased proliferation and differentiation in both control and arsenic-exposed animals. Expression levels of 31% of neurogenesis-related genes including those involved in Alzheimer's disease, apoptosis, axonogenesis, growth, Notch signaling, and transcription factors were altered after arsenic exposure and restored after enrichment. Using a concentration previously considered safe by the EPA, perinatal arsenic exposure altered hippocampal morphology and gene expression, but did not inhibit the cellular neurogenic response to enrichment. It is possible that behavioral deficits observed during adulthood in animals exposed to arsenic during development derive from the lack of differentiated neural

  18. Asthma induction in mice leads to appearance of alpha2-3- and alpha2-6-linked sialic acid residues in respiratory goblet-like cells

    DEFF Research Database (Denmark)

    Kirkeby, Svend; Jensen, Niels-Erik Viby; Mandel, Ulla;

    2008-01-01

    Allergic asthmatic inflammation in mice was induced by sensitization with ovalbumin and lipopolysaccharide from Escherichia coli and visualized in the airways of asthmatic mice by spatial and temporal changes of carbohydrates containing sialic acid residues. Immunohistochemistry was used to demon...

  19. Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice

    Science.gov (United States)

    Yun, Sanghee; Donovan, Michael H.; Ross, Michele N.; Richardson, Devon R.; Reister, Robin; Farnbauch, Laure A.; Fischer, Stephanie J.; Riethmacher, Dieter; Gershenfeld, Howard K.; Lagace, Diane C.; Eisch, Amelia J.

    2016-01-01

    Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient–rather than permanent–inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA+ mice tested between 12–30 days post-TAM displayed indices of a stress-induced anxiety phenotype–longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype–longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety

  20. Long-term, low-level adolescent nicotine exposure produces dose-dependent changes in cocaine sensitivity and reward in adult mice.

    Science.gov (United States)

    Kelley, Brian M; Rowan, James D

    2004-01-01

    Cigarette smoking by adolescents is a strong predictor of future drug use, abuse, and dependence. While this "gateway drug effect" is assumed to be related to psychosocial factors, data from our laboratory suggests that adolescent nicotine use may permanently disrupt reward systems through changes in dopamine receptor function. Behavioral pharmacological methods known to be indirectly (motor activity) and directly (conditioned-place-preference) related to drug reinforcement were used to examine changes in cocaine sensitivity. Testing was performed on adult mice that were exposed to nicotine (0.3, 1.0, and 3.0 mg/kg, SC, M-F, b.i.d.) or saline during adolescence (postnatal days 25-57). Prior to testing, subjects had a 28 day drug-free, time-off period. After acclimation to the testing apparatus, the locomotor effects (30 min, 30 cm traveled) of cocaine (5, 10, and 20 mg/kg, IP) were measured daily; cocaine tests were preceded and followed by saline control tests. Following the acute dose-response curve, mice received saline followed by 5 days of 20.0 mg/kg cocaine. Thereafter, mice underwent condition-place-preference testing. A pre-test was performed to determine compartment preference (i.e., no injection, 20 min test). Cocaine (10 mg/kg, IP) was paired with the subjects non-preferred side and saline with the other. Conditioning sessions were conducted for 8 days with the order of drug/saline injections counter-balanced across subjects. A drug-free, post-test occurred on the day following the final conditioning session. A dose-dependent relationship between adolescent nicotine exposure and cocaine reward was noted in the adult mice across both test conditions. Subjects exposed to nicotine showed an increased response to cocaine's motor activating effects and a decreased response to cocaine's rewarding effects. A follow-up study was undertaken to evaluate dopamine D1, D2, and D3 receptor function in adult mice exposed to the highest dose of nicotine from the first

  1. Adolescent Social Defeat Induced Alterations in Social Behavior and Cognitive Flexibility in Adult Mice: Effects of Developmental Stage and Social Condition

    Science.gov (United States)

    Zhang, Fan; Yuan, Sanna; Shao, Feng; Wang, Weiwen

    2016-01-01

    Negative social experiences during adolescence increase the risk of psychiatric disorders in adulthood. Using “resident-intruder” stress, the present study aimed to investigate the effects of adolescent social defeat on emotional and cognitive symptoms associated with psychiatric disorders during adulthood and the effects of the developmental stage and social condition on this process. In Experiment 1, animals were exposed to social defeat or manipulation for 10 days during early adolescence (EA, postnatal days [PND] 28–37), late adolescence (LA, PND 38–47), and adulthood (ADULT, PND 70–79) and then singly housed until the behavioral tests. Behaviors, including social avoidance of the defeat context and cortically mediated cognitive flexibility in an attentional set-shifting task (AST), were assessed during the week following stress or after 6 weeks during adulthood. We determined that social defeat induced significant and continuous social avoidance across age groups at both time points. The mice that experienced social defeat during adulthood exhibited short-term impairments in reversal learning (RL) on the AST that dissipated after 6 weeks. In contrast, social defeat during EA but not LA induced a delayed deficit in extra-dimensional set-shifting (EDS) in adulthood but not during adolescence. In Experiment 2, we further examined the effects of social condition (isolation or social housing after stress) on the alterations induced by social defeat during EA in adult mice. The adult mice that had experienced stress during EA exhibited social avoidance similar to the avoidance identified in Experiment 1 regardless of the isolation or social housing after the stress. However, social housing after the stress ameliorated the cognitive flexibility deficits induced by early adolescent social defeat in the adult mice, and the social condition had no effect on cognitive function. These findings suggest that the effects of social defeat on emotion and cognitive

  2. Adolescent Social Defeat Induced Alterations in Social Behavior and Cognitive Flexibility in Adult Mice: Effects of Developmental Stage and Social Condition.

    Science.gov (United States)

    Zhang, Fan; Yuan, Sanna; Shao, Feng; Wang, Weiwen

    2016-01-01

    Negative social experiences during adolescence increase the risk of psychiatric disorders in adulthood. Using "resident-intruder" stress, the present study aimed to investigate the effects of adolescent social defeat on emotional and cognitive symptoms associated with psychiatric disorders during adulthood and the effects of the developmental stage and social condition on this process. In Experiment 1, animals were exposed to social defeat or manipulation for 10 days during early adolescence (EA, postnatal days [PND] 28-37), late adolescence (LA, PND 38-47), and adulthood (ADULT, PND 70-79) and then singly housed until the behavioral tests. Behaviors, including social avoidance of the defeat context and cortically mediated cognitive flexibility in an attentional set-shifting task (AST), were assessed during the week following stress or after 6 weeks during adulthood. We determined that social defeat induced significant and continuous social avoidance across age groups at both time points. The mice that experienced social defeat during adulthood exhibited short-term impairments in reversal learning (RL) on the AST that dissipated after 6 weeks. In contrast, social defeat during EA but not LA induced a delayed deficit in extra-dimensional set-shifting (EDS) in adulthood but not during adolescence. In Experiment 2, we further examined the effects of social condition (isolation or social housing after stress) on the alterations induced by social defeat during EA in adult mice. The adult mice that had experienced stress during EA exhibited social avoidance similar to the avoidance identified in Experiment 1 regardless of the isolation or social housing after the stress. However, social housing after the stress ameliorated the cognitive flexibility deficits induced by early adolescent social defeat in the adult mice, and the social condition had no effect on cognitive function. These findings suggest that the effects of social defeat on emotion and cognitive function are

  3. Adolescent social defeat induced alterations in anxious behavior and cognitive flexibility in adult mice: effects of developmental stage and social condition

    Directory of Open Access Journals (Sweden)

    Fang Zhang

    2016-07-01

    Full Text Available Negative social experiences during adolescence increase the risk of psychiatric disorders in adulthood. Using resident-intruder stress, the present study aimed to investigate the effects of adolescent social defeat on emotional and cognitive symptoms associated with psychiatric disorders during adulthood and the effects of the developmental stage and social condition on this process. In experiment 1, animals were exposed to social defeat or manipulation for 10 days during early adolescence (EA, PND 28-37, late adolescence (LA, PND 38-47, and adulthood (ADULT, PND 70-79 and then singly housed until the behavioral tests. Behaviors, including social avoidance of the defeat context and cortically mediated cognitive flexibility in an attentional set-shifting task (AST, were assessed during the week following stress or after 6 weeks during adulthood. We determined that social defeat induced significant and continuous social avoidance across age groups at both time points. The mice that experienced social defeat during adulthood exhibited short-term impairments in reversal learning on the AST that dissipated after 6 weeks. In contrast, social defeat during EA but not LA induced a delayed deficit in extra-dimensional set-shifting in adulthood but not during adolescence. In experiment 2, we further examined the effects of social condition (isolation or social housing after stress on the alterations induced by social defeat during EA in adult mice. The adult mice that had experienced stress during EA exhibited social avoidance similar to the avoidance identified in experiment 1 regardless of the isolation or social housing after the stress. However, social housing after the stress ameliorated the cognitive flexibility deficits induced by early adolescent social defeat in the adult mice, and the social condition had no effect on cognitive function. These findings suggest that the effects of social defeat on emotion and cognitive function are differentially

  4. Conditional deletion of Abca3 in alveolar type II cells alters surfactant homeostasis in newborn and adult mice

    OpenAIRE

    Besnard, Valérie; Matsuzaki, Yohei; Clark, Jean; Xu, Yan; Wert, Susan E.; Ikegami, Machiko; Stahlman, Mildred T.; Weaver, Timothy E.; Hunt, Alan N.; Postle, Anthony D.; Whitsett, Jeffrey A.

    2010-01-01

    ATP-binding cassette A3 (ABCA3) is a lipid transport protein required for synthesis and storage of pulmonary surfactant in type II cells in the alveoli. Abca3 was conditionally deleted in respiratory epithelial cells (Abca3Δ/Δ) in vivo. The majority of mice in which Abca3 was deleted in alveolar type II cells died shortly after birth from respiratory distress related to surfactant deficiency. Approximately 30% of the Abca3Δ/Δ mice survived after birth. Surviving Abca3Δ/Δ mice developed emphys...

  5. Methylphenidate treatment leads to abnormalities on krebs cycle enzymes in the brain of young and adult rats.

    Science.gov (United States)

    Réus, Gislaine Z; Scaini, Giselli; Furlanetto, Camila B; Morais, Meline O S; Jeremias, Isabela C; Mello-Santos, Lis Mairá; Freitas, Karolina V; Quevedo, João; Streck, Emilio L

    2013-08-01

    Studies have shown a relationship between energy metabolism and methylphenidate (MPH); however, there are no studies evaluating the effects of MPH in Krebs cycle. So, we investigated if MPH treatment could alter the activity of citrate synthase (CS), malate dehydrogenase (MD), and isocitrate dehydrogenase (ID) in the brain of young and adult Wistar rats. Our results showed that MPH (2 and 10 mg/kg) reduced CS in the striatum and prefrontal cortex (PF), with MPH at all doses in the cerebellum and hippocampus after chronic treatment in young rats. In adult rats the CS was reduced in the cerebellum after acute treatment with MPH at all doses, and after chronic treatment in the PF and cerebellum with MPH (10 mg/kg), and in the hippocampus with MPH (2 and 10 mg/kg). The ID decreased in the hippocampus and striatum with MPH (2 and 10 mg/kg), and in the cortex (10 mg/kg) after acute treatment in young rats. In adult rats acute treatment with MPH (2 and 10 mg/kg) reduced ID in the cerebellum, and with MPH (10 mg/kg) in the cortex; chronic treatment with MPH (10 mg/kg) decreased ID in the PF; with MPH (2 and 10 mg/kg) in the cerebellum, and with MPH at all doses in the hippocampus. The MD did not alter. In conclusion, our results suggest that MPH can alter enzymes of Krebs cycle in brain areas involved with circuits related with attention deficit hyperactivity disorder; however, such effects depend on age of animal and treatment regime.

  6. Low birth weight leads to obesity, diabetes and increased leptin levels in adults: the CoLaus study

    OpenAIRE

    Jornayvaz F.R.; Vollenweider P; Bochud M; Mooser V; Waeber G.; Marques-Vidal P.

    2016-01-01

    Background Low birth weight is associated with increased rates of obesity, insulin resistance and type 2 diabetes, but the precise mechanisms for this association remain unclear. We aimed to assess the relationships between birth weight and markers of glucose homeostasis or obesity in adults. Methods Cross-sectional population-based study on 1458 women and 1088 men aged 35–75 years living in Lausanne, Switzerland. Birth weight was self-reported and categorized into ≤2.5, 2.6–3.5, 3.6–4.0 and ...

  7. Human CD34+ CD133+ hematopoietic stem cells cultured with growth factors including Angptl5 efficiently engraft adult NOD-SCID Il2rγ-/- (NSG mice.

    Directory of Open Access Journals (Sweden)

    Adam C Drake

    Full Text Available Increasing demand for human hematopoietic stem cells (HSCs in clinical and research applications necessitates expansion of HSCs in vitro. Before these cells can be used they must be carefully evaluated to assess their stem cell activity. Here, we expanded cord blood CD34(+ CD133(+ cells in a defined medium containing angiopoietin like 5 and insulin-like growth factor binding protein 2 and evaluated the cells for stem cell activity in NOD-SCID Il2rg(-/- (NSG mice by multi-lineage engraftment, long term reconstitution, limiting dilution and serial reconstitution. The phenotype of expanded cells was characterized by flow cytometry during the course of expansion and following engraftment in mice. We show that the SCID repopulating activity resides in the CD34(+ CD133(+ fraction of expanded cells and that CD34(+ CD133(+ cell number correlates with SCID repopulating activity before and after culture. The expanded cells mediate long-term hematopoiesis and serial reconstitution in NSG mice. Furthermore, they efficiently reconstitute not only neonate but also adult NSG recipients, generating human blood cell populations similar to those reported in mice reconstituted with uncultured human HSCs. These findings suggest an expansion of long term HSCs in our culture and show that expression of CD34 and CD133 serves as a marker for HSC activity in human cord blood cell cultures. The ability to expand human HSCs in vitro should facilitate clinical use of HSCs and large-scale construction of humanized mice from the same donor for research applications.

  8. The depressogenic-like effect of acute and chronic treatment with dexamethasone and its influence on the activity of antidepressant drugs in the forced swim test in adult mice.

    Science.gov (United States)

    Wróbel, Andrzej; Serefko, Anna; Wlaź, Piotr; Poleszak, Ewa

    2014-10-01

    There is a close relationship between chronic stress, glucocorticoids and depression. Psychiatric and cognitive symptoms resembling major depression have been observed in patients experiencing elevated glucocorticoid levels, and a high percentage of people suffering from depression have undergone a stressful event/events prior to the onset of this mental disorder. In our study, we investigated whether acute and chronic treatment of dexamethasone induces depression-like behavior in mice and if dexamethasone therapy influences the activity of antidepressant drugs with diverse modes of action. The antidepressant-like effect was assessed by the forced swim test in adult mice. The depressogenic-like activity of dexamethasone turned out to be dose-dependent: only the highest tested dose of the glucocorticoid (i.e., 64μg/kg) given as a single injection increased immobility time, whereas 16μg/kg/day of dexamethasone (but not 4μg/kg/day) administered repeatedly induced a significant alteration in animal behavior. These depressogenic doses of dexamethasone (i.e., 64μg/kg and 16μg/kg/day for an acute and repeated administration, respectively) diminished the antidepressant potential of the therapeutic doses of imipramine (10mg/kg), amitriptyline (10mg/kg), tianeptine (25mg/kg), mianserin (10mg/kg), citalopram (15mg/kg) and moclobemide (25mg/kg). Two main findings of our study should be particularly underlined: (1) both single and repeated administration of dexamethasone evoked a depression-like behavior of mice, (2) both single and repeated administration of dexamethasone were able to modify the activity of the antidepressant agents from various pharmacological groups, which may lead to a considerable reduction in the efficacy of pharmacotherapy prescribed for patients with mood disorders.

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

    OpenAIRE

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

    2014-01-01

    Recent evidence suggests 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 hypothesized 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 ...

  10. Immature Neurons and Radial Glia, But Not Astrocytes or Microglia, Are Altered in Adult Cntnap2 and Shank3 Mice, Models of Autism

    Science.gov (United States)

    Martinez, Susana; Gould, Elizabeth

    2016-01-01

    Abstract Autism spectrum disorder (ASD) is often associated with cognitive deficits and excessive anxiety. Neuroimaging studies have shown atypical structure and neural connectivity in the hippocampus, medial prefrontal cortex (mPFC), and striatum, regions associated with cognitive function and anxiety regulation. Adult hippocampal neurogenesis is involved in many behaviors that are disrupted in ASD, including cognition, anxiety, and social behaviors. Additionally, glial cells, such as astrocytes and microglia, are important for modulating neural connectivity during development, and glial dysfunction has been hypothesized to be a key contributor to the development of ASD. Cells with astroglial characteristics are known to serve as progenitor cells in the developing and adult brain. Here, we examined adult neurogenesis in the hippocampus, as well as astroglia and microglia in the hippocampus, mPFC, and striatum of two models that display autism-like phenotypes, Cntnap2−/− and Shank3+/ΔC transgenic mice. We found a substantial decrease in the number of immature neurons and radial glial progenitor cells in the ventral hippocampus of both transgenic models compared with wild-type controls. No consistent differences were detected in the number or size of astrocytes or microglia in any other brain region examined. Future work is needed to explore the functional contribution of adult neurogenesis to autism-related behaviors as well as to temporally characterize glial plasticity as it is associated with ASD. PMID:27785461

  11. Multiple roads lead to Rome: combined high-intensity aerobic and strength training vs. gross motor activities leads to equivalent improvement in executive functions in a cohort of healthy older adults.

    Science.gov (United States)

    Berryman, Nicolas; Bherer, Louis; Nadeau, Sylvie; Lauzière, Séléna; Lehr, Lora; Bobeuf, Florian; Lussier, Maxime; Kergoat, Marie Jeanne; Vu, Thien Tuong Minh; Bosquet, Laurent

    2014-01-01

    The effects of physical activity on cognition in older adults have been extensively investigated in the last decade. Different interventions such as aerobic, strength, and gross motor training programs have resulted in improvements in cognitive functions. However, the mechanisms underlying the relationship between physical activity and cognition are still poorly understood. Recently, it was shown that acute bouts of exercise resulted in reduced executive control at higher relative exercise intensities. Considering that aging is characterized by a reduction in potential energy ([Formula: see text] max - energy cost of walking), which leads to higher relative walking intensity for the same absolute speed, it could be argued that any intervention aimed at reducing the relative intensity of the locomotive task would improve executive control while walking. The objective of the present study was to determine the effects of a short-term (8 weeks) high-intensity strength and aerobic training program on executive functions (single and dual task) in a cohort of healthy older adults. Fifty-one participants were included and 47 (age, 70.7 ± 5.6) completed the study which compared the effects of three interventions: lower body strength + aerobic training (LBS-A), upper body strength + aerobic training (UBS-A), and gross motor activities (GMA). Training sessions were held 3 times every week. Both physical fitness (aerobic, neuromuscular, and body composition) and cognitive functions (RNG) during a dual task were assessed before and after the intervention. Even though the LBS-A and UBS-A interventions increased potential energy to a higher level (Effect size: LBS-A-moderate, UBS-A-small, GMA-trivial), all groups showed equivalent improvement in cognitive function, with inhibition being more sensitive to the intervention. These findings suggest that different exercise programs targeting physical fitness and/or gross motor skills may lead to equivalent improvement in

  12. The scent of stress: environmental challenge in the peripartum environment of mice affects emotional behaviours of the adult offspring in a sex-specific manner.

    Science.gov (United States)

    Lerch, S; Dormann, C; Brandwein, C; Gass, P; Chourbaji, S

    2016-06-01

    Early adverse experiences are known to influence the risk of developing psychiatric disorders later. To shed further light on the development of laboratory mice, we systematically examined the influence of a prenatal or postnatal olfactory stressor, namely unfamiliar male mouse faeces, presented to pregnant or nursing mouse dams. Maternal and offspring behaviours were then examined. Maternal behaviours relative to controls revealed changes in nest building by the pregnant dams exposed to the unfamiliar faeces. There were no differences among groups on pup retrieval or exploration by the dams. Behavioural phenotyping of male and female offspring as adults included measures of exploration, anxiety, social and depressive-like behaviours. Additionally, serum corticosterone was assessed as a marker of physiological stress response. Group differences were dependent on the sex of the adult offspring. Males raised by dams that were stressed during pregnancy presented elevated emotionality as indicated by increased numbers of faecal boluses in the open field paradigm. Consistent with the effects of prenatal stress on the males only the prenatally stressed females had higher body weights than their respective controls. Indeed, males in both experimental groups had higher circulating corticosterone levels. By contrast, female offspring of dams exposed to the olfactory stressor after parturition were more anxious in the O-maze as indicated by increased latencies in entering the exposed areas of the maze. These findings emphasize the necessity for researchers to consider the pre- and postnatal environments, even of mice with almost identical genetic backgrounds, in designing experiments and interpreting their data. PMID:26408077

  13. Does Marriage Lead to Specialization? An Evaluation of Swedish Trends in Adult Earnings Before and After Marriage

    OpenAIRE

    Sundström, Marianne; Ginther, Donna K.

    2010-01-01

    We examine whether marriage leads to specialization in Sweden by implementing a model that differentiates specialization in the household by cohabitation and marriage. Our paper evaluates this model using panel data to analyze trends in earnings before and after marriage between 1985 and 1995 for married and long-term cohabiting Swedish couples with children. To identify the effect of marriage on earnings we use the reform of the widow’s pension system that resulted in a marriage boom in Swed...

  14. Pentavalent outer membrane vesicles of Vibrio cholerae induce adaptive immune response and protective efficacy in both adult and passive suckling mice models.

    Science.gov (United States)

    Sinha, Ritam; Koley, Hemanta; Nag, Dhrubajyoti; Mitra, Soma; Mukhopadhyay, Asish K; Chattopadhyay, Brajadulal

    2015-03-01

    Recently, we demonstrated oral immunizations with single serotype outer membrane vesicles of Vibrio cholerae induced serogroup specific protective immunity in the RITARD model. In our present study, we advanced our research by formulating multi-serotype outer membrane vesicles, mixing the OMVs of five virulent V. cholerae strains. Four doses of oral immunization with cholera pentavalent outer membrane vesicles (CPMVs) induced V. cholerae specific B and T cell responses. CPMVs-immunized mice generated long lasting serum IgG, IgA, IgM as well as mucosal sIgA and also elicited a higher percentage of CD4+ T cell distribution in spleen. Our study revealed that in vitro CPMVs-activated dendritic cells were secreting T cell polarizing cytokines, IL-12p40, IL-4, IL-6 and IL-1β. Moreover, purified splenic CD4+ T cells of immunized mice also secreted IL-4, IL-13 and IL-17 cytokines, indicating the initiation of Th2 and Th17 cell mediated immune responses. CPMVs immunized adult female mice and their offspring were significantly protected from heterologous challenge with wild type V. cholerae. CPMVs could be exploited for the development of a novel non-living vaccine against circulating cholera in near future.

  15. The long-term consequences of the exposure to increasing gravity levels on the muscular, vestibular and cognitive functions in adult mice.

    Science.gov (United States)

    Bojados, Mickael; Jamon, Marc

    2014-05-01

    Adult male mice C57Bl6/J were exposed to gravity levels between 1G and 4G during three weeks, and the long-term consequences on muscular, vestibular, emotional, and cognitive abilities were evaluated at the functional level to test the hypothesis of a continuum in the response to the increasing gravitational force. In agreement with the hypothesis, the growth of body mass slowed down in relation with the gravity level during the centrifugation, and weight recovery was inversely proportional. On the other hand, the long-term consequences on muscular, vestibular, emotional, and cognitive abilities did not fit the hypothesis of a continuum in the response to the gravity level. The hypergravity acted as endurance training on muscle force until 3G, then became deleterious at 4G. The vestibular reactions were not affected until 4G. Persistent emotional reactions appeared at 3G, and particularly 4G. The mice centrifuged at 3G and 4G showed an impaired spatial learning, probably in relation with the increased level of anxiety, but a greater difficulty was also observed in mice exposed at 2G, suggesting another cause for the impairment of spatial memory. The long-term response to the hypergravity was shown to depend on both the level of gravity and the duration of exposition, with different importance depending on the function considered. PMID:24509308

  16. Investigation of the neuroprotective action of saffron (Crocus sativus L.) in aluminum-exposed adult mice through behavioral and neurobiochemical assessment.

    Science.gov (United States)

    Linardaki, Zacharoula I; Orkoula, Malvina G; Kokkosis, Alexandros G; Lamari, Fotini N; Margarity, Marigoula

    2013-02-01

    In the present study, the possible reversal effects of saffron against established aluminum (Al)-toxicity in adult mice, were investigated. Control, Al-treated (50 mg AlCl(3)/kg/day diluted in the drinking water for 5 weeks) and Al+saffron (Al-treatment as previously plus 60 mg saffron extract/kg/day intraperitoneally for the last 6 days), groups of male Balb-c mice were used. We assessed learning/memory, the activity of acetylcholinesterase [AChE, salt-(SS)/detergent-soluble(DS) isoforms], butyrylcholinesterase (BuChE, SS/DS isoforms), monoamine oxidase (MAO-A, MAO-B), the levels of lipid peroxidation (MDA) and reduced glutathione (GSH), in whole brain and cerebellum. Brain Al was determined by atomic absorption spectrometry, while, for the first time, crocetin, the main active metabolite of saffron, was determined in brain after intraperitoneal saffron administration by HPLC. Al intake caused memory impairment, significant decrease of AChE and BuChE activity, activation of brain MAO isoforms but inhibition of cerebellar MAO-B, significant elevation of brain MDA and significant reduction of GSH content. Although saffron extract co-administration had no effect on cognitive performance of mice, it reversed significantly the Al-induced changes in MAO activity and the levels of MDA and GSH. AChE activity was further significantly decreased in cerebral tissues of Al+saffron group. The biochemical changes support the neuroprotective potential of saffron under toxicity.

  17. Effects of a major androgen-dependent urinary protein,. alpha. 2u-globulin on the pituitary-gonadal axis and hypothalamic monoamines in adult male mice

    Energy Technology Data Exchange (ETDEWEB)

    Ghosh, P.K.; Chandrashekar, V.; Steger, R. Bartke, A. (Southern Illinois Univ., Carbondale (USA))

    1990-01-01

    The purpose of the present study was to evaluate the effects of alpha-2u-globulin, a sex-dependent male rat urinary protein on pituitary-gonadal functions and hypothalamic monamine contents in male mice. Adult male mice, maintained under standardized laboratory conditions were injected subcutaneously with alpha-2u-globulin or with vehicle daily for 14 days and killed 16 h after the last injection. Plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T) and testicular levels of T were measured by radioimmunoassays. The concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in medial basal hypothalamus (MBH) and anterior hypothalamus (AH) were measured by high performance liquid chromatography. Administration of alpha-2u-globulin led to a significant increase in plasma FSH and LH levels. In the MBH of alpha-2u-globulin treated mice, there were significant elevations of NE, DA and 5-HT contents. In the AH, both DA and 5-HT contents were decreased while NE content remained unaltered.

  18. CYP1B1 deficiency ameliorates obesity and glucose intolerance induced by high fat diet in adult C57BL/6J mice.

    Science.gov (United States)

    Liu, Xiaocong; Huang, Tingting; Li, Lu; Tang, Yumeng; Tian, Yatao; Wang, Suqing; Fan, Cuifang

    2015-01-01

    Cytochrome P450 1B1 (CYP1B1) expression increases in multi-potential mesenchymal stromal cells C3H10T1/2 during adipogenesis, which parallel with PPARγ, a critical transcriptional factor in adipogenic process. To assess the role of CYP1B1 in fatty acid metabolism, adult C57BL/6J wild-type and CYP1B1 deficiency mice were fed with high fat diets (HFD) for 6 weeks. CYP1B1 deficiency attenuated HFD-induced obesity when compared with their wild type counterparts, and improve glucose tolerance. The reduction in body weight gain and white adipose tissue in CYP1B1 deficient mice exhibited coordinate decreases in fatty acid synthesis (PPARγ, CD36, FAS, SCD-1) and increases in fatty acid oxidation (UCP-2, CPT-1a) when compared with wild type ones. Lower hepatocyte TG contents were consistent with hepatic Oil-Red-O staining in the CYP1B1 deficiency mice. AMPK, a nutrient sensors for energy homeostasis, was activated in both fat pad and liver by CYP1B1 deficiency. However, in vitro system, knock down CYP1B1 in C3H10T1/2 cells does not abolish adipogenesis induced by adipogenic agents IDM (Insulin, Dexamethasone, Methylisobutylxanthine). Our in vivo and in vitro findings of CYP1B1 deficiency in fat metabolism suggest a complex regulation network between CYP1B1 and energy homeostasis. PMID:26064443

  19. Odor-enriched environment rescues long-term social memory, but does not improve olfaction in social isolated adult mice.

    Science.gov (United States)

    Gusmão, Isabela D; Monteiro, Brisa M M; Cornélio, Guilherme O S; Fonseca, Cristina S; Moraes, Márcio F D; Pereira, Grace S

    2012-03-17

    Prolonged permanence of animals under social isolation (SI) arouses a variety of psychological symptoms like aggression, stress, anxiety and depression. However, short-term SI is commonly used to evaluate social memory. Interestingly, the social memory cannot be accessed with delays higher than 30min in SI mice. Our hypothesis is that SI with intermediate duration, like one week (1w), impairs the long-term storage of new social information (S-LTM), without affecting anxiety or other types of memories, because the SI compromises the olfactory function of the animal. Our results demonstrated that SI impaired S-LTM, without affecting other kinds of memory or anxiety. In addition, the SI increased the latency in the buried-food finding task, but did not affect the habituation or the discrimination of odors. Next, we postulated that if continuous input to the olfactory system is fundamental for the maintenance of the olfactory function and social memory persistence, isolated mice under odor-enriched environment (OEE) should behave like group-housed (GH) animals. In fact, the OEE prevented the S-LTM deficit imposed by the SI. However, OEE did not restore the SI mice olfaction to the GH mice level. Our results suggest that SI modulates olfaction and social memory persistence, probably, by independent mechanisms. We also showed for the first time that OEE rescued S-LTM in SI mice through a mechanism not necessarily involved with olfaction. PMID:22226622

  20. Odor-enriched environment rescues long-term social memory, but does not improve olfaction in social isolated adult mice.

    Science.gov (United States)

    Gusmão, Isabela D; Monteiro, Brisa M M; Cornélio, Guilherme O S; Fonseca, Cristina S; Moraes, Márcio F D; Pereira, Grace S

    2012-03-17

    Prolonged permanence of animals under social isolation (SI) arouses a variety of psychological symptoms like aggression, stress, anxiety and depression. However, short-term SI is commonly used to evaluate social memory. Interestingly, the social memory cannot be accessed with delays higher than 30min in SI mice. Our hypothesis is that SI with intermediate duration, like one week (1w), impairs the long-term storage of new social information (S-LTM), without affecting anxiety or other types of memories, because the SI compromises the olfactory function of the animal. Our results demonstrated that SI impaired S-LTM, without affecting other kinds of memory or anxiety. In addition, the SI increased the latency in the buried-food finding task, but did not affect the habituation or the discrimination of odors. Next, we postulated that if continuous input to the olfactory system is fundamental for the maintenance of the olfactory function and social memory persistence, isolated mice under odor-enriched environment (OEE) should behave like group-housed (GH) animals. In fact, the OEE prevented the S-LTM deficit imposed by the SI. However, OEE did not restore the SI mice olfaction to the GH mice level. Our results suggest that SI modulates olfaction and social memory persistence, probably, by independent mechanisms. We also showed for the first time that OEE rescued S-LTM in SI mice through a mechanism not necessarily involved with olfaction.

  1. Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice

    OpenAIRE

    van Praag, Henriette; Shubert, Tiffany; Zhao, Chunmei; GAGE, FRED H.

    2005-01-01

    Aging causes changes in the hippocampus that may lead to cognitive decline in older adults. In young animals, exercise increases hippocampal neurogenesis and improves learning. We investigated whether voluntary wheel running would benefit mice that were sedentary until 19 months of age. Specifically, young and aged mice were housed with or without a running wheel and injected with bromodeoxyuridine or retrovirus to label newborn cells. After 1 month, learning was tested in the Morris water ma...

  2. Daily rhythmic behaviors and thermoregulatory patterns are disrupted in adult female MeCP2-deficient mice.

    Directory of Open Access Journals (Sweden)

    Robert G Wither

    Full Text Available Mutations in the X-linked gene encoding Methyl-CpG-binding protein 2 (MECP2 have been associated with neurodevelopmental and neuropsychiatric disorders including Rett Syndrome, X-linked mental retardation syndrome, severe neonatal encephalopathy, and Angelman syndrome. Although alterations in the performance of MeCP2-deficient mice in specific behavioral tasks have been documented, it remains unclear whether or not MeCP2 dysfunction affects patterns of periodic behavioral and electroencephalographic (EEG activity. The aim of the current study was therefore to determine whether a deficiency in MeCP2 is sufficient to alter the normal daily rhythmic patterns of core body temperature, gross motor activity and cortical delta power. To address this, we monitored individual wild-type and MeCP2-deficient mice in their home cage environment via telemetric recording over 24 hour cycles. Our results show that the normal daily rhythmic behavioral patterning of cortical delta wave activity, core body temperature and mobility are disrupted in one-year old female MeCP2-deficient mice. Moreover, female MeCP2-deficient mice display diminished overall motor activity, lower average core body temperature, and significantly greater body temperature fluctuation than wild-type mice in their home-cage environment. Finally, we show that the epileptiform discharge activity in female MeCP2-deficient mice is more predominant during times of behavioral activity compared to inactivity. Collectively, these results indicate that MeCP2 deficiency is sufficient to disrupt the normal patterning of daily biological rhythmic activities.

  3. Environmental cadmium and lead exposures and age-related macular degeneration in U.S. adults: The National Health and Nutrition Examination Survey 2005 to 2008

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Erin W. [Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI (United States); Schaumberg, Debra A. [Division of Preventive Medicine, Brigham and Women' s Hospital, Harvard Medical School and Department of Epidemiology, Harvard School of Public Health, Boston, MA (United States); Center for Translational Medicine, Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT (United States); Park, Sung Kyun, E-mail: sungkyun@umich.edu [Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI (United States); Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI (United States)

    2014-08-15

    Age-related macular degeneration (AMD) is a complex disease resulting from the interplay of genetic predisposition and environmental exposures, and has been linked to oxidative stress and inflammatory mechanisms. Lead and cadmium can accumulate in human retinal tissues and may damage the retina through oxidative stress, and may thereby play a role in the development of AMD. We examined associations between blood lead, blood cadmium, and urinary cadmium concentrations and the presence of AMD in 5390 participants aged 40 years and older with blood lead and blood cadmium measures and a subsample of 1548 with urinary cadmium measures in the 2005–2008 National Health and Nutrition Examination Surveys. AMD was identified by grading retinal photographs with a modification of the Wisconsin Age-Related Maculopathy Grading System. The weighted prevalence of AMD was 6.6% (n=426). Controlling for age, gender, race/ethnicity, education and body mass index, adults in the highest blood cadmium quartile had higher odds of AMD compared to the lowest quartile (odds ratio [OR], 1.56; 95% CI, 1.02–2.40), with a significant trend across quartiles (p-trend=0.02). After further adjustment for pack-years of cigarette smoking, estimates were somewhat attenuated (OR, 1.43; 95% CI, 0.91–2.27; p-trend=0.08). Similar associations were found with urinary cadmium. The association between urinary cadmium and AMD was stronger in non-Hispanic whites (NHW) than in non-Hispanic blacks (NHB) (OR, 3.31; 95% CI, 1.37–8.01 for levels above versus below the median among NHW; OR,1.45; 95% CI, 0.40–5.32 for levels above versus below the median among NHB; p-interaction=0.03). We found no association between blood lead levels and AMD. Higher cadmium body burden may increase risk of AMD, particularly among non-Hispanic white individuals; however, additional studies are needed before firm conclusions can be drawn. - Highlights: • We examined the association of cadmium and lead with age

  4. Environmental cadmium and lead exposures and age-related macular degeneration in U.S. adults: The National Health and Nutrition Examination Survey 2005 to 2008

    International Nuclear Information System (INIS)

    Age-related macular degeneration (AMD) is a complex disease resulting from the interplay of genetic predisposition and environmental exposures, and has been linked to oxidative stress and inflammatory mechanisms. Lead and cadmium can accumulate in human retinal tissues and may damage the retina through oxidative stress, and may thereby play a role in the development of AMD. We examined associations between blood lead, blood cadmium, and urinary cadmium concentrations and the presence of AMD in 5390 participants aged 40 years and older with blood lead and blood cadmium measures and a subsample of 1548 with urinary cadmium measures in the 2005–2008 National Health and Nutrition Examination Surveys. AMD was identified by grading retinal photographs with a modification of the Wisconsin Age-Related Maculopathy Grading System. The weighted prevalence of AMD was 6.6% (n=426). Controlling for age, gender, race/ethnicity, education and body mass index, adults in the highest blood cadmium quartile had higher odds of AMD compared to the lowest quartile (odds ratio [OR], 1.56; 95% CI, 1.02–2.40), with a significant trend across quartiles (p-trend=0.02). After further adjustment for pack-years of cigarette smoking, estimates were somewhat attenuated (OR, 1.43; 95% CI, 0.91–2.27; p-trend=0.08). Similar associations were found with urinary cadmium. The association between urinary cadmium and AMD was stronger in non-Hispanic whites (NHW) than in non-Hispanic blacks (NHB) (OR, 3.31; 95% CI, 1.37–8.01 for levels above versus below the median among NHW; OR,1.45; 95% CI, 0.40–5.32 for levels above versus below the median among NHB; p-interaction=0.03). We found no association between blood lead levels and AMD. Higher cadmium body burden may increase risk of AMD, particularly among non-Hispanic white individuals; however, additional studies are needed before firm conclusions can be drawn. - Highlights: • We examined the association of cadmium and lead with age

  5. Delayed Reduction of Hippocampal Synaptic Transmission and Spines Following Exposure to Repeated Subclinical Doses of Organophosphorus Pesticide in Adult Mice

    OpenAIRE

    Speed, Haley E.; Blaiss, Cory A.; Kim, Ahleum; Haws, Michael E.; Melvin, Neal R.; Jennings, Michael; Eisch, Amelia J.; Powell, Craig M.

    2011-01-01

    Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, r...

  6. Morphological aspects of Schistosoma mansoni adult worms isolated from nourished and undernourished mice: a comparative analysis by confocal laser scanning microscopy

    Directory of Open Access Journals (Sweden)

    Neves Renata Heisler

    2001-01-01

    Full Text Available Malnutrition hampers the course of schistosomiasis mansoni infection just as normal growth of adult worms. A comparative morphometric study on adult specimens (male and female recovered from undernourished (fed with a low protein diet - regional basic diet and nourished (rodent commercial laboratory food, NUVILAB white mice was performed. Tomographic images and morphometric analysis of the oral and ventral suckers, reproductive system and tegument were obtained by means of confocal laser scanning microscopy. Undernourished male specimens presented smaller morphometric values (length and width of the reproductive system (first, third and last testicular lobes and thickness of the tegument than controls. Besides that, it was demonstrated that the dorsal surface of the male worms bears large tubercles unevenly distributed, but kept grouped and flat. At the subtegumental region, vacuolated areas were detected. It was concluded that the inadequate nutritional status of the vertebrate host has a negative influence mainly in the reproductive system and topographical somatic development of male adult Schistosoma mansoni, inducing some alterations on the structure of the parasite.

  7. Adipose-derived mesenchymal stem cell transplantation promotes adult neurogenesis in the brains of Alzheimer’s disease mice

    Institute of Scientific and Technical Information of China (English)

    Yufang Yan; Tuo Ma; Kai Gong; Qiang Ao; Xiufang Zhang; Yandao Gong

    2014-01-01

    In the present study, we transplanted adipose-derived mesenchymal stem cells into the hippo-campi of APP/PS1 transgenic Alzheimer’s disease model mice. Immunofluorescence staining revealed that the number of newly generated (BrdU+) cells in the subgranular zone of the dentate gyrus in the hippocampus was signiifcantly higher in Alzheimer’s disease mice after adipose-de-rived mesenchymal stem cell transplantation, and there was also a significant increase in the number of BrdU+/DCX+neuroblasts in these animals. Adipose-derived mesenchymal stem cell transplantation enhanced neurogenic activity in the subventricular zone as well. Furthermore, adipose-derived mesenchymal stem cell transplantation reduced oxidative stress and alleviated cognitive impairment in the mice. Based on these ifndings, we propose that adipose-derived mes-enchymal stem cell transplantation enhances endogenous neurogenesis in both the subgranular and subventricular zones in APP/PS1 transgenic Alzheimer’s disease mice, thereby facilitating functional recovery.

  8. Vulnerability to chronic subordination stress-induced depression-like disorders in adult 129SvEv male mice.

    Science.gov (United States)

    Dadomo, Harold; Sanghez, Valentina; Di Cristo, Luisana; Lori, Andrea; Ceresini, Graziano; Malinge, Isabelle; Parmigiani, Stefano; Palanza, Paola; Sheardown, Malcolm; Bartolomucci, Alessandro

    2011-08-01

    Exposure to stressful life events is intimately linked with vulnerability to neuropsychiatric disorders such as major depression. Pre-clinical animal models offer an effective tool to disentangle the underlying molecular mechanisms. In particular, the 129SvEv strain is often used to develop transgenic mouse models but poorly characterized as far as behavior and neuroendocrine functions are concerned. Here we present a comprehensive characterization of 129SvEv male mice's vulnerability to social stress-induced depression-like disorders and physiological comorbidities. We employed a well characterized mouse model of chronic social stress based on social defeat and subordination. Subordinate 129SvEv mice showed body weight gain, hyperphagia, increased adipose fat pads weight and basal plasma corticosterone. Home cage phenotyping revealed a suppression of spontaneous locomotor activity and transient hyperthermia. Subordinate 129SvEv mice also showed marked fearfulness, anhedonic-like response toward a novel but palatable food, increased anxiety in the elevated plus maze and social avoidance of an unfamiliar male mouse. A direct measured effect of the stressfulness of the living environment, i.e. the amount of daily aggression received, predicted the degree of corticosterone level and locomotor activity but not of the other parameters. This is the first study validating a chronic subordination stress paradigm in 129SvEv male mice. Results demonstrated remarkable stress vulnerability and establish the validity to use this mouse strain as a model for depression-like disorders. PMID:21093519

  9. B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice.

    Science.gov (United States)

    Knittel, Gero; Liedgens, Paul; Korovkina, Darya; Seeger, Jens M; Al-Baldawi, Yussor; Al-Maarri, Mona; Fritz, Christian; Vlantis, Katerina; Bezhanova, Svetlana; Scheel, Andreas H; Wolz, Olaf-Oliver; Reimann, Maurice; Möller, Peter; López, Cristina; Schlesner, Matthias; Lohneis, Philipp; Weber, Alexander N R; Trümper, Lorenz; Staudt, Louis M; Ortmann, Monika; Pasparakis, Manolis; Siebert, Reiner; Schmitt, Clemens A; Klatt, Andreas R; Wunderlich, F Thomas; Schäfer, Stephan C; Persigehl, Thorsten; Montesinos-Rongen, Manuel; Odenthal, Margarete; Büttner, Reinhard; Frenzel, Lukas P; Kashkar, Hamid; Reinhardt, H Christian

    2016-06-01

    The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-κB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-κB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2 Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2 Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL. PMID:27048211

  10. Mutations in the control of virulence sensor gene from Streptococcus pyogenes after infection in mice lead to clonal bacterial variants with altered gene regulatory activity and virulence.

    Directory of Open Access Journals (Sweden)

    Jeffrey A Mayfield

    Full Text Available The cluster of virulence sensor (CovS/responder (CovR two-component operon (CovRS regulates ∼15% of the genes of the Group A Streptococcal pyogenes (GAS genome. Bacterial clones containing inactivating mutations in the covS gene have been isolated from patients with virulent invasive diseases. We report herein an assessment of the nature and types of covS mutations that can occur in both virulent and nonvirulent GAS strains, and assess whether a nonvirulent GAS can attain enhanced virulence through this mechanism. A group of mice were infected with a globally-disseminated clonal M1T1 GAS (isolate 5448, containing wild-type (WT CovRS (5448/CovR+S+, or less virulent engineered GAS strains, AP53/CovR+S+ and Manfredo M5/CovR+S+. SpeB negative GAS clones from wound sites and/or from bacteria disseminated to the spleen were isolated and the covS gene was subjected to DNA sequence analysis. Numerous examples of inactivating mutations were found in CovS in all regions of the gene. The mutations found included frame-shift insertions and deletions, and in-frame small and large deletions in the gene. Many of the mutations found resulted in early translation termination of CovS. Thus, the covS gene is a genomic mutagenic target that gives GAS enhanced virulence. In cases wherein CovS- was discovered, these clonal variants exhibited high lethality, further suggesting that randomly mutated covS genes occur during the course of infection, and lead to the development of a more invasive infection.

  11. Elucidating the role of the TRPM7 alpha-kinase: TRPM7 kinase inactivation leads to magnesium deprivation resistance phenotype in mice.

    Science.gov (United States)

    Ryazanova, Lillia V; Hu, Zhixian; Suzuki, Sayuri; Chubanov, Vladimir; Fleig, Andrea; Ryazanov, Alexey G

    2014-12-23

    TRPM7 is an unusual bi-functional protein containing an ion channel covalently linked to a protein kinase domain. TRPM7 is implicated in regulating cellular and systemic magnesium homeostasis. While the biophysical properties of TRPM7 ion channel and its function are relatively well characterized, the function of the TRPM7 enzymatically active kinase domain is not understood yet. To investigate the physiological role of TRPM7 kinase activity, we constructed mice carrying an inactive TRPM7 kinase. We found that these mice were resistant to dietary magnesium deprivation, surviving three times longer than wild type mice; also they displayed decreased chemically induced allergic reaction. Interestingly, mutant mice have lower magnesium bone content compared to wild type mice when fed regular diet; unlike wild type mice, mutant mice placed on magnesium-depleted diet did not alter their bone magnesium content. Furthermore, mouse embryonic fibroblasts isolated from TRPM7 kinase-dead animals exhibited increased resistance to magnesium deprivation and oxidative stress. Finally, electrophysiological data revealed that the activity of the kinase-dead TRPM7 channel was not significantly altered. Together, our results suggest that TRPM7 kinase is a sensor of magnesium status and provides coordination of cellular and systemic responses to magnesium deprivation.

  12. Over-Expression of Porcine Myostatin Missense Mutant Leads to A Gender Difference in Skeletal Muscle Growth between Transgenic Male and Female Mice

    Directory of Open Access Journals (Sweden)

    Dezun Ma

    2015-08-01

    Full Text Available Myostatin, a transforming growth factor-β family member, is a negative regulator of skeletal muscle development and growth. Piedmontese cattle breeds have a missense mutation, which results in a cysteine to tyrosine substitution in the mature myostatin protein (C313Y. This loss-of-function mutation in myostatin results in a double-muscled phenotype in cattle. Myostatin propeptide is an inhibitor of myostatin activity and is considered a potential agent to stimulate muscle growth in livestock. In this study, we generated transgenic mice overexpressing porcine myostatin missense mutant (pmMS, C313Y, and wild-type porcine myostatin propeptide (ppMS, respectively, to examine their effects on muscle growth in mice. Enhanced muscle growth was observed in both pmMS and ppMS transgenic female mice and also in ppMS transgenic male mice. However, there was no enhanced muscle growth observed in pmMS transgenic male mice. To explore why there is such a big difference in muscle growth between pmMS and ppMS transgenic male mice, the expression level of androgen receptor (AR mutant AR45 was measured by Western blot. Results indicated that AR45 expression significantly increased in pmMS transgenic male mice while it decreased dramatically in ppMS transgenic male mice. Our data demonstrate that both pmMS and ppMS act as myostatin inhibitors in the regulation of muscle growth, but the effect of pmMS in male mice is reversed by an increased AR45 expression. These results provide useful insight and basic theory to future studies on improving pork quality by genetically manipulating myostatin expression or by regulating myostatin activity.

  13. Over-Expression of Porcine Myostatin Missense Mutant Leads to A Gender Difference in Skeletal Muscle Growth between Transgenic Male and Female Mice.

    Science.gov (United States)

    Ma, Dezun; Gao, Pengfei; Qian, Lili; Wang, Qingqing; Cai, Chunbo; Jiang, Shengwang; Xiao, Gaojun; Cui, Wentao

    2015-08-24

    Myostatin, a transforming growth factor-β family member, is a negative regulator of skeletal muscle development and growth. Piedmontese cattle breeds have a missense mutation, which results in a cysteine to tyrosine substitution in the mature myostatin protein (C313Y). This loss-of-function mutation in myostatin results in a double-muscled phenotype in cattle. Myostatin propeptide is an inhibitor of myostatin activity and is considered a potential agent to stimulate muscle growth in livestock. In this study, we generated transgenic mice overexpressing porcine myostatin missense mutant (pmMS), C313Y, and wild-type porcine myostatin propeptide (ppMS), respectively, to examine their effects on muscle growth in mice. Enhanced muscle growth was observed in both pmMS and ppMS transgenic female mice and also in ppMS transgenic male mice. However, there was no enhanced muscle growth observed in pmMS transgenic male mice. To explore why there is such a big difference in muscle growth between pmMS and ppMS transgenic male mice, the expression level of androgen receptor (AR) mutant AR45 was measured by Western blot. Results indicated that AR45 expression significantly increased in pmMS transgenic male mice while it decreased dramatically in ppMS transgenic male mice. Our data demonstrate that both pmMS and ppMS act as myostatin inhibitors in the regulation of muscle growth, but the effect of pmMS in male mice is reversed by an increased AR45 expression. These results provide useful insight and basic theory to future studies on improving pork quality by genetically manipulating myostatin expression or by regulating myostatin activity.

  14. Circadian cycle dependent EEG biomarkers of pathogenicity in adult mice following prenatal exposure to in utero inflammation

    OpenAIRE

    Adler, Daniel A; Ammanuel, Simon; Lei, Jun; Dada, Tahani; Borbiev, Talaibek; Johnston, Michael V.; Kadam, Shilpa D.; Burd, Irina

    2014-01-01

    Intrauterine infection or inflammation in preterm neonates is a known risk for adverse neurological outcomes, including cognitive, motor and behavioral disabilities. Our previous data suggest that there is acute fetal brain inflammation in a mouse model of intrauterine exposure to lipopolysaccharides (LPS). We hypothesized that the in utero inflammation induced by LPS produces long-term EEG biomarkers of neurodegeneration in the exposed mice that could be determined by using continuous quanti...

  15. Evaluation of toxic effects of CdTe quantum dots on the reproductive system in adult male mice.

    Science.gov (United States)

    Li, Xiaohui; Yang, Xiangrong; Yuwen, Lihui; Yang, Wenjing; Weng, Lixing; Teng, Zhaogang; Wang, Lianhui

    2016-07-01

    Fluorescent quantum dots (QDs) are highly promising nanomaterials for various biological and biomedical applications because of their unique optical properties, such as robust photostability, strong photoluminescence, and size-tunable fluorescence. Several studies have reported the in vivo toxicity of QDs, but their effects on the male reproduction system have not been examined. In this study, we investigated the reproductive toxicity of cadmium telluride (CdTe) QDs at a high dose of 2.0 nmol per mouse and a low dose of 0.2 nmol per mouse. Body weight measurements demonstrated there was no overt toxicity for both dose at day 90 after exposure, but the high dose CdTe affected body weight up to 15 days after exposure. CdTe QDs accumulated in the testes and damaged the tissue structure for both doses on day 90. Meanwhile, either of two CdTe QDs treatments did not significantly affect the quantity of sperm, but the high dose CdTe significantly decreased the quality of sperm on day 60. The serum levels of three major sex hormones were also perturbed by CdTe QDs treatment. However, the pregnancy rate and delivery success of female mice that mated with the treated male mice did not differ from those mated with untreated male mice. These results suggest that CdTe QDs can cause testes toxicity in a dose-dependent manner. The low dose of CdTe QDs is relatively safe for the reproductive system of male mice. Our preliminary result enables better understanding of the reproductive toxicity induced by cadmium-containing QDs and provides insight into the safe use of these nanoparticles in biological and environmental systems. PMID:27135714

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

    OpenAIRE

    Ismail, Nafissa; Blaustein, Jeffrey D.

    2012-01-01

    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 6 weeks 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 decreasin...

  17. Mgat5 modulates the effect of early life stress on adult behavior and physical health in mice.

    Science.gov (United States)

    Feldcamp, Laura; Doucet, Jean-Sebastien; Pawling, Judy; Fadel, Marc P; Fletcher, Paul J; Maunder, Robert; Dennis, James W; Wong, Albert H C

    2016-10-01

    Psychosocial adversity in early life increases the likelihood of mental and physical illness, but the underlying mechanisms are poorly understood. Mgat5 is an N-acetylglucosaminyltransferase in the Golgi pathway that remodels the N-glycans of glycoproteins at the cell surface. Mice lacking Mgat5 display conditional phenotypes in behaviour, immunity, metabolism, aging and cancer susceptibility. Here we investigated potential gene-environment interactions between Mgat5 and early life adversity on behaviour and physiological measures of physical health. Mgat5(-/-) mutant and Mgat5(+/+) wild-type C57Bl/6 littermates were subject to maternal separation or foster rearing as an early life stressor, in comparison to control mice reared normally. We found an interaction between Mgat5 genotype and maternal rearing condition in which Mgat5(-/-) mice subjected to early life stress had lower glucose levels and higher bone density. Mgat5(-/-) genotype was also associated with less immobility in the forced swim test and greater sucrose consumption, consistent with a less depression-like phenotype. Cortical neuron dendrite spine density and branching was altered by Mgat5 deletion as well. In general, Mgat5 genotype affects both behaviour and physical outcomes in response to early life stress, suggesting some shared pathways for both in this model. These results provide a starting point for studying the mechanisms by which protein N-glycosylation mediates the effects of early life adversity. PMID:27329152

  18. Combined parental obesity augments single-parent obesity effects on hypothalamus inflammation, leptin signaling (JAK/STAT), hyperphagia, and obesity in the adult mice offspring.

    Science.gov (United States)

    Ornellas, Fernanda; Souza-Mello, Vanessa; Mandarim-de-Lacerda, Carlos Alberto; Aguila, Marcia Barbosa

    2016-01-01

    We aimed to evaluate the effects of maternal and/or paternal obesity on offspring body mass, leptin signaling, appetite-regulating neurotransmitters and local inflammatory markers. C57BL/6 mice received standard chow (SC, lean groups) or high-fat diet (HF, obese groups) starting from one month of age. At three months, HF mice became obese relative to SC mice. They were then mated as follows: lean mother and lean father, lean mother and obese father, obese mother and lean father, and obese mother and obese father. The offspring received the SC diet from weaning until three months of age, when they were sacrificed. In the offspring, paternal obesity did not lead to changes in the Janus kinase (JAK)/signal transducer and activation of the transcription (STAT) pathway or feeding behavior but did induce hypothalamic inflammation. On the other hand, maternal obesity resulted in increased weight gain, hyperleptinemia, decreased leptin OBRb receptor expression, JAK/STAT pathway impairment, and increased SOCS3 signaling in the offspring. In addition, maternal obesity elevated inflammatory markers and altered NPY and POMC expression in the hypothalamus. Interestingly, combined parental obesity exacerbated the deleterious outcomes compared to single-parent obesity. In conclusion, while maternal obesity is known to program metabolic changes and obesity in offspring, the current study demonstrated that obese fathers induce hypothalamus inflammation in offspring, which may contribute to the development of metabolic syndromes in adulthood.

  19. Fibroblasts from long-lived Snell dwarf mice are resistant to oxygen-induced in vitro growth arrest

    DEFF Research Database (Denmark)

    Maynard, Scott P; Miller, Richard A

    2006-01-01

    Snell dwarf mice live longer than controls, and show lower age-adjusted rates of lethal neoplastic diseases. Fibroblast cells from adult dwarf mice are resistant to the lethal effects of oxidative and nonoxidative stresses, including the carcinogen methyl methanesulfonate. We now report that dwarf...... in skin fibroblasts by the hormonal milieu of the Snell dwarf lead to resistance to multiple forms of injury, including the oxidative damage that contributes to growth arrest in vitro and neoplasia in intact mice....

  20. Connective tissue growth factor is critical for proper β-cell function and pregnancy-induced β-cell hyperplasia in adult mice.

    Science.gov (United States)

    Pasek, Raymond C; Dunn, Jennifer C; Elsakr, Joseph M; Aramandla, Mounika; Matta, Anveetha R; Gannon, Maureen

    2016-09-01

    During pregnancy, maternal β-cells undergo compensatory changes, including increased β-cell mass and enhanced glucose-stimulated insulin secretion. Failure of these adaptations to occur results in gestational diabetes mellitus. The secreted protein connective tissue growth factor (CTGF) is critical for normal β-cell development and promotes regeneration after partial β-cell ablation. During embryogenesis, CTGF is expressed in pancreatic ducts, vasculature, and β-cells. In adult pancreas, CTGF is expressed only in the vasculature. Here we show that pregnant mice with global Ctgf haploinsufficiency (Ctgf(LacZ/+)) have an impairment in maternal β-cell proliferation; no difference was observed in virgin Ctgf(LacZ/+) females. Using a conditional CTGF allele, we found that mice with a specific inactivation of CTGF in endocrine cells (Ctgf(ΔEndo)) develop gestational diabetes during pregnancy, but this is due to a reduction in glucose-stimulated insulin secretion rather than impaired maternal β-cell proliferation. Moreover, virgin Ctgf(ΔEndo) females also display impaired GSIS with glucose intolerance, indicating that underlying β-cell dysfunction precedes the development of gestational diabetes in this animal model. This is the first time a role for CTGF in β-cell function has been reported. PMID:27460898

  1. Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-β plaque formation in organotypic hippocampal slice cultures.

    Science.gov (United States)

    Hellwig, Sabine; Masuch, Annette; Nestel, Sigrun; Katzmarski, Natalie; Meyer-Luehmann, Melanie; Biber, Knut

    2015-01-01

    The role of microglia in amyloid-β (Aβ) deposition is controversial. In the present study, an organotypic hippocampal slice culture (OHSC) system with an in vivo-like microglial-neuronal environment was used to investigate the potential contribution of microglia to Aβ plaque formation. We found that microglia ingested Aβ, thereby preventing plaque formation in OHSCs. Conversely, Aβ deposits formed rapidly in microglia-free wild-type slices. The capacity to prevent Aβ plaque formation was absent in forebrain microglia from young adult but not juvenile 5xFamilial Alzheimer's disease (FAD) mice. Since no loss of Aβ clearance capacity was observed in both wild-type and cerebellar microglia from 5xFAD animals, the high Aβ1-42 burden in the forebrain of 5xFAD animals likely underlies the exhaustion of microglial Aβ clearance capacity. These data may therefore explain why Aβ plaque formation has never been described in wild-type mice, and point to a beneficial role of microglia in AD pathology. We also describe a new method to study Aβ plaque formation in a cell culture setting.

  2. Production of the first offspring from oocytes derived from fresh and cryopreserved pre-antral follicles of adult mice

    DEFF Research Database (Denmark)

    Kagawa, Norika; Kuwayama, Masashige; Nakata, Kumiko;

    2007-01-01

    , as well as in women who wish to delay pregnancy and child raising until they are older. This study reports the birth of 10 healthy mouse pups derived from oocytes obtained from pre-antral follicles after adult ovary tissue cryopreservation and allotransplantation. High in-vitro maturation (55...

  3. The Effect of Ethanol Extract of Aerial Parts of the Mentha piperita in the Acquisition, Tolerance Expression and Dependence to Morphine in Adult Male Mice

    Directory of Open Access Journals (Sweden)

    N Khajeh

    2015-04-01

    Full Text Available Background & aim: Morphine dependence is a compulsive pattern of drug taking, resulting from the positive reinforcement of the rewarding effects of drug taking and the negative reinforcement of withdrawal syndrome that accompanies the cessation of drug taking. The objective of this study was to investigate the effect of ethanol extract of aerial parts of the Mentha piperita in the acquisition, tolerance expression and dependence to morphine in adult male mice Methods: In the present study, 75 NMRI mice were divided into fifiteen groups. The Hot-plate test was used to survey the morphine activity. Morphine was injected (2.5, 5, 10, 20, 40 mg/kg, i.p. twice daily for seven days, except in 8th day in which morphine was administrated at a single dose (50 mg/kg. The extract (50, 75, 100 mg/kg was injected for eight days. The control animals were intact, and sham animals only received morphine. Naloxone was injected (10 mg/kg five hours after the final dose of morphine and the withdrawal signs were recorded during a 30 minute period. The data were expressed as mean values ± SEM and tested, using analysis of one-way ANOVA test. Results: Peppermint extract at doses of 75 and 100 kg significantly improved the tolerance expression and dependence to morphine in animals and significantly reduced the symptoms of withdrawal. Conclusion: Peppermint extract was commuted morphine tolerance and dependence in mice.The plant contained component(s that alleviate morphine withdrawal syndrome. The extract possibly be effective in improving tolerance to morphine.

  4. Hepatic PPARγ Is Not Essential for the Rapid Development of Steatosis After Loss of Hepatic GH Signaling, in Adult Male Mice.

    Science.gov (United States)

    Kineman, Rhonda D; Majumdar, Neena; Subbaiah, Papasani V; Cordoba-Chacon, Jose

    2016-05-01

    Our group has previously reported de novo lipogenesis (DNL) and hepatic triglyceride content increases in chow-fed male mice within 7 days of hepatocyte-specific GH receptor knockdown (aLivGHRkd). Here, we report that these changes are associated with an increase in hepatic expression of peroxisome proliferator-activated receptor γ (PPARγ), consistent with previous reports showing steatosis is associated with an increase in PPARγ expression in mice with congenital loss of hepatic GH signaling. PPARγ is thought to be an important driver of steatosis by enhancing DNL, as well as increasing the uptake and esterification of extrahepatic fatty acids (FAs). In order to determine whether hepatic PPARγ is critical for the rapid development of steatosis in the aLivGHRkd mouse model, we have generated aLivGHRkd mice, with or without PPARγ (ie, adult-onset, hepatocyte-specific double knockout of GHR and PPARγ). Hepatic PPARγ was not required for the rapid increase in liver triglyceride content or FA indexes of DNL (16:0/18:2 and 16:1/16:0). However, loss of hepatic PPARγ blunted the rise in fatty acid translocase/CD36 and monoacylglycerol acyltransferase 1 expression induced by aLivGHRkd, and this was associated with a reduction in the hepatic content of 18:2. These results suggest that the major role of PPARγ is to enhance pathways critical in uptake and reesterification of extrahepatic FA. Because FAs have been reported to directly increase PPARγ expression, we speculate that in the aLivGHRkd mouse, the FA produced by DNL enhances the expression of PPARγ, which in turn increases extrahepatic FA uptake, thereby further enhancing PPARγ activity and exacerbating steatosis overtime. PMID:26950202

  5. Propagation of RML prions in mice expressing PrP devoid of GPI anchor leads to formation of a novel, stable prion strain.

    Directory of Open Access Journals (Sweden)

    Sukhvir Paul Mahal

    Full Text Available PrP(C, a host protein which in prion-infected animals is converted to PrP(Sc, is linked to the cell membrane by a GPI anchor. Mice expressing PrP(C without GPI anchor (tgGPI⁻ mice, are susceptible to prion infection but accumulate anchorless PrP(Sc extra-, rather than intracellularly. We investigated whether tgGPI⁻ mice could faithfully propagate prion strains despite the deviant structure and location of anchorless PrP(Sc. We found that RML and ME7, but not 22L prions propagated in tgGPI⁻ brain developed novel cell tropisms, as determined by the Cell Panel Assay (CPA. Surprisingly, the levels of proteinase K-resistant PrP(Sc (PrP(res in RML- or ME7-infected tgGPI⁻ brain were 25-50 times higher than in wild-type brain. When returned to wild-type brain, ME7 prions recovered their original properties, however RML prions had given rise to a novel prion strain, designated SFL, which remained unchanged even after three passages in wild-type mice. Because both RML PrP(Sc and SFL PrP(Sc are stably propagated in wild-type mice we propose that the two conformations are separated by a high activation energy barrier which is abrogated in tgGPI⁻ mice.

  6. Effect of maternal and post weaning folate supply on gene-specific DNA methylation in the small intestine of weaning and adult Apc+/Min and wild type mice.

    Directory of Open Access Journals (Sweden)

    Jill Ann Mckay

    2011-05-01

    Full Text Available Increasing evidence supports the developmental origins of adult health and disease hypothesis which argues for a causal relationship between adverse early life nutrition and increased disease risk in adulthood. Modulation of epigenetic marks, e.g. DNA methylation and consequential altered gene expression, has been proposed as a mechanism mediating these effects. Via its role as a methyl donor, dietary folate supply may influence DNA methylation. As aberrant methylation is an early event in colorectal cancer (CRC pathogenesis, we hypothesised low maternal and/or post-weaning folate intake may influence methylation of genes involved in CRC development. We investigated the effects of maternal folate depletion during pregnancy and lactation on selected gene methylation in the small intestine (SI of wild type (WT and Apc+/Min mice at weaning and as adults. We also investigated the effects of folate depletion post-weaning on gene methylation in adult mice. Female C57Bl6/J mice were fed low or normal folate diets from mating with Apc+/Min males to the end of lactation. A sub set of offspring were killed at weaning. Remaining offspring were weaned on to low or normal folate diets, resulting in 4 treatment groups of Apc+/Min and WT mice. p53 was more methylated in weaning and adult WT compared with Apc+/Min mice (p>0.001. Igf2 and Apc were hypermethylated in adult Apc+/Mi n compared with WT mice (p=0.004 & p=0.012 respectively. Low maternal folate reduced p53 methylation in adults (p=0.04. Low post-weaning folate increased Apc methylation in Apc+/Min mice only (p=0.008 for interaction. These observations demonstrate that folate depletion in early life can alter epigenetic marks in a gene specific manner. Also, the differential effects of altered folate supply on DNA methylation in WT and Apc+/Min mice suggest that genotype may modulate epigenetic responses to environmental cues and may have implications for the development of personalised nutrition.

  7. Greater neurobehavioral deficits occur in adult mice after repeated, as compared to single, mild traumatic brain injury (mTBI).

    Science.gov (United States)

    Nichols, Jessica N; Deshane, Alok S; Niedzielko, Tracy L; Smith, Cory D; Floyd, Candace L

    2016-02-01

    Mild traumatic brain injury (mTBI) accounts for the majority of all brain injuries and affected individuals typically experience some extent of cognitive and/or neuropsychiatric deficits. Given that repeated mTBIs often result in worsened prognosis, the cumulative effect of repeated mTBIs is an area of clinical concern and on-going pre-clinical research. Animal models are critical in elucidating the underlying mechanisms of single and repeated mTBI-associated deficits, but the neurobehavioral sequelae produced by these models have not been well characterized. Thus, we sought to evaluate the behavioral changes incurred after single and repeated mTBIs in mice utilizing a modified impact-acceleration model. Mice in the mTBI group received 1 impact while the repeated mTBI group received 3 impacts with an inter-injury interval of 24h. Classic behavior evaluations included the Morris water maze (MWM) to assess learning and memory, elevated plus maze (EPM) for anxiety, and forced swim test (FST) for depression/helplessness. Additionally, species-typical behaviors were evaluated with the marble-burying and nestlet shredding tests to determine motivation and apathy. Non-invasive vibration platforms were used to examine sleep patterns post-mTBI. We found that the repeated mTBI mice demonstrated deficits in MWM testing and poorer performance on species-typical behaviors. While neither single nor repeated mTBI affected behavior in the EPM or FST, sleep disturbances were observed after both single and repeated mTBI. Here, we conclude that behavioral alterations shown after repeated mTBI resemble several of the deficits or disturbances reported by patients, thus demonstrating the relevance of this murine model to study repeated mTBIs.

  8. piRNA biogenesis during adult spermatogenesis in mice is independent of the ping-pong mechanism

    Institute of Scientific and Technical Information of China (English)

    Ergin Beyret; Na Liu; Haifan Lin

    2012-01-01

    piRNAs,a class of small non-coding RNAs associated with PIWI proteins,have broad functions in germline development,transposon silencing,and epigenetic regulation.In diverse organisms,a subset of piRNAs derived from repeat sequences are produced via the interplay between two PIWI proteins.This mechanism,termed "ping-pong"cycle,operates among the PIWI proteins of the primordial mouse testis; however,its involvement in postnatal testes remains elusive.Here we show that adult testicular piRNAs are produced independent of the ping-pong mechanism.We identified and characterized large populations of piRNAs in the adult and postnatal developing testes associated with MILI and MIWI,the only PIWI proteins detectable in these testes.No interaction between MILI and MIWI or sequence feature for the ping-pong mechanism among their piRNAs was detected in the adult testis.The majority of MILI-and MIWI-associated piRNAs originate from the same DNA strands within the same loci.Both populations of piRNAs are biased for 5′ Uracil but not for Adenine on the 10th nucleotide position,and display no complementarity.Furthermore,in Miwi mutants,MILI-associated piRNAs are not downregulated,but instead upregulated.These results indicate that the adult testicular piRNAs are predominantly,if not exclusively,produced by a primary processing mechanism instead of the ping-pong mechanism.In this primary pathway,biogenesis of MILI-and MIWI-associated piRNAs may compete for the same precursors; the types of piRNAs produced tend to be non-selectively dictated by the available precursors in the cell; and precursors with introns tend to be spliced before processed into piRNAs.

  9. Pre- and postnatally administered ACTH, Organon 2766 and CRF facilitate or inhibit active avoidance task performance in young adult mice.

    Science.gov (United States)

    Honour, L C; White, M H

    1988-01-01

    This study investigated the effect of learning/memory-related neuropeptides on behavioral task performance in later life. A 1 mg/kg dosage of adrenocorticotropic hormone 4-9, Organon 2766, ACTH/MSH 4-10, ACTH 1-24, CRF, or diluent was subcutaneously injected into either pregnant females or into newborn pups during specific neural developmental windows. Each of the progeny was trained in an active-avoidance task and tested for acquisition on postpartum days 35-37. The mice were then tested for memory task performance and reacquisition on days 42-44 postpartum using the identical experimental paradigm as that used in the training sessions. Prenatal treatment with these memory-related neuropeptides resulted in significant facilitation of learning/memory task performance in male and female mice treated with Organon 2766 (p less than 0.001), and a significant inhibition of learning/memory task performance in males and females treated with ACTH 1-24 (p less than 0.01). Additional sex-specific performance facilitations and inhibitions resulted from the pre- or postnatal administration of the various neuropeptides used in this study. These results suggest that neuropeptides, when available in increased amounts during specific neural developmental windows, can significantly improve or suppress related behavioral performance capability in later life.

  10. Overexpression of γ-aminobutyric acid transporter subtype I leads to susceptibility to kainic acid-induced seizure in transgenic mice

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    γ-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter,and the GABAergic synaptic transmission is normally terminated by the rapid uptake through GABA transporters.With transgenic mice ubiquitously overexpressing GABA transporter subtype I (GAT1),the present study explored the pathophysiological role of GAT1 in epileptogenesis.Though displaying no spontaneous seizure activity,these mice exhibit altered electroencephalographic patterns and increased susceptibility to seizure induced by kainic acid.In addition,the GABAA receptor and glutamate transporters are up-regulated in transgenic mice,which perhaps reflects a compensatory or corrective change to the elevated level of GAT1.These preliminary findings support the hypothesis that excitatory and inhibitory neurotransmission,and seizure susceptibility can be altered by neurotransmitter transporters.

  11. Ablation of Cx47 in transgenic mice leads to the loss of MUPP1, ZONAB and multiple connexins at oligodendrocyte-astrocyte gap junctions.

    Science.gov (United States)

    Li, Xinbo; Penes, M; Odermatt, B; Willecke, K; Nagy, J I

    2008-10-01

    Oligodendrocytes in CNS are linked to astrocytes by heterotypic gap junctions composed of Cx32 and Cx47 in oligodendrocytes and Cx30 and Cx43 in astrocytes. These gap junctions also harbour regulatory proteins, including ZO-1 and ZONAB. Here, we investigated the localization of multi-PDZ domain protein 1 (MUPP1) at these gap junctions and examined accessory proteins and connexins associated with oligodendrocytes in Cx47-knockout mice. In every CNS region tested, punctate immunolabelling for MUPP1 was found on all oligodendrocyte somata in wild-type mice. These MUPP1-positive puncta were colocalized with punctate labelling for oligodendrocytic Cx32 or Cx47, and with astrocytic Cx30 or Cx43 at oligodendrocyte-astrocyte (O/A) gap junctions, but were not found at astrocyte-astrocyte gap junctions. In Cx47-knockout mice, immunolabelling of MUPP1 and ZONAB was absent on oligodendrocytes, whereas some ZO-1-positive puncta remained. In Cx32-knockout mice, MUPP1 and ZONAB persisted at O/A gap junctions. The absence of Cx47 in Cx47-knockout mice was accompanied by a total loss of punctate labelling for Cx30, Cx32 and Cx43 on oligodendrocyte somata, and by a dramatic increase in immunolabelling for Cx32 along myelinated fibers. These results demonstrate MUPP1 at O/A gap junctions and Cx47-dependent targeting of connexins to the plasma membranes of oligodendrocyte somata. Further, it appears that deficits in myelination reported in Cx47-knockout mice may arise not only from a loss of Cx47 but also from the accompanied loss of gap junctions and their regulatory proteins at oligodendrocyte somata, and that loss of Cx47 may be partly compensated for by elevated levels of Cx32 along myelinated fibers. PMID:18973575

  12. Maternal Microchimerism Leads to the Presence of Interleukin-2 in Interleukin-2 Knock Out Mice: Implications for the Role of Interleukin-2 in Thymic Function

    OpenAIRE

    Wrenshall, Lucile E.; Stevens, Elliot T.; Smith, Deandra R.; Miller, John D.

    2007-01-01

    The role of interleukin-2 (IL-2) in thymic development is uncertain. Not surprisingly, IL-2 knockout (KO) mice have been used to address this question. However, as we report here, such mice are chimeric, containing both IL-2 KO cells and IL-2-expressing cells transferred in utero from their heterozygous mothers. These cells produce IL-2 in amounts detectable by conventional means, and their presence in lymphoid tissues confounds efforts to define the true IL-2 KO phenotype. To minimize the am...

  13. Cardiac-Specific Overexpression of SCN5A Gene Leads to Shorter P Wave Duration and PR Interval in Transgenic Mice

    OpenAIRE

    Zhang, Teng; Yong, Sandro L.; Tian, Xiao-Li; Wang, Qing K.

    2007-01-01

    SCN5A plays a critical role in cardiac electrophysiology and its mutations, either gain- or loss-of-functions, are associated with lethal arrhythmias. In this study we investigated the effect of overexpression of SCN5A on the cardiac phenotype in a transgenic mouse model (TG-WT L10). Compared to NTG mice, heart rate, QRS duration and QT intervals remained unchanged in TG-WT mice. Moreover, no sponta