Science.gov

Sample records for adult mice showed

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

    PubMed Central

    Johnson, Carolyn; Wilbrecht, Linda

    2011-01-01

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

  2. Life-long in vivo cell-lineage tracing shows that no oogenesis originates from putative germline stem cells in adult mice.

    PubMed

    Zhang, Hua; Liu, Lian; Li, Xin; Busayavalasa, Kiran; Shen, Yan; Hovatta, Outi; Gustafsson, Jan-Åke; Liu, Kui

    2014-12-16

    Whether or not oocyte regeneration occurs in adult life has been the subject of much debate. In this study, we have traced germ-cell lineages over the life spans of three genetically modified mouse models and provide direct evidence that oogenesis does not originate from any germline stem cells (GSCs) in adult mice. By selective ablation of all existing oocytes in a Gdf9-Cre;iDTR mouse model, we have demonstrated that no new germ cells were ever regenerated under pathological conditions. By in vivo tracing of oocytes and follicles in the Sohlh1-CreER(T2);R26R and Foxl2-CreER(T2);mT/mG mouse models, respectively, we have shown that the initial pool of oocytes is the only source of germ cells throughout the life span of the mice and that no adult oogenesis ever occurs under physiological conditions. Our findings clearly show that there are no GSCs that contribute to adult oogenesis in mice and that the initial pool of oocytes formed in early life is the only source of germ cells throughout the entire reproductive life span.

  3. New Hippocampal Neurons Are Not Obligatory for Memory Formation; Cyclin D2 Knockout Mice with No Adult Brain Neurogenesis Show Learning

    ERIC Educational Resources Information Center

    Jaholkowski, Piotr; Kiryk, Anna; Jedynak, Paulina; Abdallah, Nada M. Ben; Knapska, Ewelina; Kowalczyk, Anna; Piechal, Agnieszka; Blecharz-Klin, Kamilla; Figiel, Izabela; Lioudyno, Victoria; Widy-Tyszkiewicz, Ewa; Wilczynski, Grzegorz M.; Lipp, Hans-Peter; Kaczmarek, Leszek; Filipkowski, Robert K.

    2009-01-01

    The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs…

  4. Adult neurogenesis in serotonin transporter deficient mice.

    PubMed

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

    2007-09-01

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

  5. In Utero and Lactational Exposure to PCBs in Mice: Adult Offspring Show Altered Learning and Memory Depending on Cyp1a2 and Ahr Genotypes

    PubMed Central

    Curran, Christine P.; Genter, Mary Beth; Patel, Krishna V.; Schaefer, Tori L.; Skelton, Matthew R.; Williams, Michael T.; Vorhees, Charles V.

    2011-01-01

    Background: Both coplanar and noncoplanar polychlorinated biphenyls (PCBs) exhibit neurotoxic effects in animal studies, but individual congeners do not always produce the same effects as PCB mixtures. Humans genetically have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2)-uninduced basal levels and > 12-fold variability in aryl hydrocarbon receptor (AHR)affinity; because CYP1A2 is known to sequester coplanar PCBs and because AHR ligands include coplanar PCBs, both genotypes can affect PCB response. Objectives: We aimed to develop a mouse paradigm with extremes in Cyp1a2 and Ahr genotypes to explore genetic susceptibility to PCB-induced developmental neurotoxicity using an environmentally relevant mixture of PCBs. Methods: We developed a mixture of eight PCBs to simulate human exposures based on their reported concentrations in human tissue, breast milk, and food supply. We previously characterized specific differences in PCB congener pharmacokinetics and toxicity, comparing high-affinity–AHR Cyp1a2 wild-type [Ahrb1_Cyp1a2(+/+)], poor-affinity–AHR Cyp1a2 wild-type [Ahrd_Cyp1a2(+/+)], and high-affinity–AHR Cyp1a2 knockout [Ahrb1_Cyp1a2(–/–)] mouse lines [Curran CP, Vorhees CV, Williams MT, Genter MB, Miller ML, Nebert DW. 2011. In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes. Toxicol Sci 119:189–208]. Dams received a mixture of three coplanar and five noncoplanar PCBs on gestational day 10.5 and postnatal day (PND) 5. In the present study we conducted behavioral phenotyping of exposed offspring at PND60, examining multiple measures of learning, memory, and other behaviors. Results: We observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2(–/–) mice, including impaired novel object recognition and increased failure rate in the Morris water maze. However, all PCB-treated genotypes showed significant differences on

  6. Bex1 knock out mice show altered skeletal muscle regeneration

    SciTech Connect

    Koo, Jae Hyung Smiley, Mark A.; Lovering, Richard M.; Margolis, Frank L.

    2007-11-16

    Bex1 and Calmodulin (CaM) are upregulated during skeletal muscle regeneration. We confirm this finding and demonstrate the novel finding that they interact in a calcium-dependent manner. To study the role of Bex1 and its interaction with CaM in skeletal muscle regeneration, we generated Bex1 knock out (Bex1-KO) mice. These mice appeared to develop normally and are fertile, but displayed a functional deficit in exercise performance compared to wild type (WT) mice. After intramuscular injection of cardiotoxin, which causes extensive and reproducible myotrauma followed by recovery, regenerating muscles of Bex1-KO mice exhibited elevated and prolonged cell proliferation, as well as delayed cell differentiation, compared to WT mice. Thus, our results provide the first evidence that Bex1-KO mice show altered muscle regeneration, and allow us to propose that the interaction of Bex1 with Ca{sup 2+}/CaM may be involved in skeletal muscle regeneration.

  7. Drug-induced regeneration in adult mice

    PubMed Central

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

    2015-01-01

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

  8. Mice Lacking Endoglin in Macrophages Show an Impaired Immune Response

    PubMed Central

    Ojeda-Fernández, Luisa; Recio-Poveda, Lucía; Aristorena, Mikel; Lastres, Pedro; Blanco, Francisco J.; Sanz-Rodríguez, Francisco; Gallardo-Vara, Eunate; de las Casas-Engel, Mateo; Corbí, Ángel; Arthur, Helen M.; Bernabeu, Carmelo; Botella, Luisa M.

    2016-01-01

    Endoglin is an auxiliary receptor for members of the TGF-β superfamily and plays an important role in the homeostasis of the vessel wall. Mutations in endoglin gene (ENG) or in the closely related TGF-β receptor type I ACVRL1/ALK1 are responsible for a rare dominant vascular dysplasia, the Hereditary Hemorrhagic Telangiectasia (HHT), or Rendu-Osler-Weber syndrome. Endoglin is also expressed in human macrophages, but its role in macrophage function remains unknown. In this work, we show that endoglin expression is triggered during the monocyte-macrophage differentiation process, both in vitro and during the in vivo differentiation of blood monocytes recruited to foci of inflammation in wild-type C57BL/6 mice. To analyze the role of endoglin in macrophages in vivo, an endoglin myeloid lineage specific knock-out mouse line (Engfl/flLysMCre) was generated. These mice show a predisposition to develop spontaneous infections by opportunistic bacteria. Engfl/flLysMCre mice also display increased survival following LPS-induced peritonitis, suggesting a delayed immune response. Phagocytic activity is impaired in peritoneal macrophages, altering one of the main functions of macrophages which contributes to the initiation of the immune response. We also observed altered expression of TGF-β1 target genes in endoglin deficient peritoneal macrophages. Overall, the altered immune activity of endoglin deficient macrophages could help to explain the higher rate of infectious diseases seen in HHT1 patients. PMID:27010826

  9. Aged mice receiving caffeine since adulthood show distinct patterns of anxiety-related behavior.

    PubMed

    Botton, Paulo Henrique S; Pochmann, Daniela; Rocha, Andreia S; Nunes, Fernanda; Almeida, Amanda S; Marques, Daniela M; Porciúncula, Lisiane O

    2017-03-01

    Caffeine is the psychostimulant most consumed worldwide. Anxiogenic effects of caffeine have been described in adult animals with controversial findings about its anxiogenic potential. Besides, the effects of caffeine on anxiety with aging are still poorly known. In this study, adult mice (6months old) started to receive caffeine (0.3 and 1.0mg/mL, drinking water) during 12-14months only in the light cycle and at weekdays. The open field (OF) and elevated plus maze (EPM) testing were used to determine the effects of caffeine on anxiety-related behavior in adult and aged mice (18-20months old). Because aging alters synaptic proteins, we also evaluated SNAP-25 (as a nerve terminals marker), GFAP (as an astrocyte marker) and adenosine A1 and A2A receptors levels in the cortex. According to the OF analysis, caffeine did not change both hypolocomotion and anxiety with aging. However, aged mice showed less anxiety behavior in the EPM, but after receiving caffeine (0.3mg/mL) during adulthood they were anxious as adult mice. While SNAP-25 and adenosine A2A receptors increased with aging, both GFAP and adenosine A1 receptors were not affected. Caffeine at moderate dose prevented the age-related increase of the SNAP-25, with no effect on adenosine A2A receptors. The absence of effect for the highest dose suggests that tolerance to caffeine may have developed over time. Aged mice showed high responsiveness to the OF, being difficult to achieve any effect of caffeine. On the other hand this substance sustained the adult anxious behavior over time in a less stressful paradigm, and this effect was coincident with changes in the SNAP-25, suggesting the involvement of this synaptic protein in the ability of caffeine to preserve changes related to emotionality with aging.

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

    PubMed Central

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

    2017-01-01

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

  11. Croton grewioides Baill. (Euphorbiaceae) Shows Antidiarrheal Activity in Mice

    PubMed Central

    da Silva, Anne Dayse Soares; de Melo e Silva, Karoline; Neto, José Clementino; Costa, Vicente Carlos de Oliveira; Pessôa, Hilzeth de Luna F.; Tavares, Josean Fechine; da Silva, Marcelo Sobral; Cavalcante, Fabiana de Andrade

    2016-01-01

    Based on chemotaxonomy, we decided to investigate the possible antidiarrheal activity in mice of a crude ethanolic extract obtained from aerial parts of Croton grewioides (CG-EtOH). We tested for any possible toxicity in rat erythrocytes and acute toxicity in mice. Antidiarrheal activity was assessed by determining the effect of CG-EtOH on defecation frequency, liquid stool, intestinal motility and intestinal fluid accumulation. CG-EtOH showed no in vitro cytotoxicity and was not orally lethal. In contrast, the extract given intraperitoneally (at 2000 mg/kg) was lethal, but only in females. CG-EtOH produced a significant and equipotent antidiarrheal activity, both in defecation frequency (ED50 = 106.0 ± 8.1 mg/kg) and liquid stools (ED50 = 105.0 ± 9.2 mg/kg). However, CG-EtOH (125 mg/kg) decreased intestinal motility by only 22.7% ± 4.4%. Moreover, extract markedly inhibited the castor oil-induced intestinal contents (ED50 = 34.6 ± 5.4 mg/kg). We thus conclude that CG-EtOH is not orally lethal and contains active principles with antidiarrheal activity, and this effect seems to involve mostly changes in intestinal secretion. SUMMARY CG-EtOH showed no in vitro cytotoxicity and was not orally lethal. In contrast, the extract given intraperitoneally (at 2000 mg/kg) was lethal, but only in females.CG-EtOH probably contains active metabolites with antidiarrheal activity.CG-EtOH reduced the frequency and number of liquid stools.Metabolites presents in the CG-EtOH act mainly by reducing intestinal fluid and, to a lesser extent, reducing intestinal motility. Abbreviations Used: CG-EtOH: crude ethanolic extract obtained from the aerial parts of C. grewioides; WHO: World Health Organization; ED50: dose of a drug that produces 50% of its maximum effect; Emax: maximum effect PMID:27365990

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

    PubMed

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

    2009-02-01

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

  13. Hypoxia induces heart regeneration in adult mice.

    PubMed

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

    2017-01-12

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

  14. Adult spinal V2a interneurons show increased excitability and serotonin-dependent bistability.

    PubMed

    Husch, Andreas; Dietz, Shelby B; Hong, Diana N; Harris-Warrick, Ronald M

    2015-02-15

    In mice, most studies of the organization of the spinal central pattern generator (CPG) for locomotion, and its component neuron classes, have been performed on neonatal [postnatal day (P)2-P4] animals. While the neonatal spinal cord can generate a basic locomotor pattern, it is often argued that the CPG network is in an immature form whose detailed properties mature with postnatal development. Here, we compare intrinsic properties and serotonergic modulation of the V2a class of excitatory spinal interneurons in behaviorally mature (older than P43) mice to those in neonatal mice. Using perforated patch recordings from genetically tagged V2a interneurons, we revealed an age-dependent increase in excitability. The input resistance increased, the rheobase values decreased, and the relation between injected current and firing frequency (F/I plot) showed higher excitability in the adult neurons, with almost all neurons firing tonically during a current step. The adult action potential (AP) properties became narrower and taller, and the AP threshold hyperpolarized. While in neonates the AP afterhyperpolarization was monophasic, most adult V2a interneurons showed a biphasic afterhyperpolarization. Serotonin increased excitability and depolarized most neonatal and adult V2a interneurons. However, in ∼30% of adult V2a interneurons, serotonin additionally elicited spontaneous intrinsic membrane potential bistability, resulting in alternations between hyperpolarized and depolarized states with a dramatically decreased membrane input resistance and facilitation of evoked plateau potentials. This was never seen in younger animals. Our findings indicate a significant postnatal development of the properties of locomotor-related V2a interneurons, which could alter their interpretation of synaptic inputs in the locomotor CPG.

  15. "Binge" drinking experience in adolescent mice shows sex differences and elevated ethanol intake in adulthood.

    PubMed

    Strong, Moriah N; Yoneyama, Naomi; Fretwell, Andrea M; Snelling, Chris; Tanchuck, Michelle A; Finn, Deborah A

    2010-06-01

    Binge drinking, defined as achieving blood ethanol concentrations (BEC) of 80 mg%, has been increasing in adolescents and was reported to predispose later physical dependence. The present experiments utilized an animal model of binge drinking to compare the effect of ethanol "binge" experience during adolescence or adulthood on subsequent ethanol intake in male and female C57BL/6 mice. Adolescent and adult mice were initially exposed to the scheduled high alcohol consumption procedure, which produces BECs that exceed the levels for binge drinking following a 30-min ethanol session every third day. Ethanol intake and BECs were significantly higher in the adolescent ( approximately 3 g/kg, 199 mg%) versus adult ( approximately 2 g/kg, 135 mg%) mice during the first three ethanol sessions, but were more equivalent during the final two ethanol sessions (1.85-2.0 g/kg, 129-143 mg%). Then, separate groups of the ethanol-experienced mice were tested with ethanol naïve adolescent and adult mice for 2-h limited access (10% and 20% solutions) or 24-h (5%, 10% and 20% solutions) ethanol preference drinking. Limited access ethanol intake was significantly higher in female versus male mice, but was not altered by age or ethanol experience. In contrast, 24-h ethanol intake was significantly higher in the adolescent versus adult mice and in female versus male mice. Furthermore, binge drinking experience in the adolescent mice significantly increased subsequent ethanol intake, primarily due to intake in female mice. Thus, adolescent binge drinking significantly increased unlimited ethanol intake during adulthood, with female mice more susceptible to this effect.

  16. Narp knockout mice show normal reactivity to novelty but attenuated recovery from neophobia.

    PubMed

    Blouin, Ashley M; Lee, Jongah J; Tao, Bo; Smith, Dani R; Johnson, Alexander W; Baraban, Jay M; Reti, Irving M

    2013-11-15

    Narp knockout (KO) mice demonstrate cognitive inflexibility and addictive behavior, which are associated with abnormal reactivity to a novel stimulus. To assess reactivity to novelty, we tested Narp KO and wild-type (WT) mice on a neophobia procedure. Both Narp KO and WT mice showed a similar decrease in consumption upon initial exposure to a novel flavor, but Narp KO mice did not increase consumption with subsequent exposures to the novel flavor like the WT mice. Therefore, Narp KO mice do not have abnormal reactivity to novelty but show deficits in adapting behavior to reflect the updated value of a stimulus.

  17. NCAM-deficient mice show prominent abnormalities in serotonergic and BDNF systems in brain - Restoration by chronic amitriptyline.

    PubMed

    Aonurm-Helm, Anu; Anier, Kaili; Zharkovsky, Tamara; Castrén, Eero; Rantamäki, Tomi; Stepanov, Vladimir; Järv, Jaak; Zharkovsky, Alexander

    2015-12-01

    Mood disorders are associated with alterations in serotonergic system, deficient BDNF (brain-derived neurotrophic factor) signaling and abnormal synaptic plasticity. Increased degradation and reduced functions of NCAM (neural cell adhesion molecule) have recently been associated with depression and NCAM deficient mice show depression-related behavior and impaired learning. The aim of the present study was to investigate potential changes in serotonergic and BDNF systems in NCAM knock-out mice. Serotonergic nerve fiber density and SERT (serotonin transporter) protein levels were robustly reduced in the hippocampus, prefrontal cortex and basolateral amygdala of adult NCAM(-)(/-) mice. This SERT reduction was already evident during early postnatal development. [(3)H]MADAM binding experiments further demonstrated reduced availability of SERT in cell membranes of NCAM(-)(/-) mice. Moreover, the levels of serotonin and its major metabolite 5-HIAA were down regulated in the brains of NCAM(-)(/-) mice. NCAM(-)(/-) mice also showed a dramatic reduction in the BDNF protein levels in the hippocampus and prefrontal cortex. This BDNF deficiency was associated with reduced phosphorylation of its receptor TrkB. Importantly, chronic administration of antidepressant amitriptyline partially or completely restored these changes in serotonergic and BDNF systems, respectively. In conclusion, NCAM deficiency lead to prominent and persistent abnormalities in brain serotonergic and BDNF systems, which likely contributes to the behavioral and neurobiological phenotype of NCAM(-/-) mice.

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

    PubMed

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

    2014-01-31

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

  19. Mice lacking brain-type creatine kinase activity show defective thermoregulation

    PubMed Central

    Streijger, Femke; Pluk, Helma; Oerlemans, Frank; Beckers, Gaby; Bianco, Antonio C.; Ribeiro, Miriam O.; Wieringa, Bé; Van der Zee, Catharina E.E.M.

    2010-01-01

    The cytosolic brain-type creatine kinase and mitochondrial ubiquitous creatine kinase (CK-B and UbCKmit) are expressed during the prepubescent and adult period of mammalian life. These creatine kinase (CK) isoforms are present in neural cell types throughout the central and peripheral nervous system and in smooth muscle containing tissues, where they have an important role in cellular energy homeostasis. Here, we report on the coupling of CK activity to body temperature rhythm and adaptive thermoregulation in mice. With both brain-type CK isoforms being absent, the body temperature reproducibly drops ~1.0°C below normal during every morning (inactive) period in the daily cycle. Facultative non-shivering thermogenesis is also impaired, since CK−−/−− mice develop severe hypothermia during 24 h cold exposure. A relationship with fat metabolism was suggested because comparison of CK−−/−− mice with wildtype controls revealed decreased weight gain associated with less white and brown fat accumulation and smaller brown adipocytes. Also, circulating levels of glucose, triglycerides and leptin are reduced. Extensive physiological testing and uncoupling protein1 analysis showed, however, that the thermogenic problems are not due to abnormal responsiveness of brown adipocytes, since noradrenaline infusion produced a normal increase of body temperature. Moreover, we demonstrate that the cyclic drop in morning temperature is also not related to altered rhythmicity with reduced locomotion, diminished food intake or increased torpor sensitivity. Although several integral functions appear altered when CK is absent in the brain, combined findings point into the direction of inefficient neuronal transmission as the dominant factor in the thermoregulatory defect. PMID:19419668

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2015-11-01

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

  2. Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy.

    PubMed

    Mader, Jessica R; Resch, Zachary T; McLean, Gary R; Mikkelsen, Jakob H; Oxvig, Claus; Marler, Ronald J; Conover, Cheryl A

    2013-10-01

    We investigated pregnancy-associated plasma protein-A (PAPP-A) in diabetic nephropathy. Normal human kidney showed specific staining for PAPP-A in glomeruli, and this staining was markedly increased in diabetic kidney. To assess the possible contribution of PAPP-A in the development of diabetic nephropathy, we induced diabetes with streptozotocin in 14-month-old WT and Papp-A knockout (KO) mice. Renal histopathology was evaluated after 4 months of stable hyperglycemia. Kidneys from diabetic WT mice showed multiple abnormalities including thickening of Bowman's capsule (100% of mice), increased glomerular size (80% of mice), tubule dilation (80% of mice), and mononuclear cell infiltration (90% of mice). Kidneys of age-matched non-diabetic WT mice had similar evidence of tubule dilation and mononuclear cell infiltration to those of diabetic WT mice, indicating that these changes were predominantly age-related. However, thickened Bowman's capsule and increased glomerular size appeared specific for the experimental diabetes. Kidneys from diabetic Papp-A KO mice had significantly reduced or no evidence of changes in Bowman's capsule thickening and glomerular size. There was also a shift to larger mesangial area and increased macrophage staining in diabetic WT mice compared with Papp-A KO mice. In summary, elevated PAPP-A expression in glomeruli is associated with diabetic nephropathy in humans and absence of PAPP-A is associated with resistance to the development of indicators of diabetic nephropathy in mice. These data suggest PAPP-A as a potential therapeutic target for diabetic nephropathy.

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

    PubMed

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

    2008-02-01

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

  4. Mice lacking components of adaptive immunity show increased Brucella abortus virB mutant colonization.

    PubMed

    Rolán, Hortensia García; Tsolis, Renée M

    2007-06-01

    The Brucella abortus type IV secretion system (T4SS), encoded by the virB genes, is essential for survival in mononuclear phagocytes in vitro. In the mouse model, a B. abortus virB mutant was initially able to colonize the spleen at the level of the wild type for approximately 3 to 5 days, which coincided with the development of adaptive immunity. To investigate the relationship between survival in macrophages cultivated in vitro and persistence in tissues in vivo, we tested the ability of mutant mice lacking components of adaptive immunity to eliminate the virB mutant from the spleen during a mixed infection with the B. abortus wild type. Ifng(-/-) or beta(2)m(-/-) mice were able to clear the virB mutant to the same degree as control mice. However, spleens of Rag1(-/-) mice and Igh6(-/-) mice were more highly colonized by the virB mutant than control mice after 14 to 21 days, suggesting that, in these mice, there is not an absolute requirement for the T4SS to mediate persistence of B. abortus in the spleen. Macrophages isolated from Igh6(-/-) mice killed the virB mutant to the same extent as macrophages from control mice, showing that the reduced ability of these mice to clear the virB mutant from the spleen does not correlate with diminished macrophage function in vitro. These results show that in the murine model host, the T4SS is required for persistence beyond 3 to 5 days after infection and suggest that the T4SS may contribute to evasion of adaptive immune mechanisms by B. abortus.

  5. Localized brain differences in Arc expression between mice showing low vs. high propensity to ethanol sensitization.

    PubMed

    Nona, Christina N; Lam, Marcus; Nobrega, José N

    2016-03-01

    Behavioral sensitization to ethanol (EtOH) manifests as a progressive and enduring increase in locomotor activity with repeated drug exposure. However, not all mice sensitize to EtOH and the neuronal mechanisms mediating vulnerability and resistance to EtOH sensitization remain unclear. We examined regional brain expression of the immediate early gene activity-regulated cytoskeleton-associated protein (Arc) in order to identify brain areas in which neuroplastic changes may contribute to the development and expression of EtOH sensitization. Male DBA/2J mice received 5 biweekly injections of EtOH (2.2g/kg, i.p.) or saline (SAL). They were categorized as high- (HS) or low-sensitized (LS) on the basis of final locomotor activity scores. In both LS and HS mice sacrificed after the last sensitization injection, Arc expression was decreased throughout the brain in comparison to SAL animals. A similar pattern was seen in mice sacrificed after an EtOH challenge two weeks after the last sensitization injection. However in this cohort, Arc expression was significantly increased in the central amygdala (CeA) in LS mice and in SAL mice receiving EtOH for the first time. No significant increases in Arc expression were seen in brains of sensitized (HS) animals. These results indicate an acute EtOH challenge results in different patterns of Arc expression in brains of LS, HS, and SAL mice. The dramatic increases in Arc expression in the CeA in LS and SAL mice showing little or no behavioral activation suggests that neural activity in this region may serve to inhibit the stimulant effects of EtOH. The observation that HS mice do not show increases in Arc expression with an EtOH challenge suggests the possibility that increased tolerance to the Arc-inducing effects of EtOH may be a factor in behavioral sensitization.

  6. Mice lacking the galanin gene show decreased sensitivity to nicotine conditioned place preference.

    PubMed

    Neugebauer, Nichole M; Henehan, Robert M; Hales, Claire A; Picciotto, Marina R

    2011-03-01

    Previous work has indicated that the neuropeptide galanin decreases sensitivity to the rewarding effects of morphine and cocaine, but increases alcohol drinking. The aim of the current study was to examine the role of galanin signaling in nicotine reward by testing the effects of nicotine in mice lacking galanin peptide (GAL-/-) as compared to wild-type (GAL+/+) controls. Using an unbiased, three-chamber conditioned place preference (CPP) paradigm the dose-response function for nicotine CPP was tested in GAL-/- and GAL+/+ mice. Since activation of extracellular signal-related kinase (ERK2) is involved in the rewarding effects of several classes of drugs of abuse, we then measured the level of ERK2 phosphorylation in the nucleus accumbens shell (NACsh) and core (NACco) of GAL-/- and GAL+/+ mice following re-exposure to the CPP chamber previously paired with nicotine as a marker of mesolimbic system activation. Finally, we examined whether acute nicotine administration affects ERK2 activity in GAL-/- and GAL+/+ mice. GAL-/- mice required a higher dose of nicotine to induce a significant CPP compared to GAL+/+ mice. In the conditioning groups showing significant expression of nicotine CPP, only GAL+/+ mice showed ERK2 activation in the NACsh. This suggests that the nicotine CPP observed in GAL+/+ mice resulted in differential recruitment of ERK signaling in the NACsh compared to GAL-/- mice. In addition, no activation of ERK2 was observed following acute nicotine administration in either genotype. These data, along with prior results, suggest that galanin alters sensitivity to drugs of abuse differentially, with morphine, cocaine and amphetamine place preference suppressed, and nicotine and alcohol preference increased, by galanin signaling.

  7. Heart regeneration in adult MRL mice

    NASA Astrophysics Data System (ADS)

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

    2001-08-01

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

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

    PubMed

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

    2016-04-28

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

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

    PubMed

    Serradj, Nadjet; Picquet, Florence; Jamon, Marc

    2013-11-01

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

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

    PubMed

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

    2012-02-14

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

  11. Heterozygous Che-1 KO mice show deficiencies in object recognition memory persistence.

    PubMed

    Zalcman, Gisela; Corbi, Nicoletta; Di Certo, Maria Grazia; Mattei, Elisabetta; Federman, Noel; Romano, Arturo

    2016-10-06

    Transcriptional regulation is a key process in the formation of long-term memories. Che-1 is a protein involved in the regulation of gene transcription that has recently been proved to bind the transcription factor NF-κB, which is known to be involved in many memory-related molecular events. This evidence prompted us to investigate the putative role of Che-1 in memory processes. For this study we newly generated a line of Che-1(+/-) heterozygous mice. Che-1 homozygous KO mouse is lethal during development, but Che-1(+/-) heterozygous mouse is normal in its general anatomical and physiological characteristics. We analyzed the behavioral characteristic and memory performance of Che-1(+/-) mice in two NF-κB dependent types of memory. We found that Che-1(+/-) mice show similar locomotor activity and thigmotactic behavior than wild type (WT) mice in an open field. In a similar way, no differences were found in anxiety-like behavior between Che-1(+/-) and WT mice in an elevated plus maze as well as in fear response in a contextual fear conditioning (CFC) and object exploration in a novel object recognition (NOR) task. No differences were found between WT and Che-1(+/-) mice performance in CFC training and when tested at 24h or 7days after training. Similar performance was found between groups in NOR task, both in training and 24h testing performance. However, we found that object recognition memory persistence at 7days was impaired in Che-1(+/-) heterozygous mice. This is the first evidence showing that Che-1 is involved in memory processes.

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

    PubMed

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

    2015-11-01

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

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

    PubMed

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

    2014-09-01

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

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

    PubMed Central

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

    2016-01-01

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

  15. Elastin-insufficient mice show normal cardiovascular remodeling in 2K1C hypertension despite higher baseline pressure and unique cardiovascular architecture.

    PubMed

    Wagenseil, Jessica E; Knutsen, Russell H; Li, Dean Y; Mecham, Robert P

    2007-07-01

    Mice heterozygous for the elastin gene (ELN(+/-)) show unique cardiovascular properties, including increased blood pressure and smaller, thinner arteries with an increased number of lamellar units. Some of these properties are also observed in humans with supravalvular aortic stenosis, a disease caused by functional heterozygosity of the elastin gene. The arterial geometry in ELN(+/-) mice is contrary to the increased thickness that would be expected in an animal demonstrating hypertensive remodeling. To determine whether this is due to a decreased capability for cardiovascular remodeling or to a novel adaptation of the ELN(+/-) cardiovascular system, we increased blood pressure in adult ELN(+/+) and ELN(+/-) mice using the two-kidney, one-clip Goldblatt model of hypertension. Successfully clipped mice have a systolic pressure increase of at least 15 mmHg over sham-operated animals. ELN(+/+) and ELN(+/-)-clipped mice show significant increases over sham-operated mice in cardiac weight, arterial thickness, and arterial cross-sectional area with no changes in lamellar number. There are no significant differences in most mechanical properties with clipping in either genotype. These results indicate that ELN(+/+) and ELN(+/-) hearts and arteries remodel similarly in response to adult induced hypertension. Therefore, the cardiovascular properties of ELN(+/-) mice are likely due to developmental remodeling in response to altered hemodynamics and reduced elastin levels.

  16. Pancreas-specific aquaporin 12 null mice showed increased susceptibility to caerulein-induced acute pancreatitis.

    PubMed

    Ohta, Eriko; Itoh, Tomohiro; Nemoto, Tomomi; Kumagai, Jiro; Ko, Shigeru B H; Ishibashi, Kenichi; Ohno, Mayuko; Uchida, Keiko; Ohta, Akihito; Sohara, Eisei; Uchida, Shinichi; Sasaki, Sei; Rai, Tatemitsu

    2009-12-01

    Aquaporin 12 (AQP12) is the most recently identified member of the mammalian AQP family and is specifically expressed in pancreatic acinar cells. In vitro expression studies have revealed that AQP12 is localized at intracellular sites. To determine the physiological roles of AQP12 in the pancreas, we generated knockout mice for this gene (AQP12-KO). No obvious differences were observed under normal conditions between wild-type (WT) and AQP12-KO mice in terms of growth, blood chemistry, pancreatic fluid content, or histology. However, when we induced pancreatitis through the administration of a cholecystokinin-8 (CCK-8) analog, the AQP12-KO mice showed more severe pathological damage to this organ than WT mice. Furthermore, when we analyzed exocytosis in the pancreatic acini using a two-photon excitation imaging method, the results revealed larger exocytotic vesicles (vacuoles) in the acini of AQP12-KO mice at a high CCK-8 dose (100 nM). From these results, we conclude that AQP12 may function in the mechanisms that control the proper secretion of pancreatic fluid following rapid and intense stimulation.

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    Hu, Weilian; Dai, Dehui; Li, Wei

    2013-08-01

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

  19. Ghrelin knockout mice show decreased voluntary alcohol consumption and reduced ethanol-induced conditioned place preference.

    PubMed

    Bahi, Amine; Tolle, Virginie; Fehrentz, Jean-Alain; Brunel, Luc; Martinez, Jean; Tomasetto, Catherine-Laure; Karam, Sherif M

    2013-05-01

    Recent work suggests that stomach-derived hormone ghrelin receptor (GHS-R1A) antagonism may reduce motivational aspects of ethanol intake. In the current study we hypothesized that the endogenous GHS-R1A agonist ghrelin modulates alcohol reward mechanisms. For this purpose ethanol-induced conditioned place preference (CPP), ethanol-induced locomotor stimulation and voluntary ethanol consumption in a two-bottle choice drinking paradigm were examined under conditions where ghrelin and its receptor were blocked, either using ghrelin knockout (KO) mice or the specific ghrelin receptor (GHS-R1A) antagonist "JMV2959". We showed that ghrelin KO mice displayed lower ethanol-induced CPP than their wild-type (WT) littermates. Consistently, when injected during CPP-acquisition, JMV2959 reduced CPP-expression in C57BL/6 mice. In addition, ethanol-induced locomotor stimulation was lower in ghrelin KO mice. Moreover, GHS-R1A blockade, using JMV2959, reduced alcohol-stimulated locomotion only in WT but not in ghrelin KO mice. When alcohol consumption and preference were assessed using the two-bottle choice test, both genetic deletion of ghrelin and pharmacological antagonism of the GHS-R1A (JMV2959) reduced voluntary alcohol consumption and preference. Finally, JMV2959-induced reduction of alcohol intake was only observed in WT but not in ghrelin KO mice. Taken together, these results suggest that ghrelin neurotransmission is necessary for the stimulatory effect of ethanol to occur, whereas lack of ghrelin leads to changes that reduce the voluntary intake as well as conditioned reward by ethanol. Our findings reveal a major, novel role for ghrelin in mediating ethanol behavior, and add to growing evidence that ghrelin is a key mediator of the effects of multiple abused drugs.

  20. Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation.

    PubMed

    Chidgey, M; Brakebusch, C; Gustafsson, E; Cruchley, A; Hail, C; Kirk, S; Merritt, A; North, A; Tselepis, C; Hewitt, J; Byrne, C; Fassler, R; Garrod, D

    2001-11-26

    The desmosomal cadherin desmocollin (Dsc)1 is expressed in upper epidermis where strong adhesion is required. To investigate its role in vivo, we have genetically engineered mice with a targeted disruption in the Dsc1 gene. Soon after birth, null mice exhibit flaky skin and a striking punctate epidermal barrier defect. The epidermis is fragile, and acantholysis in the granular layer generates localized lesions, compromising skin barrier function. Neutrophils accumulate in the lesions and further degrade the tissue, causing sloughing (flaking) of lesional epidermis, but rapid wound healing prevents the formation of overt lesions. Null epidermis is hyperproliferative and overexpresses keratins 6 and 16, indicating abnormal differentiation. From 6 wk, null mice develop ulcerating lesions resembling chronic dermatitis. We speculate that ulceration occurs after acantholysis in the fragile epidermis because environmental insults are more stringent and wound healing is less rapid than in neonatal mice. This dermatitis is accompanied by localized hair loss associated with formation of utriculi and dermal cysts, denoting hair follicle degeneration. Possible resemblance of the lesions to human blistering diseases is discussed. These results show that Dsc1 is required for strong adhesion and barrier maintenance in epidermis and contributes to epidermal differentiation.

  1. Mice deficient in dihydrolipoyl succinyltransferase show increased vulnerability to mitochondrial toxins

    PubMed Central

    Yang, Lichuan; Shi, Qingli; Ho, Daniel J.; Starkov, Anatoly A.; Wille, Elizabeth J.; Xu, Hui; Chen, HL; Zhang, Steven; Stack, Cliona M.; Calingasan, Noel Y.; Gibson, Gary E.; Beal, M. Flint

    2013-01-01

    The activity of a key mitochondrial tricarboxylic acid cycle enzyme, α-ketoglutarate dehydrogenase complex (KGDHC), declines in many neurodegenerative diseases. KGDHC consists of three subunits. The dihydrolipoyl succinyltransferase (DLST) component is unique to KGDHC. DLST+/- mice showed reduced mRNA and protein levels and decreased brain mitochondrial KGDHC activity. Neurotoxic effects of mitochondrial toxins were exacerbated in DLST+/- mice. MPTP produced a significantly greater reduction of striatal dopamine and tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta of DLST+/- mice. DLST deficiency enhanced the severity of lipid peroxidation in the substantia nigra after MPTP treatment. Striatal lesions induced by either malonate or 3-nitropropionic acid (3-NP) were significantly larger in DLST+/- mice than in wildtype controls. DLST deficiency enhanced the 3-NP inhibition of mitochondria enzymes, and 3-NP induced protein and DNA oxidations. These observations support the hypothesis that reductions in KGDHC may impair the adaptability of the brain and contribute to the pathogenesis of neurodegenerative diseases. PMID:19660549

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

    PubMed Central

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

    2016-01-01

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

  3. Endogenous cerebellar neurogenesis in adult mice with progressive ataxia

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    1988-08-01

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

  5. Ghrelin O-acyltransferase knockout mice show resistance to obesity when fed high-sucrose diet.

    PubMed

    Kouno, Tetsuya; Akiyama, Nobuteru; Ito, Takahito; Okuda, Tomohiko; Nanchi, Isamu; Notoya, Mitsuru; Oka, Shogo; Yukioka, Hideo

    2016-02-01

    Ghrelin is an appetite-stimulating hormone secreted from stomach. Since the discovery that acylation of the serine-3 residue by ghrelin O-acyltransferase (GOAT) is essential for exerting its functions, GOAT has been regarded as an therapeutic target for attenuating appetite, and thus for the treatment of obesity and diabetes. However, contrary to the expectations, GOAT-knockout (KO) mice have not shown meaningful body weight reduction, under high-fat diet. Here, in this study, we sought to determine whether GOAT has a role in body weight regulation and glucose metabolism with a focus on dietary sucrose, because macronutrient composition of diet is important for appetite regulation. We found that peripherally administered acylated-ghrelin, but not unacylated one, stimulated sucrose consumption in a two-bottle-drinking test. The role of acylated-ghrelin in sucrose preference was further supported by the finding that GOAT KO mice consumed less sucrose solution compared with WT littermates. Then, we investigated the effect of dietary composition of sucrose on food intake and body weight in GOAT KO and WT mice. As a result, when fed on high-fat diet, food intake and body weight were similar between GOAT KO and WT mice. However, when fed on high-fat, high-sucrose diet, GOAT KO mice showed significantly reduced food intake and marked resistance to obesity, leading to amelioration of glucose metabolism. These results suggest that blockade of acylated-ghrelin production offers therapeutic potential for obesity and metabolic disorders caused by overeating of palatable food.

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

    PubMed

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

    2013-10-01

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

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

    PubMed Central

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

    2015-01-01

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

  8. Aged PrP null mice show defective processing of neuregulins in the peripheral nervous system.

    PubMed

    Benvegnù, Stefano; Gasperini, Lisa; Legname, Giuseppe

    2011-05-01

    A prion, a protease-resistant conformer of the cellular prion protein (PrP(C)), is the causative agent of transmissible spongiform encephalopathies or prion diseases. While this property is well established for the aberrantly folded protein, the physiological function of PrP(C) remains elusive. Among different putative functions, the non-pathogenic protein isoform PrP(C) is involved in several cellular processes. Here, we show that PrP(C) regulates the cleavage of neuregulin-1 proteins (NRG1). Neuregulins provide key axonal signals that regulate several processes, including glial cells proliferation, survival and myelination. Interestingly, mice devoid of PrP(C) (Prnp⁰/⁰) were recently shown to have a late-onset demyelinating disease in the peripheral nervous system (PNS) but not in the central nervous system (CNS). We found that NRG1 processing is developmentally regulated in the PNS and, by comparing wildtype and Prnp⁰/⁰ mice, that PrP(C) influences NRG1 processing in old, but not in young, animals. In addition, we found that also the processing of neuregulin-3, another neuregulin family member, is altered in the PNS of Prnp⁰/⁰ mice. These differences in neuregulin proteins processing are not paralleled in the CNS, thus suggesting a different cellular function for PrP(C) between the CNS and the PNS.

  9. Immunization with recombinant leucine aminopeptidase showed protection against Fasciola gigantica in mice.

    PubMed

    Changklungmoa, Narin; Kueakhai, Pornanan; Riengrojpitak, Suda; Chaithirayanon, Kulathida; Chaichanasak, Pannigan; Preyavichyapugdee, Narin; Chantree, Pathanin; Sansri, Veerawat; Itagaki, Tadashi; Sobhon, Prasert

    2013-10-01

    Leucine aminopeptidase (LAP) is expressed in all stages of Fasciola gigantica and, hence, is considered as a potential vaccine candidate. In this study, we have tested a vaccine potential of LAP and the types of immune responses it elicited in vaccinated mice. Recombinant F. gigantica leucine aminopeptidase (rFgLAP) was expressed in Escherichia coli, BL21 (DE3). The imprinting control region mice subcutaneously immunized with 50 μg of rFgLAP combined with Freund's adjuvant (n = 10) exhibited a significant reduction in worm recoveries when compared with non-immunized and Freund's adjuvant controls at 60.8 and 64.3%, respectively, and both T helper (Th)1 and Th2 humoral immune responses were elicited in the hosts as reflected by the levels of IgG1 and IgG2a, with Th2 predominating. The levels of IgG1- and IgG2a-specific antibodies to rFgLAP were inversely and significantly correlated with the numbers of worm recoveries. The rFgLAP-vaccinated mice showed significantly reduced levels of serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase and liver damage. These indicated that rFgLAP has a potential as a vaccine candidate against F. gigantica, whose efficacy will be studied further in economic animals including cattle, sheep, and goat.

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

    PubMed

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

    2012-05-01

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

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

    PubMed

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

    2005-09-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-06-01

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

  14. Atf3 mutant mice show reduced axon regeneration and impaired regeneration-associated gene induction after peripheral nerve injury

    PubMed Central

    Gey, Manuel; Wanner, Renate; Schilling, Corinna; Pedro, Maria T.; Sinske, Daniela

    2016-01-01

    Axon injury in the peripheral nervous system (PNS) induces a regeneration-associated gene (RAG) response. Atf3 (activating transcription factor 3) is such a RAG and ATF3's transcriptional activity might induce ‘effector’ RAGs (e.g. small proline rich protein 1a (Sprr1a), Galanin (Gal), growth-associated protein 43 (Gap43)) facilitating peripheral axon regeneration. We provide a first analysis of Atf3 mouse mutants in peripheral nerve regeneration. In Atf3 mutant mice, facial nerve regeneration and neurite outgrowth of adult ATF3-deficient primary dorsal root ganglia neurons was decreased. Using genome-wide transcriptomics, we identified a neuropeptide-encoding RAG cluster (vasoactive intestinal peptide (Vip), Ngf, Grp, Gal, Pacap) regulated by ATF3. Exogenous administration of neuropeptides enhanced neurite growth of Atf3 mutant mice suggesting that these molecules might be effector RAGs of ATF3's pro-regenerative function. In addition to the induction of growth-promoting molecules, we present data that ATF3 suppresses growth-inhibiting molecules such as chemokine (C-C motif) ligand 2. In summary, we show a pro-regenerative ATF3 function during PNS nerve regeneration involving transcriptional activation of a neuropeptide-encoding RAG cluster. ATF3 is a general injury-inducible factor, therefore ATF3-mediated mechanisms identified herein might apply to other cell and injury types. PMID:27581653

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    2014-12-01

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

  17. MRL/MpJ-Fas(lpr) mice show abnormalities in ovarian function and morphology with the progression of autoimmune disease.

    PubMed

    Otani, Yuki; Ichii, Osamu; Otsuka-Kanazawa, Saori; Chihara, Masataka; Nakamura, Teppei; Kon, Yasuhiro

    2015-01-01

    The immune system is known to affect reproductive function, and maternal-fetal immune tolerance is essential for a successful pregnancy. To investigate the relationship between autoimmune disease and female reproductive function, we performed a comparative analysis of the ovarian phenotypes for C57BL/6 mice, autoimmune disease-prone MRL/MpJ (MRL/+) mice and congenic MRL/MpJ-Fas(lpr) (MRL/lpr) mice harboring a mutation in the Fas gene that speeds disease onset. Both MRL-background strains showed earlier vaginal opening than C57BL/6 mice. The estrous cycle became irregular by 6 and 12 months of age in MRL/lpr mice and mice of the other two strains, respectively. Histological analysis at 3 months revealed that the number of primordial follicles was smaller in MRL-background mice than in C57BL/6 mice after 3 months. In addition, MRL/lpr and MRL/+ mice displayed lower numbers of ovarian follicles and corpora lutea at 3 and 6 months, and 6 and 12 months, respectively, than that in age-matched C57BL/6 mice. MRL/lpr and MRL/+ mice developed ovarian interstitial glands after 3 and 6 months, respectively. In particular, MRL/lpr mice showed numerous infiltrating lymphocytes within the ovarian interstitia, and partially stratified ovarian surface epithelia with more developed microvilli than that observed in C57BL/6 mice at 6 months. No significant differences in serum hormone levels were observed between the strains. In conclusion, MRL/lpr mice display altered ovarian development, morphology and function consistent with the progression of severe autoimmune disease, as these findings are less severe in MRL/+ counterparts.

  18. Two Genetically Similar H9N2 Influenza A Viruses Show Different Pathogenicity in Mice

    PubMed Central

    Liu, Qingtao; Liu, Yuzhuo; Yang, Jing; Huang, Xinmei; Han, Kaikai; Zhao, Dongmin; Bi, Keran; Li, Yin

    2016-01-01

    H9N2 Avian influenza virus has repeatedly infected humans and other mammals, which highlights the need to determine the pathogenicity and the corresponding mechanism of this virus for mammals. In this study, we found two H9N2 viruses with similar genetic background but with different pathogenicity in mice. The A/duck/Nanjing/06/2003 (NJ06) virus was highly pathogenic for mice, with a 50% mouse lethal dose (MLD50) of 102.83 50% egg infectious dose (EID50), whereas the A/duck/Nanjing/01/1999 (NJ01) virus was low pathogenic for mice, with a MLD50 of >106.81 EID50. Further studies showed that the NJ06 virus grew faster and reached significantly higher titers than NJ01 in vivo and in vitro. Moreover, the NJ06 virus induced more severe lung lesions, and higher levels of inflammatory cellular infiltration and cytokine response in lungs than NJ01 did. However, only 12 different amino acid residues (HA-K157E, NA-A9T, NA-R435K, PB2-T149P, PB2-K627E, PB1-R187K, PA-L548M, PA-M550L, NP-G127E, NP-P277H, NP-D340N, NS1-D171N) were found between the two viruses, and all these residues except for NA-R435K were located in the known functional regions involved in interaction of viral proteins or between the virus and host factors. Summary, our results suggest that multiple amino acid differences may be responsible for the higher pathogenicity of the NJ06 virus for mice, resulting in lethal infection, enhanced viral replication, severe lung lesions, and excessive inflammatory cellular infiltration and cytokine response in lungs. These observations will be helpful for better understanding the pathogenic potential and the corresponding molecular basis of H9N2 viruses that might pose threats to human health in the future. PMID:27867373

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

    PubMed Central

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

    2017-01-01

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

  20. Adults with Dyslexia Show Deficits on Spatial Frequency Doubling and Visual Attention Tasks

    ERIC Educational Resources Information Center

    Buchholz, Judy; McKone, Elinor

    2004-01-01

    We examine the visual processing of high-functioning adults with developmental dyslexia (mean Performance IQ=126.5) and current phonological problems. In comparison to an age- and IQ-matched control group, the group with dyslexia showed deficits in two tasks associated with magnocellular/dorsal pathway function. For the "frequency doubling"…

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

    PubMed

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

    2015-03-01

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

  2. Abnormal Mammary Adipose Tissue Environment of Brca1 Mutant Mice Show a Persistent Deposition of Highly Vascularized Multilocular Adipocytes.

    PubMed

    Jones, Laundette P; Buelto, Destiney; Tago, Elaine; Owusu-Boaitey, Kwadwo E

    2011-12-08

    A major challenge to breast cancer research is the identification of alterations in the architecture and composition of the breast that are associated with breast cancer progression. The aim of the present investigation was to characterize the mammary adipose phenotype from Brca1 mutant mice in the expectation that this would shed light on the role of the mammary tissue environment in the early stages of breast tumorigenesis. We observed that histological sections of mammary tissue from adult Brca1 mutant mice abnormally display small, multilocular adipocytes that are reminiscent of brown adipose tissue (BAT) as compared to wildtype mice. Using a marker for BAT, the uncoupling protein 1 (UCP1), we demonstrated that these multilocular adipose regions in Brca1 mutant mice stain positive for UCP1. Transcriptionally, UCP1 mRNA levels in the Brca1 mutant mice were elevated greater than 50-fold compared to age-matched mammary glands from wildtype mice. Indeed, BAT has characteristics that are favorable for tumor growth, including high vascularity. Therefore, we also demonstrated that the multilocular brown adipose phenotype in the mammary fat pad of Brca1 mutant mice displayed regions of increased vascularity as evidenced by a significant increase in the protein expression of CD31, a marker for angiogenesis. This Brca1 mutant mouse model should provide a physiologically relevant context to determine whether brown adipose tissue can play a role in breast cancer development.

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

    PubMed

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

    2012-09-01

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

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

    PubMed

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

    2016-07-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2017-04-01

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

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

    PubMed

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

    2014-02-01

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

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

    PubMed

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

    2015-08-01

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

  8. Ceruloplasmin gene-deficient mice with experimental autoimmune encephalomyelitis show attenuated early disease evolution.

    PubMed

    Gresle, Melissa M; Schulz, Katrin; Jonas, Anna; Perreau, Victoria M; Cipriani, Tania; Baxter, Alan G; Miranda-Hernandez, Socorro; Field, Judith; Jokubaitis, Vilija G; Cherny, Robert; Volitakis, Irene; David, Samuel; Kilpatrick, Trevor J; Butzkueven, Helmut

    2014-06-01

    We conducted a microarray study to identify genes that are differentially regulated in the spinal cords of mice with the inflammatory disease experimental autoimmune encephalomyelitis (EAE) relative to healthy mice. In total 181 genes with at least a two-fold increase in expression were identified, and most of these genes were associated with immune function. Unexpectedly, ceruloplasmin (Cp), a ferroxidase that converts toxic ferrous iron to its nontoxic ferric form and also promotes the efflux of iron from astrocytes in the CNS, was shown to be highly upregulated (13.2-fold increase) in EAE spinal cord. Expression of Cp protein is known to be increased in several neurological conditions, but the role of Cp regulation in CNS autoimmune disease is not known. To investigate this, we induced EAE in Cp gene knockout, heterozygous, and wild-type mice. Cp knockout mice were found to have slower disease evolution than wild-type mice (EAE days 13-17; P = 0.05). Interestingly, Cp knockout mice also exhibited a significant increase in the number of astrocytes with reactive morphology in early EAE compared with wild-type mice at the same stage of disease. CNS iron levels were not increased with EAE in these mice. Based on these observations, we propose that an increase in Cp expression could contribute to tissue damage in early EAE. In addition, endogenous CP either directly or indirectly inhibits astrocyte reactivity during early disease, which could also worsen early disease evolution.

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

    PubMed

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

    2015-08-04

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2016-10-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  15. Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta

    SciTech Connect

    Wang, Yuehai; Lu, Huixia; Huang, Ziyang; Lin, Huili; Lei, Zhenmin; Tang, Mengxiong; Gao, Fei; Dong, Mei; Li, Rongda; Lin, Ling

    2014-07-18

    Highlights: • Titers of ANA and anti-dsDNA antibodies were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • The spleen weights and glomerular areas were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • Expressions of IgG and C3 in glomeruli were similar in ApoE{sup −/−} and Fas{sup −/−} mice. • IgG, C3 and macrophage infiltration in aortic plaques were found in ApoE{sup −/−} mice. - Abstract: Background: Apolipoprotein E-knockout (ApoE{sup −/−}) mice is a classic model of atherosclerosis. We have found that ApoE{sup −/−} mice showed splenomegaly, higher titers of serum anti-nuclear antibody (ANA) and anti-dsDNA antibody compared with C57B6/L (B6) mice. However, whether ApoE{sup −/−} mice show autoimmune injury remains unclear. Methods and results: Six females and six males in each group, ApoE{sup −/−}, Fas{sup −/−} and B6 mice, were used in this study. The titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein were measured by ELISA after 4 months of high-fat diet. The spleen weight and the glomerular area were determined. The expressions of IgG, C3 and macrophage in kidney and atherosclerotic plaque were detected by immunostaining followed by morphometric analysis. Similar to the characteristics of Fas{sup −/−} mice, a model of systemic lupus erythematosus (SLE), ApoE{sup −/−} mice, especially female, displayed significant increases of spleen weight and glomerular area when compared to B6 mice. Also, elevated titers of serum ANA, anti-dsDNA antibody and creatinine and urine protein. Moreover, the expressions of IgG, C3 and macrophage in glomeruli and aortic plaques were found in ApoE{sup −/−} mice. In addition, the IgG and C3 expressions in glomeruli and plaques significantly increased (or a trend of increase) in female ApoE{sup −/−} mice compared with males. Conclusions: Apolipoprotein E-knockout mice on high-fat diet show autoimmune injury on kidney and aorta.

  16. Adolescent earthquake survivors' show increased prefrontal cortex activation to masked earthquake images as adults.

    PubMed

    Du, Xue; Wei, Dongtao; Ganzel, Barbara L; Kim, Pilyoung; Zhang, Qinglin; Qiu, Jiang

    2015-03-01

    The great Sichuan earthquake in China on May 12, 2008 was a traumatic event to many who live near the earthquake area. However, at present, there are few studies that explore the long-term impact of the adolescent trauma exposure on adults' brain function. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the brain activation evoked by masked trauma-related stimuli (earthquake versus neutral images) in 14 adults who lived near the epicenter of the great Sichuan earthquake when they were adolescents (trauma-exposed group) and 14 adults who lived farther from the epicenter of the earthquake when they were adolescents (control group). Compared with the control group, the trauma-exposed group showed significant elevation of activation in the right anterior cingulate cortex (ACC) and the medial prefrontal cortex (MPFC) in response to masked earthquake-related images. In the trauma-exposed group, the right ACC activation was negatively correlated with the frequency of symptoms of post-traumatic stress disorder (PTSD). These findings differ markedly from the long-term effects of trauma exposure in adults. This suggests that trauma exposure during adolescence may have a unique long-term impact on ACC/MPFC function, top-down modulation of trauma-related information, and subsequent symptoms of PTSD.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2014-07-01

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

  20. Ultrasonic Vocalizations of Male Mice Differ among Species and Females Show Assortative Preferences for Male Calls

    PubMed Central

    Musolf, Kerstin; Meindl, Stefanie; Larsen, Angela L.; Kalcounis-Rueppell, Matina C.; Penn, Dustin J.

    2015-01-01

    Male house mice (Mus musculus) emit ultrasonic vocalizations (USVs) during courtship, which attract females, and we aimed to test whether females use these vocalizations for species or subspecies recognition of potential mates. We recorded courtship USVs of males from different Mus species, Mus musculus subspecies, and populations (F1 offspring of wild-caught Mus musculus musculus, Mus musculus domesticus (and F1 hybrid crosses), and Mus spicilegus), and we conducted playback experiments to measure female preferences for male USVs. Male vocalizations contained at least seven distinct syllable types, whose frequency of occurrence varied among species, subspecies, and populations. Detailed analyses of multiple common syllable types indicated that Mus musculus and Mus spicilegus could be discriminated based on spectral and temporal characteristics of their vocalizations, and populations of Mus musculus were also distinctive regardless of the classification model used. Females were able to discriminate USVs from different species, and showed assortative preferences for conspecific males. We found no evidence that females discriminate USVs of males from a different subspecies or separate populations of the same species, even though our spectral analyses identified acoustic features that differ between species, subspecies, and populations of the same species. Our results provide the first comparison of USVs between Mus species or between Mus musculus subspecies, and the first evidence that male USVs potentially facilitate species recognition. PMID:26309246

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

    PubMed Central

    2013-01-01

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

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

    PubMed

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

    2015-10-01

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

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

    PubMed Central

    Ieraci, Alessandro; Mallei, Alessandra; Popoli, Maurizio

    2016-01-01

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

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

    PubMed

    Ieraci, Alessandro; Mallei, Alessandra; Popoli, Maurizio

    2016-01-01

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

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

    PubMed

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

    2016-04-28

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2015-01-29

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

  11. Heterozygous caveolin-3 mice show increased susceptibility to palmitate-induced insulin resistance.

    PubMed

    Talukder, M A Hassan; Preda, Marilena; Ryzhova, Larisa; Prudovsky, Igor; Pinz, Ilka M

    2016-03-01

    Insulin resistance and diabetes are comorbidities of obesity and affect one in 10 adults in the United States. Despite the high prevalence, the mechanisms of cardiac insulin resistance in obesity are still unclear. We test the hypothesis that the insulin receptor localizes to caveolae and is regulated through binding to caveolin-3 (CAV3). We further test whether haploinsufficiency forCAV3 increases the susceptibility to high-fat-induced insulin resistance. We used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of theIR We show that haploinsufficiency forCAV3 increases susceptibility to palmitate-induced global insulin resistance and causes cardiomyopathy. On the basis of fluorescence energy transfer (FRET) experiments, we show thatCAV3 andIRdirectly interact in cardiomyocytes. Palmitate impairs insulin signaling by a decrease in insulin-stimulated phosphorylation of Akt that corresponds to an 87% decrease in insulin-stimulated glucose uptake inHL-1 cardiomyocytes. Despite loss of Akt phosphorylation and lower glucose uptake, palmitate increased insulin-independent serine phosphorylation ofIRS-1 by 35%. In addition, we found lipid induced downregulation ofCD36, the fatty acid transporter associated with caveolae. This may explain the problem the diabetic heart is facing with the simultaneous impairment of glucose uptake and lipid transport. Thus, these findings suggest that loss ofCAV3 interferes with downstream insulin signaling and lipid uptake, implicatingCAV3 as a regulator of theIRand regulator of lipid uptake in the heart.

  12. IL-1 receptor-antagonist (IL-1Ra) knockout mice show anxiety-like behavior by aging.

    PubMed

    Wakabayashi, Chisato; Numakawa, Tadahiro; Odaka, Haruki; Ooshima, Yoshiko; Kiyama, Yuji; Manabe, Toshiya; Kunugi, Hiroshi; Iwakura, Yoichiro

    2015-07-10

    Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus.

  13. Young MLP deficient mice show diastolic dysfunction before the onset of dilated cardiomyopathy

    PubMed Central

    Lorenzen-Schmidt, Ilka; Stuyvers, Bruno D.; ter Keurs, Henk E.D.J.; Date, Moto-o; Hoshijima, Masahiko; Chien, Kenneth R.; McCulloch, Andrew D.; Omens, Jeffrey H.

    2015-01-01

    Targeted deletion of cytoskeletal muscle LIM protein (MLP) in mice consistently leads to dilated cardiomyopathy (DCM) after one or more months. However, next to nothing is known at present about the mechanisms of this process. We investigated whether diastolic performance including passive mechanics and systolic behavior are altered in 2-week-old MLP knockout (MLPKO) mice, in which heart size, fractional shortening and ejection fraction are still normal. Right ventricular trabeculae were isolated from 2-week-old MLPKO and wildtype mice and placed in an apparatus that allowed force measurements and sarcomere length measurements using laser diffraction. During a twitch from the unloaded state at 1 Hz, MLPKO muscles relengthened to slack length more slowly than controls, although the corresponding force relaxation time was unchanged. Active developed stress at a diastolic sarcomere length of 2.00 μm was preserved in MLPKO trabeculae over a wide range of pacing frequencies. Force relaxation under the same conditions was consistently prolonged compared with wildtype controls, whereas time to peak and maximum rate of force generation were not significantly altered. Ca2+ content of the sarcoplasmic reticulum (SR) and the quantities of Ca2+ handling proteins were similar in both genotypes. In summary, young MLPKO mice revealed substantial alterations in passive myocardial properties and relaxation time, but not in most systolic characteristics. These results indicate that the progression to heart failure in the MLPKO model may be driven by diastolic myocardial dysfunction and abnormal passive properties rather than systolic dysfunction. PMID:15978612

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

    PubMed Central

    2009-01-01

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

  15. Apolipoprotein E-knockout mice show increased titers of serum anti-nuclear and anti-dsDNA antibodies

    SciTech Connect

    Wang, Yuehai; Huang, Ziyang; Lu, Huixia; Lin, Huili; Wang, Zhenhua; Chen, Xiaoqing; Ouyang, Qiufang; Tang, Mengxiong; Hao, Panpan; Ni, Jingqin; Xu, Dongming; Zhang, Mingxiang; Zhang, Qunye; Lin, Ling; and others

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer Titers of ANA and anti-dsDNA antibodies were higher in ApoE{sup -/-} than C57B6/L mice. Black-Right-Pointing-Pointer Spleen was greater and splenocyte apoptosis lower in ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer Level of TLR4 was lower in spleen tissue of ApoE{sup -/-} than B6 mice. Black-Right-Pointing-Pointer The TLR4 pathway may participate in maintaining the balance of splenocyte apoptosis. Black-Right-Pointing-Pointer The TLR4 pathway may participate in antibody production in spleen tissue. -- Abstract: Apolipoprotein E-knockout (ApoE{sup -/-}) mice, atherosclerosis-prone mice, show an autoimmune response, but the pathogenesis is not fully understood. We investigated the pathogenesis in female and male ApoE{sup -/-} mice. The spleens of all ApoE{sup -/-} and C57BL/6 (B6) mice were weighed. The serum IgG level and titers of anti-nuclear antibody (ANA) and anti-double-stranded DNA (anti-dsDNA) antibody were assayed by ELISA. Apoptosis of spleen tissue was evaluated by TUNEL. TLR4 level in spleen tissue was tested by immunohistochemistry and Western blot analysis. Levels of MyD88, p38, phosphorylated p38 (pp38), interferon regulatory factor 3 (IRF3) and Bcl-2-associated X protein (Bax) in spleen tissue were detected by Western blot analysis. We also survey the changes of serum autoantibodies, spleen weight, splenocyte apoptosis and the expressions of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue in male ApoE{sup -/-} mice after 4 weeks of lipopolysaccharide (LPS), Toll-like receptor 4 ligand, administration. ApoE{sup -/-} mice showed splenomegaly and significantly increased serum level of IgG and titers of ANA and anti-dsDNA antibody as compared with B6 mice. Splenocyte apoptosis and the expression of TLR4, MyD88, pp38, IRF3 and Bax in spleen tissue were significantly lower in ApoE{sup -/-} than B6 mice. The expression of TLR4, MyD88, IRF3, pp38, and Bax differed by sex in ApoE{sup -/-} spleen tissue. The

  16. PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress.

    PubMed

    Lehmann, Michael L; Mustafa, Tomris; Eiden, Adrian M; Herkenham, Miles; Eiden, Lee E

    2013-05-01

    The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) regulates activation of the hypothalamic-pituitary-adrenal (HPA) axis and the adrenal gland in response to various stressors. We previously found that in response to acute psychological stress (restraint), elevated corticotrophin-releasing hormone (CRH) mRNA levels in the hypothalamic paraventricular nucleus (PVN) as well as elevated plasma corticosterone (CORT) were profoundly attenuated in PACAP-deficient mice. To determine whether HPA axis responses and stress-induced depressive-like behaviors in a chronic stress paradigm are affected by PACAP deficiency, we subjected mice to 14 days of social defeat stress. Defeat-exposed PACAP-/- mice showed a marked attenuation of stress-induced increases in serum CORT levels, cellular PVN ΔFosB immunostaining, and depressive-like behaviors (social interaction and forced swim tests) compared to wild-type control mice. The PACAP-/- mice showed reduced PVN FosB-positive cell numbers, but relatively elevated cell counts in several forebrain areas including the medial prefrontal cortex, after social stress. PACAP appears to be specific for mediating HPA activation only in psychological stress because marked elevations in plasma CORT after a systemic stressor (lipopolysaccharide administration) occurred regardless of genotype. We conclude that chronically elevated CORT is a key component of depressive effects of social defeat, and that attenuation of the CORT response at the level of the PVN, as well as extrahypothalamic forebrain regions, in PACAP-deficient mice protects from development of depressive behavior.

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

    PubMed

    Yohn, Nicole L; Blendy, Julie A

    2017-02-01

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

  18. Mice lacking hypertension candidate gene ATP2B1 in vascular smooth muscle cells show significant blood pressure elevation.

    PubMed

    Kobayashi, Yusuke; Hirawa, Nobuhito; Tabara, Yasuharu; Muraoka, Hidenori; Fujita, Megumi; Miyazaki, Nobuko; Fujiwara, Akira; Ichikawa, Yasuhiro; Yamamoto, Yuichiro; Ichihara, Naoaki; Saka, Sanae; Wakui, Hiromichi; Yoshida, Shin-ichiro; Yatsu, Keisuke; Toya, Yoshiyuki; Yasuda, Gen; Kohara, Katsuhiko; Kita, Yoshikuni; Takei, Kohtaro; Goshima, Yoshio; Ishikawa, Yoshihiro; Ueshima, Hirotsugu; Miki, Tetsuro; Umemura, Satoshi

    2012-04-01

    We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na(+)-Ca(2+) exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells.

  19. Astrocytes from adult Wistar rats aged in vitro show changes in glial functions.

    PubMed

    Souza, Débora Guerini; Bellaver, Bruna; Raupp, Gustavo Santos; Souza, Diogo Onofre; Quincozes-Santos, André

    2015-11-01

    Astrocytes, the most versatile cells of the central nervous system, play an important role in the regulation of neurotransmitter homeostasis, energy metabolism, antioxidant defenses and the anti-inflammatory response. Recently, our group characterized cortical astrocyte cultures from adult Wistar rats. In line with that work, we studied glial function using an experimental in vitro model of aging astrocytes (30 days in vitro after reaching confluence) from newborn (NB), adult (AD) and aged (AG) Wistar rats. We evaluated metabolic parameters, such as the glucose uptake, glutamine synthetase (GS) activity, and glutathione (GSH) content, as well as the GFAP, GLUT-1 and xCT expression. AD and AG astrocytes take up less glucose than NB astrocytes and had decreased GLUT1 expression levels. Furthermore, AD and AG astrocytes exhibited decreased GS activity compared to NB cells. Simultaneously, AD and AG astrocytes showed an increase in GSH levels, along with an increase in xCT expression. NB, AD and AG astrocytes presented similar morphology; however, differences in GFAP levels were observed. Taken together, these results improve the knowledge of cerebral senescence and represent an innovative tool for brain studies of aging.

  20. Female mice lacking Xist RNA show partial dosage compensation and survive to term

    PubMed Central

    Yang, Lin; Kirby, James E.; Sunwoo, Hongjae; Lee, Jeannie T.

    2016-01-01

    X-chromosome inactivation (XCI) compensates for differences in X-chromosome number between male and female mammals. XCI is orchestrated by Xist RNA, whose expression in early development leads to transcriptional silencing of one X chromosome in the female. Knockout studies have established a requirement for Xist with inviability of female embryos that inherit an Xist deletion from the father. Here, we report that female mice lacking Xist RNA can, surprisingly, develop and survive to term. Xist-null females are born at lower frequency and are smaller at birth, but organogenesis is mostly normal. Transcriptomic analysis indicates significant overexpression of hundreds of X-linked genes across multiple tissues. Therefore, Xist-null mice can develop to term in spite of a deficiency of dosage compensation. However, the degree of X-autosomal dosage imbalance was less than anticipated (1.14-fold to 1.36-fold). Thus, partial dosage compensation can be achieved without Xist, supporting the idea of inherent genome balance. Nevertheless, to date, none of the mutant mice has survived beyond weaning stage. Sudden death is associated with failure of postnatal organ maturation. Our data suggest Xist-independent mechanisms of dosage compensation and demonstrate that small deviations from X-autosomal balance can have profound effects on overall fitness. PMID:27542829

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

    PubMed

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

    2016-05-01

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

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

    PubMed Central

    Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-il; Moon, Minho

    2016-01-01

    Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic. PMID:27432189

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

    PubMed

    Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-Il; Moon, Minho

    2016-08-31

    Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic.

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

    PubMed

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

    2009-09-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  6. IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours.

    PubMed

    Yasumura, Misato; Yoshida, Tomoyuki; Yamazaki, Maya; Abe, Manabu; Natsume, Rie; Kanno, Kouta; Uemura, Takeshi; Takao, Keizo; Sakimura, Kenji; Kikusui, Takefumi; Miyakawa, Tsuyoshi; Mishina, Masayoshi

    2014-10-14

    IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPδ. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety.

  7. IL1RAPL1 knockout mice show spine density decrease, learning deficiency, hyperactivity and reduced anxiety-like behaviours

    PubMed Central

    Yasumura, Misato; Yoshida, Tomoyuki; Yamazaki, Maya; Abe, Manabu; Natsume, Rie; Kanno, Kouta; Uemura, Takeshi; Takao, Keizo; Sakimura, Kenji; Kikusui, Takefumi; Miyakawa, Tsuyoshi; Mishina, Masayoshi

    2014-01-01

    IL-1 receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic intellectual disability and is associated with autism. IL1RAPL1 mediates excitatory synapse formation through trans-synaptic interaction with PTPδ. Here, we showed that the spine density of cortical neurons was significantly reduced in IL1RAPL1 knockout mice. The spatial reference and working memories and remote fear memory were mildly impaired in IL1RAPL1 knockout mice. Furthermore, the behavioural flexibility was slightly reduced in the T-maze test. Interestingly, the performance of IL1RAPL1 knockout mice in the rotarod test was significantly better than that of wild-type mice. Moreover, IL1RAPL1 knockout mice consistently exhibited high locomotor activity in all the tasks examined. In addition, open-space and height anxiety-like behaviours were decreased in IL1RAPL1 knockout mice. These results suggest that IL1RAPL1 ablation resulted in spine density decrease and affected not only learning but also behavioural flexibility, locomotor activity and anxiety. PMID:25312502

  8. Factor XIII-A transglutaminase deficient mice show signs of metabolically healthy obesity on high fat diet

    PubMed Central

    Myneni, Vamsee D.; Mousa, Aisha; Kaartinen, Mari T.

    2016-01-01

    F13A1 gene, which encodes for Factor XIII-A blood clotting factor and a transglutaminase enzyme, was recently identified as a potential causative gene for obesity in humans. In our previous in vitro work, we showed that FXIII-A regulates preadipocyte differentiation and modulates insulin signaling via promoting plasma fibronectin assembly into the extracellular matrix. To understand the role of FXIII-A in whole body energy metabolism, here we have characterized the metabolic phenotype of F13a1−/− mice. F13a1−/− and F13a1+/+ type mice were fed chow or obesogenic, high fat diet for 20 weeks. Weight gain, total fat mass and fat pad mass, glucose handling, insulin sensitivity, energy expenditure and, morphological and biochemical analysis of adipose tissue was performed. We show that mice lacking FXIII-A gain weight on obesogenic diet, similarly as wild type mice, but exhibit a number of features of metabolically healthy obesity such as protection from developing diet-induced insulin resistance and hyperinsulinemia. Mice also show normal fasting glucose levels, larger adipocytes, decreased extracellular matrix accumulation and inflammation of adipose tissue, as well as decreased circulating triglycerides. This study reveals that FXIII-A transglutaminase can regulate whole body insulin sensitivity and may have a role in the development of diet-induced metabolic disturbances. PMID:27759118

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2015-08-01

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

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

    PubMed

    Garthe, Alexander; Roeder, Ingo; Kempermann, Gerd

    2016-02-01

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

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

    PubMed

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

    2015-02-11

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

  13. A direct relationship between aggressive behavior in the resident/intruder test and cell oxidative status in adult male mice.

    PubMed

    Rammal, Hassan; Bouayed, Jaouad; Soulimani, Rachid

    2010-02-10

    Disturbances in oxidative metabolism are involved in many acute and chronic diseases, as well as in several other conditions. The objective of the present study was to examine the relationship between the level of intracellular reactive oxygen species in the peripheral blood granulocytes of mice, as evaluated by 2',7'-dichlorofluorescin diacetate (DCFH-DA), a sensor of reactive oxygen species, and the aggressive behavior of these mice, as estimated by the resident/intruder test. Our results showed a significant, linear and positive relationship (P<0.001) between the intracellular redox status of peripheral blood granulocytes and the aggressive behavior levels of adult male mice (correlation coefficients (R(2)) ranging from 0.75 to 0.77). This suggests that the granulocytes of aggressively behaving mice have high levels of oxidative stress.

  14. Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging.

    PubMed

    Kang, S; Louboutin, J-P; Datta, P; Landel, C P; Martinez, D; Zervos, A S; Strayer, D S; Fernandes-Alnemri, T; Alnemri, E S

    2013-02-01

    mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals.

  15. Proteomic Analysis of Aortae from Human Lipoprotein(a) Transgenic Mice Shows an Early Metabolic Response Independent of Atherosclerosis

    PubMed Central

    Rodger, Euan J.; Suetani, Rachel J.; Jones, Gregory T.; Kleffmann, Torsten; Carne, Alan; Legge, Michael; McCormick, Sally P. A.

    2012-01-01

    Background Elevated low density lipoprotein (LDL) and lipoprotein(a) are independent risk factors for the development of atherosclerosis. Using a proteomic approach we aimed to determine early changes in arterial protein expression in transgenic mice containing both human LDL and lipoprotein(a) in circulation. Methods and Results Plasma lipid analyses showed the lipoprotein(a) transgenic mice had significantly higher lipid levels than wildtype, including a much increased LDL and high density lipoprotein (HDL) cholesterol. Analysis of aortae from lipoprotein(a) mice showed lipoprotein(a) accumulation but no lipid accumulation or foam cells, leaving the arteries essentially atherosclerosis free. Using two-dimensional gel electrophoresis and mass spectrometry, we identified 34 arterial proteins with significantly altered abundance (P<0.05) in lipoprotein(a) transgenic mice compared to wildtype including 17 that showed a ≥2 fold difference. Some proteins of interest showed a similarly altered abundance at the transcript level. These changes collectively indicated an initial metabolic response that included a down regulation in energy, redox and lipid metabolism proteins and changes in structural proteins at a stage when atherosclerosis had not yet developed. Conclusions Our study shows that human LDL and lipoprotein(a) promote changes in the expression of a unique set of arterial proteins which may be early indicators of the metabolic disturbances preceding atherosclerosis. PMID:22276189

  16. ASIC1a Deficient Mice Show Unaltered Neurodegeneration in the Subacute MPTP Model of Parkinson Disease

    PubMed Central

    Komnig, Daniel; Imgrund, Silke; Reich, Arno; Gründer, Stefan; Falkenburger, Björn H.

    2016-01-01

    Inflammation contributes to the death of dopaminergic neurons in Parkinson disease and can be accompanied by acidification of extracellular pH, which may activate acid-sensing ion channels (ASIC). Accordingly, amiloride, a non-selective inhibitor of ASIC, was protective in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease. To complement these findings we determined MPTP toxicity in mice deficient for ASIC1a, the most common ASIC isoform in neurons. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. We determined the number of dopaminergic neurons in the substantia nigra, assayed by stereological counting 14 days after the last MPTP injection, the number of Nissl positive neurons in the substantia nigra, and the concentration of catecholamines in the striatum. There was no difference between ASIC1a-deficient mice and wildtype controls. We are therefore not able to confirm that ASIC1a are involved in MPTP toxicity. The difference might relate to the subacute MPTP model we used, which more closely resembles the pathogenesis of Parkinson disease, or to further targets of amiloride. PMID:27820820

  17. Central administration of obestatin fails to show inhibitory effects on food and water intake in mice.

    PubMed

    Van Dijck, Annemie; Annemie, Van Dijck; Van Dam, Debby; Debby, Van Dam; Vergote, Valentijn; Valentijn, Vergote; De Spiegeleer, Bart; Bart, De Spiegeleer; Luyten, Walter; Walter, Luyten; Schoofs, Liliane; Liliane, Schoofs; De Deyn, Peter Paul; Peter Paul, De Deyn

    2009-08-07

    Obestatin is a ghrelin-associated peptide hormone with presumed anorexigenic and inhibitory effect on gastric propulsive motility activity. Recent literature, however, discloses much contestation over satiety and gastrointestinal motility-related functionalities of obestatin. In addition, antidipsinogenic effects in rodents by obestatin were recently reported. The present study was set up to bring more clarity into the contested effects of obestatin on food and water intake. Additionally, the stability of obestatin in brain tissue homogenate was investigated. The in vitro incubation of obestatin in brain homogenates revealed disappearance half-life times of 19 min for crude brain homogenate to 27 min for brain membrane homogenate. For the behavioural studies, male C57Bl/6 mice were intracerebroventricularly treated with 0.2 nmol murine amidated obestatin or vehicle at the age of 3 months. An additional group of mice was treated with 0.3 nmol of corticotropin releasing factor (CRF) as a positive control of suppression of food intake. Food and water intake were studied over a period of 5 h in metabolic cages. Under our experimental conditions, no suppressive effects of obestatin on food or water intake were observed, whereas CRF evoked a significant suppression of food intake, which proves the internal validity of the study design.

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

    ERIC Educational Resources Information Center

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

    2007-01-01

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

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

    PubMed Central

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

    2016-01-01

    Cigarette smoke (CS) and ethanol (EtOH) are known to synergize in the causation of cancers of the upper aerodigestive tract and of the liver. Little is known about possible interactions between these agents in other organs. These premises prompted us to evaluate the clastogenic effects resulting from the inhalation for 3 weeks of mainstream CS and oral administration of EtOH, which were tested either individually or in combination in cells of adult BDF1 mice and their fetuses. CS exerted clastogenic effects in haematopoietic cells of adult male mice by increasing the frequency of micronucleated erythroid cells both in bone marrow and in peripheral blood as well as the frequency of micronucleated and polynucleated pulmonary alveolar macrophages. Likewise, exposure to CS of pregnant mice resulted in a clastogenic damage in maternal bone marrow cells and in the liver and peripheral blood of their fetuses. Under all experimental conditions, EtOH was consistently devoid of clastogenic effects when given alone. In adult mice, EtOH exhibited a mild stimulating effect on the clastogenicity of CS in haematopoietic cells, while an opposite effect was observed in the respiratory tract, where EtOH attenuated the cytogenetic alterations induced by CS in pulmonary alveolar macrophages. At variance with the mild synergism observed in haematopoietic cells of adult mice, EtOH inhibited the clastogenicity of CS in the liver and peripheral blood cells of transplacentally exposed fetuses. Therefore, the effects of EtOH in CS-exposed mice show different trends depending both on the life stage and on the cells analyzed. PMID:27907070

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

    PubMed Central

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

    2011-01-01

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

  1. Habituation under stress: shocked mice show nonassociative learning in a T-maze.

    PubMed

    Mitchell, D; Osborne, E W; O'Boyle, M W

    1985-03-01

    Conflicting predictions of reinforcement and neophobia-arousal theories were evaluated in a simple choice task. Four groups of C57BL/6J mice were administered daily two-trial tests in a uniform T-maze for 10 consecutive days. For three groups, the contingencies of footshock treatments were manipulated to reinforce alternation, perseveration, or both. A control group that was not administered footshock alternated, but all three groups that were stressed perseverated more and more across tests, despite the differences in reinforcement contingencies. These results are inconsistent with the predictions of reinforcement theory but consistent with the view that stressed or aroused animals are neophobic and use nonassociative learning (habituation) to distinguish between novel and familiar alternatives.

  2. Nanoemulsified green tea extract shows improved hypocholesterolemic effects in C57BL/6 mice.

    PubMed

    Kim, Young Jun; Houng, Soung-Jin; Kim, Jae Hoon; Kim, Young-Rok; Ji, Hong Geun; Lee, Sung-Joon

    2012-02-01

    Nanoemulsification of nutrients could improve bioavailability by enhancing intestinal uptake. We investigated the antioxidant and hypolipidemic effects of nanoemulsified green tea extract (NGTE). Antioxidant effect was measured by 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging assay and dichlorofluorescein diacetate (DCFH-DA) assay. C57BL/6 mice were fed a control high-fat diet, green tea extract (GTE), or NGTE diet for 4 weeks. In composition analysis, GTE and NGTE contained similar total catechin concentrations. The antioxidative effect of GTE was comparable with that of NGTE. In the ABTS assay, GTE had a marked effect, although NGTE was more effective than GTE in the DCFH-DA assay. In the mouse feeding experiment, total and low-density lipoprotein (LDL) cholesterol concentrations were significantly reduced after NGTE treatment in comparison with GTE treatment in high-fat-fed C57BL/6J mice over the course of 4 weeks. The hypocholesterolemic effects were greater in the NGTE group compared with the GTE group (24% vs. 15.4% LDL cholesterol reduction compared with the control). Expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase was significantly down-regulated. Protein expression of LDL receptor was significantly increased in the livers of both the GTE- and NGTE-treated groups (+234.1%, P<.01 and +274.7%, P<.001), with a greater effect in the NGTE than in the GTE group. Cholesterol 7α-hydroxylase gene expression was similarly increased in both the GTE and NGTE groups. These results suggest that nanoemulsification significantly increased hypocholesterolemic effects of GTE in vivo due to increased bioavailability.

  3. MRL/MpJ mice show unique pathological features after experimental kidney injury.

    PubMed

    Shiozuru, Daichi; Ichii, Osamu; Kimura, Junpei; Nakamura, Teppei; Elewa, Yaser Hosny Ali; Otsuka-Kanazawa, Saori; Kon, Yasuhiro

    2016-02-01

    Clarification of the renal repair process is crucial for developing novel therapeutic strategies for kidney injury. MRL/MpJ mice have a unique repair process characterized by low scar formation. The pathological features of experimentally injured MRL/MpJ and C57BL/6 mouse kidneys were compared to examine the renal repair process. The dilation and atrophy of renal tubules were observed in folic acid (FA)-induced acute kidney injury (AKI) in both strains, and the histopathological injury scores and number of interleukin (IL)-1F6-positive damaged distal tubules and kidney injury molecule 1 (KIM-1)-positive damaged proximal tubules drastically increased 1 day after AKI induction. However, KIM-1-positive tubules and the elevation of serum renal function markers were significantly fewer and lower, respectively, in MRL/MpJ mice at days 2 and 7 after AKI. After traumatic kidney injury (TKI) via needle puncture, severe tubular necrotic lesions in the punctured area and fibrosis progressed in both strains. Indices for fibrosis such as aniline blue-positive area, number of alpha smooth muscle actin-positive myofibroblasts, and messenger RNA expression levels of Tgfb1 and Mmp2 indicated lower fibrotic activity in MRL/MpJ kidneys. Characteristically, only MRL/MpJ kidneys manifested remarkable calcification around the punctured area beginning 7 days after TKI. The pathological features of injured MRL/MpJ and C57BL/6 kidneys differed, especially those of kidneys with mild proximal tubular injuries after FA-induced AKI. Lower fibrotic activity and increased calcification after TKI were observed in MRL/MpJ kidneys. These findings clarified the unique pathological characteristics of MRL/MpJ mouse kidneys and contribute to understanding of the renal repair process after kidney injury.

  4. Immunosuppression in early postnatal days induces persistent and allergen-specific immune tolerance to asthma in adult mice.

    PubMed

    Chen, Yan; Zhang, Jin; Lu, Yong; Wang, Libo

    2015-01-01

    Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV) was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs) were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma.

  5. Older Adults Show Deficits in Retrieving and Decoding Associative Mediators Generated at Study

    ERIC Educational Resources Information Center

    Hertzog, Christopher; Fulton, Erika K.; Mandviwala, Lulua; Dunlosky, John

    2013-01-01

    We instructed the use of mediators to encode paired-associate items, and then measured both cued recall of targets and mediators. Older adults (n = 49) and younger adults (n = 57) studied a mixed list of concrete and abstract noun pairs under instructions to either generate a sentence or an image to form a new association between normatively…

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

    PubMed

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

    2008-01-01

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

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

    PubMed

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

    2014-08-01

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

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

    PubMed

    Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-05-01

    We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model.

  9. CD38 Knockout Mice Show Significant Protection Against Ischemic Brain Damage Despite High Level Poly-ADP-Ribosylation.

    PubMed

    Long, Aaron; Park, Ji H; Klimova, Nina; Fowler, Carol; Loane, David J; Kristian, Tibor

    2017-01-01

    Several enzymes in cellular bioenergetics metabolism require NAD(+) as an essential cofactor for their activity. NAD(+) depletion following ischemic insult can result in cell death and has been associated with over-activation of poly-ADP-ribose polymerase PARP1 as well as an increase in NAD(+) consuming enzyme CD38. CD38 is an NAD(+) glycohydrolase that plays an important role in inflammatory responses. To determine the contribution of CD38 activity to the mechanisms of post-ischemic brain damage we subjected CD38 knockout (CD38KO) mice and wild-type (WT) mice to transient forebrain ischemia. The CD38KO mice showed a significant amelioration in both histological and neurologic outcome following ischemic insult. Decrease of hippocampal NAD(+) levels detected during reperfusion in WT mice was only transient in CD38KO animals, suggesting that CD38 contributes to post-ischemic NAD(+) catabolism. Surprisingly, pre-ischemic poly-ADP-ribose (PAR) levels were dramatically higher in CD38KO animals compared to WT animals and exhibited reduction post-ischemia in contrast to the increased levels in WT animals. The high PAR levels in CD38 mice were due to reduced expression levels of poly-ADP-ribose glycohydrolase (PARG). Thus, the absence of CD38 activity can not only directly affect inflammatory response, but also result in unpredicted alterations in the expression levels of enzymes participating in NAD(+) metabolism. Although the CD38KO mice showed significant protection against ischemic brain injury, the changes in enzyme activity related to NAD(+) metabolism makes the determination of the role of CD38 in mechanisms of ischemic brain damage more complex.

  10. PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress

    PubMed Central

    Lehmann, Michael L.; Mustafa, Tomris; Eiden, Adrian M.; Herkenham, Miles; Eiden, Lee E.

    2012-01-01

    Summary The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) regulates activation of the hypothalamic-pituitary-adrenal (HPA) axis and the adrenal gland in response to various stressors. We previously found that in response to acute psychological stress (restraint), elevated corticotrophin-releasing hormone (CRH) mRNA levels in the hypothalamic paraventricular nucleus (PVN) as well as elevated plasma corticosterone (CORT) were profoundly attenuated in PACAP-deficient mice. To determine whether HPA axis responses and stress-induced depressive-like behaviors in a chronic stress paradigm are affected by PACAP deficiency, we subjected mice to 14 days of social defeat stress. Defeat-exposed PACAP−/− mice showed a marked attenuation of stress-induced increases in serum CORT levels, cellular PVN ΔFosB immunostaining, and depressive-like behaviors (social interaction and forced swim tests) compared to wild-type control mice. The PACAP−/− mice showed reduced PVN FosB-positive cell numbers, but relatively elevated cell counts in several forebrain areas including the medial prefrontal cortex, after social stress. PACAP appears to be specific for mediating HPA activation only in psychological stress because marked elevations in plasma CORT after a systemic stressor (lipopolysaccharide administration) occurred regardless of genotype. We conclude that chronically elevated CORT is a key component of depressive effects of social defeat, and that attenuation of the CORT response at the level of the PVN, as well as extrahypothalamic forebrain regions, in PACAP-deficient mice protects from development of depressive behavior. PMID:23062748

  11. Adults with dyslexia show deficits on spatial frequency doubling and visual attention tasks.

    PubMed

    Buchholz, Judy; McKone, Elinor

    2004-02-01

    We examine the visual processing of high-functioning adults with developmental dyslexia (mean Performance IQ = 126.5) and current phonological problems. In comparison to an age- and IQ-matched control group, the group with dyslexia showed deficits in two tasks associated with magnocellular/dorsal pathway function. For the 'frequency doubling' stimulus (grating of 0.25 cpd modulated at 25 Hz counterphase flicker), contrast thresholds for detection were raised in the dyslexic group. In conjunction visual search, a display time sufficient for controls to achieve ceiling accuracy at all set sizes (30 ms per item) was inadequate to allow shifts of attention around the display for the group with dyslexia. In contrast, normal performance was found on 'popout' visual search and on a ventral stream acuity task. Correlational analysis revealed a significant relationship between degree of deficit in conjunction search and phonological difficulty. The deficits revealed were specific to functions that rely on magnocellular input. They cannot be attributed to concentration lapses, eye movement problems or slow reaction times in the dyslexic group.

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

    PubMed

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

    2008-06-01

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

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

    PubMed Central

    Zhang, Shasha; Liu, Yan; Rao, Yi

    2013-01-01

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

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

    PubMed

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

    2011-04-01

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

  15. Otx1 null mutant mice show partial segregation of sensory epithelia comparable to lamprey ears

    NASA Technical Reports Server (NTRS)

    Fritzsch, B.; Signore, M.; Simeone, A.

    2001-01-01

    We investigated the development of inner ear innervation in Otx1 null mutants, which lack a horizontal canal, between embryonic day 12 (E12) and postnatal day 7 (P7) with DiI and immunostaining for acetylated tubulin. Comparable to control animals, horizontal crista-like fibers were found to cross over the utricle in Otx1 null mice. In mutants these fibers extend toward an area near the endolymphatic duct, not to a horizontal crista. Most Otx1 null mutants had a small patch of sensory hair cells at this position. Measurement of the area of the utricular macula suggested it to be enlarged in Otx1 null mutants. We suggest that parts of the horizontal canal crista remain incorporated in the utricular sensory epithelium in Otx1 null mutants. Other parts of the horizontal crista appear to be variably segregated to form the isolated patch of hair cells identifiable by the unique fiber trajectory as representing the horizontal canal crista. Comparison with lamprey ear innervation reveals similarities in the pattern of innervation with the dorsal macula, a sensory patch of unknown function. SEM data confirm that all foramina are less constricted in Otx1 null mutants. We propose that Otx1 is not directly involved in sensory hair cell formation of the horizontal canal but affects the segregation of the horizontal canal crista from the utricle. It also affects constriction of the two main foramina in the ear, but not their initial formation. Otx1 is thus causally related to horizontal canal morphogenesis as well as morphogenesis of these foramina.

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

    PubMed Central

    Pristerà, Alessandro; Lin, Wei; Kaufmann, Anna-Kristin; Brimblecombe, Katherine R.; Threlfell, Sarah; Dodson, Paul D.; Magill, Peter J.; Fernandes, Cathy; Cragg, Stephanie J.; Ang, Siew-Lan

    2015-01-01

    Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice. We show that deletion of Foxa1/2 results in down-regulation of tyrosine hydroxylase, the rate-limiting enzyme of dopamine (DA) biosynthesis, specifically in dopaminergic neurons of the substantia nigra pars compacta (SNc). In addition, DA synthesis and striatal DA transmission were reduced after Foxa1/2 deletion. Furthermore, the burst-firing activity characteristic of SNc mDA neurons was drastically reduced in the absence of FOXA1/2. These molecular and functional alterations lead to a severe feeding deficit in adult Foxa1/2 mutant mice, independently of motor control, which could be rescued by l-DOPA treatment. FOXA1/2 therefore control the maintenance of molecular and physiological properties of SNc mDA neurons and impact on feeding behavior in adult mice. PMID:26283356

  17. Mice doubly-deficient in lysosomal hexosaminidase A and neuraminidase 4 show epileptic crises and rapid neuronal loss.

    PubMed

    Seyrantepe, Volkan; Lema, Pablo; Caqueret, Aurore; Dridi, Larbi; Bel Hadj, Samar; Carpentier, Stephane; Boucher, Francine; Levade, Thierry; Carmant, Lionel; Gravel, Roy A; Hamel, Edith; Vachon, Pascal; Di Cristo, Graziella; Michaud, Jacques L; Morales, Carlos R; Pshezhetsky, Alexey V

    2010-09-16

    Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts G(M2) to G(M3) ganglioside. Hexa(-/-) mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise G(M2) ganglioside via a lysosomal sialidase into glycolipid G(A2), which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4(-/-);Hexa(-/-)) show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa(-/-) or Neu4(-/-) siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating G(M2) ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa(-/-) mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa(-/-) mice.

  18. Plasma and serum lipidomics of healthy white adults shows characteristic profiles by subjects' gender and age.

    PubMed

    Ishikawa, Masaki; Maekawa, Keiko; Saito, Kosuke; Senoo, Yuya; Urata, Masayo; Murayama, Mayumi; Tajima, Yoko; Kumagai, Yuji; Saito, Yoshiro

    2014-01-01

    Blood is a commonly used biofluid for biomarker discovery. Although blood lipid metabolites are considered to be potential biomarker candidates, their fundamental properties are not well characterized. We aimed to (1) investigate the matrix type (serum vs. plasma) that may be preferable for lipid biomarker exploration, (2) elucidate age- and gender-associated differences in lipid metabolite levels, and (3) examine the stability of lipid metabolites in matrix samples subjected to repeated freeze-thaw cycles. Using liquid chromatography-mass spectrometry, we performed lipidomic analyses for fasting plasma and serum samples for four groups (15 subjects/group) of young and elderly (25-34 and 55-64 years old, respectively) males and females and for an additional aliquot of samples from young males, which were subjected to repeated freeze-thaw cycles. Lysophosphatidylcholine and diacylglycerol levels were higher in serum than in plasma samples, suggesting that the clotting process influences serum lipid metabolite levels. Gender-associated differences highlighted that the levels of many sphingomyelin species were significantly higher in females than in males, irrespective of age and matrix (plasma and serum). Age-associated differences were more prominent in females than in males, and in both matrices, levels of many triacylglycerols were significantly higher in elderly females than in young females. Plasma and serum levels of most lipid metabolites were reduced by freeze-thawing. Our results indicate that plasma is an optimal matrix for exploring lipid biomarkers because it represents the original properties of an individual's blood sample. In addition, the levels of some blood lipid species of healthy adults showed gender- and age-associated differences; thus, this should be considered during biomarker exploration and its application in diagnostics. Our fundamental findings on sample selection and handling procedures for measuring blood lipid metabolites is important

  19. Transgenic Mice with Increased Astrocyte Expression of IL-6 Show Altered Effects of Acute Ethanol on Synaptic Function

    PubMed Central

    Hernandez, Ruben V.; Puro, Alana C.; Manos, Jessica C.; Huitron-Resendiz, Salvador; Reyes, Kenneth C.; Liu, Kevin; Vo, Khanh; Roberts, Amanda J.; Gruol, Donna L.

    2015-01-01

    A growing body of evidence has revealed that resident cells of the central nervous system (CNS), and particularly the glial cells, comprise a neuroimmune system that serves a number of functions in the normal CNS and during adverse conditions. Cells of the neuroimmune system regulate CNS functions through the production of signaling factors, referred to as neuroimmune factors. Recent studies show that ethanol can activate cells of the neuroimmune system, resulting in the elevated production of neuroimmune factors, including the cytokine interleukin-6 (IL-6). Here we analyzed the consequences of this CNS action of ethanol using transgenic mice that express elevated levels of IL-6 through increased astrocyte expression (IL-6-tg) to model the increased IL-6 expression that occurs with ethanol use. Results show that increased IL-6 expression induces neuroadaptive changes that alter the effects of ethanol. In hippocampal slices from non-transgenic (non-tg) littermate control mice, synaptically evoked dendritic field excitatory postsynaptic potential (fEPSP) and somatic population spike (PS) at the Schaffer collateral to CA1 pyramidal neuron synapse were reduced by acute ethanol (20 or 60 mM). In contrast, acute ethanol enhanced the fEPSP and PS in hippocampal slices from IL-6 tg mice. Long-term synaptic plasticity of the fEPSP (i.e., LTP) showed the expected dose-dependent reduction by acute ethanol in non-tg hippocampal slices, whereas LTP in the IL-6 tg hippocampal slices was resistant to this depressive effect of acute ethanol. Consistent with altered effects of acute ethanol on synaptic function in the IL-6 tg mice, EEG recordings showed a higher level of CNS activity in the IL-6 tg mice than in the non-tg mice during the period of withdrawal from an acute high dose of ethanol. These results suggest a potential role for neuroadaptive effects of ethanol-induced astrocyte production of IL-6 as a mediator or modulator of the actions of ethanol on the CNS, including

  20. Transgenic mice with increased astrocyte expression of IL-6 show altered effects of acute ethanol on synaptic function.

    PubMed

    Hernandez, Ruben V; Puro, Alana C; Manos, Jessica C; Huitron-Resendiz, Salvador; Reyes, Kenneth C; Liu, Kevin; Vo, Khanh; Roberts, Amanda J; Gruol, Donna L

    2016-04-01

    A growing body of evidence has revealed that resident cells of the central nervous system (CNS), and particularly the glial cells, comprise a neuroimmune system that serves a number of functions in the normal CNS and during adverse conditions. Cells of the neuroimmune system regulate CNS functions through the production of signaling factors, referred to as neuroimmune factors. Recent studies show that ethanol can activate cells of the neuroimmune system, resulting in the elevated production of neuroimmune factors, including the cytokine interleukin-6 (IL-6). Here we analyzed the consequences of this CNS action of ethanol using transgenic mice that express elevated levels of IL-6 through increased astrocyte expression (IL-6-tg) to model the increased IL-6 expression that occurs with ethanol use. Results show that increased IL-6 expression induces neuroadaptive changes that alter the effects of ethanol. In hippocampal slices from non-transgenic (non-tg) littermate control mice, synaptically evoked dendritic field excitatory postsynaptic potential (fEPSP) and somatic population spike (PS) at the Schaffer collateral to CA1 pyramidal neuron synapse were reduced by acute ethanol (20 or 60 mM). In contrast, acute ethanol enhanced the fEPSP and PS in hippocampal slices from IL-6 tg mice. Long-term synaptic plasticity of the fEPSP (i.e., LTP) showed the expected dose-dependent reduction by acute ethanol in non-tg hippocampal slices, whereas LTP in the IL-6 tg hippocampal slices was resistant to this depressive effect of acute ethanol. Consistent with altered effects of acute ethanol on synaptic function in the IL-6 tg mice, EEG recordings showed a higher level of CNS activity in the IL-6 tg mice than in the non-tg mice during the period of withdrawal from an acute high dose of ethanol. These results suggest a potential role for neuroadaptive effects of ethanol-induced astrocyte production of IL-6 as a mediator or modulator of the actions of ethanol on the CNS, including

  1. Action of the noradrenergic system on adult-born cells is required for olfactory learning in mice.

    PubMed

    Moreno, Melissa M; Bath, Kevin; Kuczewski, Nicola; Sacquet, Joëlle; Didier, Anne; Mandairon, Nathalie

    2012-03-14

    We have previously shown that an experience-driven improvement in olfactory discrimination (perceptual learning) requires the addition of newborn neurons in the olfactory bulb (OB). Despite this advance, the mechanisms which govern the selective survival of newborn OB neurons following learning remain largely unknown. We propose that activity of the noradrenergic system is a critical mediator providing a top-down signal to control the selective survival of newly born cells and support perceptual learning. In adult mice, we used pharmacological means to manipulate the noradrenergic system and neurogenesis and to assess their individual and additive effects on behavioral performance on a perceptual learning task. We then looked at the effects of these manipulations on regional survival of adult-born cells in the OB. Finally, using confocal imaging and electrophysiology, we investigated potential mechanisms by which noradrenaline could directly influence the survival of adult-born cells. Consistent with our hypotheses, direct manipulation of noradrenergic transmission significantly effect on adult-born cell survival and perceptual learning. Specifically, learning required both the presence of adult-born cell and noradrenaline. Finally, we provide a mechanistic link between these effects by showing that adult-born neurons receive noradrenergic projections and are responsive to noradrenaline. Based upon these data we argue that noradrenergic transmission is a key mechanism selecting adult-born neurons during learning and demonstrate that top-down neuromodulation acts on adult-born neuron survival to modulate learning performance.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    1992-04-01

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

  6. Effect of dietary selenium and cancer cell xenograft on peripheral T and B lymphocytes in adult nude mice.

    PubMed

    Cheng, Wen-Hsing; Holmstrom, Alexandra; Li, Xiangdong; Wu, Ryan T Y; Zeng, Huawei; Xiao, Zhengguo

    2012-05-01

    Selenium (Se) is known to regulate tumorigenesis and immunity at the nutritional and supranutritional levels. Because the immune system provides critical defenses against cancer and the athymic, immune-deficient NU/J nude mice are known to gradually develop CD8(+) and CD4(+) T cells, we investigated whether B and T cell maturation could be modulated by dietary Se and by tumorigenesis in nude mice. Fifteen homozygous nude mice were fed a Se-deficient, Torula yeast basal diet alone (Se-) or supplemented with 0.15 (Se+) or 1.0 (Se++) mg Se/kg (as Na(2)SeO(4)) for 6 months, followed by a 7-week time course of PC-3 prostate cancer cell xenograft (2 × 10(6) cells/site, 2 sites/mouse). Here, we show that peripheral B cell levels decreased in nude mice fed the Se -  or Se++ diet and the CD4(+) T cell levels increased in mice fed the Se++ diet. During the PC-3 cell tumorigenesis, dietary Se status did not affect peripheral CD4(+) or CD8(+) T cells in nude mice whereas mice fed with the Se++ diet appeared to exhibit greater peripheral CD25(+)CD4(+) T cells on day 9. Dietary Se status did not affect spleen weight in nude mice 7 weeks after the xenograft. Spleen weight was associated with frequency of peripheral CD4(+), but not CD8(+) T cells. Taken together, dietary Se at the nutritional and supranutritional levels regulates peripheral B and T cells in adult nude mice before and after xenograft with PC-3 prostate cancer cells.

  7. Male mice housed in groups engage in frequent fighting and show a lower response to additional bone loading than females or individually housed males that do not fight.

    PubMed

    Meakin, Lee B; Sugiyama, Toshihiro; Galea, Gabriel L; Browne, William J; Lanyon, Lance E; Price, Joanna S

    2013-05-01

    Experiments to investigate bone's physiological adaptation to mechanical loading frequently employ models that apply dynamic loads to bones in vivo and assess the changes in mass and architecture that result. It is axiomatic that bones will only show an adaptive response if the applied artificial loading environment differs in a significant way from that to which the bones have been habituated by normal functional loading. It is generally assumed that this normal loading is similar between experimental groups. In the study reported here we found that this was not always the case. Male and female 17-week-old C57BL/6 mice were housed in groups of six, and a single episode (40 cycles) of non-invasive axial loading, engendering 2,200 με on the medial surface of the proximal tibiae in sample mice, was applied to right tibiae on alternate days for two weeks. This engendered an adaptive increase in bone mass in females, but not males. Observation revealed the main difference in behaviour between males and females was that males were involved in fights 1.3 times per hour, whereas the females never fought. We therefore housed all mice individually. In females, there was a similar significant osteogenic response to loading in cortical and trabecular bone of both grouped and individual mice. In contrast, in males, adaptive increases in the loaded compared with non-loaded control bones was only apparent in animals housed individually. Our interpretation of these findings is that the frequent vigorous fighting that occurs between young adult males housed in groups could be sufficient to engender peak strains and strain rates that equal or exceed the stimulus derived from artificial loading. This indicates the importance of ensuring that physical activity is consistent between groups. Reducing the background level of the naturally engendered strain environment allows adaptive responses to artificial loading to be demonstrated at lower loads.

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

    PubMed Central

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

    2017-01-01

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

  9. Sod1 gene ablation in adult mice leads to physiological changes at the neuromuscular junction similar to changes that occur in old wild-type mice.

    PubMed

    Ivannikov, Maxim V; Van Remmen, Holly

    2015-07-01

    Reactive oxygen species (ROS) are believed to be important mediators of muscle atrophy and weakness in aging and many degenerative conditions. However, the mechanisms and physiological processes specifically affected by elevated ROS in neuromuscular units that contribute to muscle weakness during aging are not well defined. Here we investigate the effects of chronic oxidative stress on neurotransmission and excitation-contraction (EC) coupling mechanisms in the levator auris longus (LAL) muscle from young (4-8 months) and old (22-28 months) wild-type mice and young adult Cu-Zn superoxide dismutase 1 knockout (Sod1(-/-)) mice. The frequency of spontaneous neurotransmitter release and the amplitude of evoked neurotransmitter release in young Sod1(-/-) and old wild-type LAL neuromuscular junctions were significantly reduced from the young wild-type values, and those declines were mirrored by decreases in synaptic vesicle pool size. Presynaptic cytosolic calcium concentration and mitochondrial calcium uptake amplitudes showed substantial increases in stimulated young Sod1(-/-) and old axon terminals. Surprisingly, LAL muscle fibers from old mice showed a greater excitability than fibers from either young wild-type or young Sod1(-/-) LAL. Both evoked excitatory junction potential (EJP) and spontaneous mini EJP amplitudes were considerably higher in LAL muscles from old mice than in fibers from young Sod1(-/-) LAL muscle. Despite a greater excitability, sarcoplasmic calcium influx in both old wild-type and young Sod1(-/-) LAL muscle fibers was significantly less. Sarcoplasmic reticulum calcium levels were also reduced in both old wild-type and young Sod1(-/-) mice, but the difference was not statistically significant in muscle fibers from old wild-type mice. The protein ratio of triad calcium channels RyR1/DHPR was not different in all groups. However, fibers from both young Sod1(-/-) and old mice had substantially elevated levels of protein carbonylation and S

  10. Do Adults with Mental Retardation Show Pictorial Superiority Effects in Recall and Recognition?

    ERIC Educational Resources Information Center

    Cherry, Katie E.; Applegate, Heather; Reese, Celinda M.

    2002-01-01

    A study examined memory for pictures and words in 16 adults with mental retardation and 24 controls. Pictorial superiority effects occurred in free recall and recognition for both intelligence-level groups. Correlational analyses indicated working memory span was primarily related to recall performance, irrespective of stimulus format. (Contains…

  11. Knock-out of HCN1 subunit flattens dorsal-ventral frequency gradient of medial entorhinal neurons in adult mice.

    PubMed

    Giocomo, Lisa M; Hasselmo, Michael E

    2009-06-10

    Layer II stellate cells at different locations along the dorsal to ventral axis of medial entorhinal cortex show differences in the frequency of intrinsic membrane potential oscillations and resonance (Giocomo et al., 2007). The frequency differences scale with differences in the size and spacing of grid-cell firing fields recorded in layer II of the medial entorhinal cortex in behaving animals. To determine the mechanism for this difference in intrinsic frequency, we analyzed oscillatory properties in adult control mice and adult mice with a global deletion of the HCN1 channel. Data from whole-cell patch recordings show that the oscillation frequency gradient along the dorsal-ventral axis previously shown in juvenile rats also appears in control adult mice, indicating that the dorsal-ventral gradient generalizes across age and species. Knock-out of the HCN1 channel flattens the dorsal-ventral gradient of the membrane potential oscillation frequency, the resonant frequency, the time constant of the "sag" potential and the amplitude of the sag potential. This supports a role of the HCN1 subunit in the mechanism of the frequency gradient in these neurons. These findings have important implications for models of grid cells and generate predictions for future in vivo work on entorhinal grid cells.

  12. Mice devoid of interferon regulatory factor 1 (IRF-1) show normal expression of type I interferon genes.

    PubMed Central

    Reis, L F; Ruffner, H; Stark, G; Aguet, M; Weissmann, C

    1994-01-01

    The transcription factor interferon regulatory factor 1 (IRF-1) binds tightly to the interferon (IFN)-beta promoter and has been implicated in the induction of type I IFNs. We generated mice devoid of functional IRF-1 by targeted gene disruption. As reported by others, IRF-1-deficient mice showed a discrete phenotype: the CD4/CD8 ratio was increased and IFN-gamma-induced levels of macrophage iNO synthase mRNA were strongly diminished. However, type I IFN induction in vivo by virus or double-stranded RNA was unimpaired, as evidenced by serum IFN titers and IFN mRNA levels in spleen, liver and lung. There was also no impairment in the response of type I IFN-inducible genes. Therefore, IRF-1 is not essential for these processes in vivo. Images PMID:7957048

  13. Mice with Deficient BK Channel Function Show Impaired Prepulse Inhibition and Spatial Learning, but Normal Working and Spatial Reference Memory

    PubMed Central

    Azzopardi, Erin; Ruettiger, Lukas; Ruth, Peter; Schmid, Susanne

    2013-01-01

    Genetic variations in the large-conductance, voltage- and calcium activated potassium channels (BK channels) have been recently implicated in mental retardation, autism and schizophrenia which all come along with severe cognitive impairments. In the present study we investigate the effects of functional BK channel deletion on cognition using a genetic mouse model with a knock-out of the gene for the pore forming α-subunit of the channel. We tested the F1 generation of a hybrid SV129/C57BL6 mouse line in which the slo1 gene was deleted in both parent strains. We first evaluated hearing and motor function to establish the suitability of this model for cognitive testing. Auditory brain stem responses to click stimuli showed no threshold differences between knockout mice and their wild-type littermates. Despite of muscular tremor, reduced grip force, and impaired gait, knockout mice exhibited normal locomotion. These findings allowed for testing of sensorimotor gating using the acoustic startle reflex, as well as of working memory, spatial learning and memory in the Y-maze and the Morris water maze, respectively. Prepulse inhibition on the first day of testing was normal, but the knockout mice did not improve over the days of testing as their wild-type littermates did. Spontaneous alternation in the y-maze was normal as well, suggesting that the BK channel knock-out does not impair working memory. In the Morris water maze knock-out mice showed significantly slower acquisition of the task, but normal memory once the task was learned. Thus, we propose a crucial role of the BK channels in learning, but not in memory storage or recollection. PMID:24303038

  14. Chronic methadone treatment shows a better cost/benefit ratio than chronic morphine in mice.

    PubMed

    Enquist, Johan; Ferwerda, Madeline; Milan-Lobo, Laura; Whistler, Jennifer L

    2012-02-01

    Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. Here, we examined whether moderate doses of methadone carry any benefits over chronic use of equianalgesic morphine, the prototypical opioid. Our data show that chronic administration of methadone produces significantly less analgesic tolerance than morphine. Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading μ-opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not.

  15. Impact of Sox9 Dosage and Hes1-mediated Notch Signaling in Controlling the Plasticity of Adult Pancreatic Duct Cells in Mice

    PubMed Central

    Hosokawa, Shinichi; Furuyama, Kenichiro; Horiguchi, Masashi; Aoyama, Yoshiki; Tsuboi, Kunihiko; Sakikubo, Morito; Goto, Toshihiko; Hirata, Koji; Tanabe, Wataru; Nakano, Yasuhiro; Akiyama, Haruhiko; Kageyama, Ryoichiro; Uemoto, Shinji; Kawaguchi, Yoshiya

    2015-01-01

    In the adult pancreas, there has been a long-standing dispute as to whether stem/precursor populations that retain plasticity to differentiate into endocrine or acinar cell types exist in ducts. We previously reported that adult Sox9-expressing duct cells are sufficiently plastic to supply new acinar cells in Sox9-IRES-CreERT2 knock-in mice. In the present study, using Sox9-IRES-CreERT2 knock-in mice as a model, we aimed to analyze how plasticity is controlled in adult ducts. Adult duct cells in these mice express less Sox9 than do wild-type mice but Hes1 equally. Acinar cell differentiation was accelerated by Hes1 inactivation, but suppressed by NICD induction in adult Sox9-expressing cells. Quantitative analyses showed that Sox9 expression increased with the induction of NICD but did not change with Hes1 inactivation, suggesting that Notch regulates Hes1 and Sox9 in parallel. Taken together, these findings suggest that Hes1-mediated Notch activity determines the plasticity of adult pancreatic duct cells and that there may exist a dosage requirement of Sox9 for keeping the duct cell identity in the adult pancreas. In contrast to the extended capability of acinar cell differentiation by Hes1 inactivation, we obtained no evidence of islet neogenesis from Hes1-depleted duct cells in physiological or PDL-induced injured conditions. PMID:25687338

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

    PubMed Central

    1983-01-01

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

  17. Adult Ovenbirds (Seiurus aurocapilla) show increased stress-responsiveness in logged forests.

    PubMed

    Leshyk, Rhiannon; Nol, Erica; Chin, Eunice H; Burness, Gary

    2013-12-01

    Forest harvesting is a form of anthropogenic disturbance, yet the effects of such disturbance on the endocrine physiology of wildlife have been infrequently studied. We investigated the effect of two methods of forest harvesting ('intensive' and 'typical' group-selection silviculture) and un-harvested control sites on the glucocorticoid levels of adult Ovenbirds (Seiurus aurocapilla), a forest interior bird species. We collected blood samples from adult males immediately after capture to examine baseline corticosterone, and then following a standardized capture and restraint protocol, to examine stress-induced levels. There was no significant repeatability in either baseline or stress-induced corticosterone levels for eleven individuals measured in both years of study. Despite no differences across harvesting treatments in male body mass or baseline corticosterone levels, males captured in sites subjected to intensive harvesting had significantly higher stress-induced corticosterone levels than males in other treatments. Currently, the mechanism driving differences in stress-reactivity is unknown although we hypothesize that the size of gaps resulting from intensive group-selection silviculture may increase perceived predation risk. In comparison to our previous work on nestling Ovenbirds, adults respond differently to stress from group-selection silviculture.

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

    PubMed

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

    2015-09-01

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

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

    PubMed

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

    2014-04-03

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

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

    PubMed

    Zoicas, Iulia; Neumann, Inga D

    2016-01-15

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

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

    PubMed

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

    2006-08-30

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

  2. Plgf-/-eNos-/- mice show defective angiogenesis associated with increased oxidative stress in response to tissue ischemia.

    PubMed

    Gigante, Bruna; Morlino, Giulia; Gentile, Maria Teresa; Persico, Maria Graziella; De Falco, Sandro

    2006-05-01

    Neo-angiogenesis is a complex phenomenon modulated by the concerted action of several molecular factors. We have generated a congenic line of knockout mice carrying null mutations of both placental growth factor (PlGF) and endothelial nitric oxide synthase (eNOS), two genes that play a pivotal role in the regulation of pathological angiogenesis. In the present study, we describe the phenotype of this new experimental animal model after surgically induced hind-limb ischemia. Plgf-/-, eNos-/-, Plgf-/- eNos-/-, and wild-type C57BL/6J mice were studied. Plgf-/- eNos-/- mice showed the most severe phenotype: self-amputation, and death occurred in up to 47% of the animals studied; in ischemic legs, capillary density was severely reduced; macrophage infiltration and oxidative stress increased as compared to the other groups of animals. These changes were associated with an up-regulation of both inducible NOS (iNOS) expression and vascular endothelial growth factor (VEGF) protein levels in ischemic limbs, and to an increased extent of protein nitration. Our results demonstrate that the deletion of these two genes, Plgf, which acts in synergism with VEGF, and eNos, a downstream mediator of VEGF, determines a significant change in the vascular response to an ischemic stimulus and that oxidative stress within the ischemic tissue represents a crucial factor to maintain tissue homeostasis.

  3. The adult pituitary shows stem/progenitor cell activation in response to injury and is capable of regeneration.

    PubMed

    Fu, Qiuli; Gremeaux, Lies; Luque, Raul M; Liekens, Daisy; Chen, Jianghai; Buch, Thorsten; Waisman, Ari; Kineman, Rhonda; Vankelecom, Hugo

    2012-07-01

    The pituitary gland constitutes, together with the hypothalamus, the regulatory core of the endocrine system. Whether the gland is capable of cell regeneration after injury, in particular when suffered at adult age, is unknown. To investigate the adult pituitary's regenerative capacity and the response of its stem/progenitor cell compartment to damage, we constructed a transgenic mouse model to conditionally destroy pituitary cells. GHCre/iDTR mice express diphtheria toxin (DT) receptor after transcriptional activation by Cre recombinase, which is driven by the GH promoter. Treatment with DT for 3 d leads to gradual GH(+) (somatotrope) cell obliteration with a final ablation grade of 80-90% 1 wk later. The stem/progenitor cell-clustering side population promptly expands after injury, concordant with the immediate increase in Sox2(+) stem/progenitor cells. In addition, folliculo-stellate cells, previously designated as pituitary stem/progenitor cells and significantly overlapping with Sox2(+) cells, also increase in abundance. In situ examination reveals expansion of the Sox2(+) marginal-zone niche and appearance of remarkable Sox2(+) cells that contain GH. When mice are left after the DT-provoked lesion, GH(+) cells considerably regenerate during the following months. Double Sox2(+)/GH(+) cells are observed throughout the regenerative period, suggesting recovery of somatotropes from stem/progenitor cells, as further supported by 5-ethynyl-2'-deoxyuridine (EdU) pulse-chase lineage tracing. In conclusion, our study demonstrates that the adult pituitary gland holds regenerative competence and that tissue repair follows prompt activation and plausible involvement of the stem/progenitor cells.

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

    NASA Technical Reports Server (NTRS)

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

    2002-01-01

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

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

    DTIC Science & Technology

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2017-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  9. Effects of social isolation and enriched environment on behavior of adult Swiss mice do not require hippocampal neurogenesis.

    PubMed

    Silva, Cristiane Felisbino; Duarte, Filipe Silveira; Lima, Thereza Christina Monteiro De; de Oliveira, Cilene Lino

    2011-11-20

    Housing conditions are important determinants of animal behavior. Their impact on behavioral output depends on the behavior of interest, species, strain, and age of the animal evaluated. In the present study, male Swiss mice reared from weaning up to 8 weeks in social isolation (SI8), in enriched environment (EE8) or in standard environment (SE8) were evaluated in the elevated plus-maze (EPM), open-field (OFT) and tail-suspension (TST) tests. The effect of housing for 6 weeks in EE followed by 2 weeks in SI (EE6SI2) and the opposite condition (SI6EE2) was also studied. Housing conditions are reported to affect hippocampal neurogenesis; therefore, the expression of doublecortin (DCX) in the dentate gyrus of the hippocampus (DG) of these mice was monitored. Data showed that SI8, EE8 and EE6SI2 reduced the stretching-attend postures in the EPM and explored more the center of the apparatus when compared to SE8. The time and the number of entries in the closed arms of the EPM was not affected indicating that effects of housing conditions in the EPM were not consequence of motor activity alteration. Accordingly, EE8 mice exploration of the OFT was similar to SE8. However, the SI8 mice explored the OFT more than the EE8 mice, suggesting hyperactivity induced by isolation. Behavior of Swiss mice in the TST was not altered, indicating that this test was not sensitive to the environmental changes in this mice strain. Compared to SE8, EE8 did not affect the number of DCX cells, whereas SI8, EE6SI2, and SI6EE2 decreased it. Taken together, our data suggest that the behavior of adult Swiss mice in the EPM and OFT was affected by environmental changes but that these changes seem to be independent of hippocampal neurogenesis.

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

    PubMed Central

    Mohammadi, Shabnam

    2014-01-01

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

  11. The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer’s Disease of humans and mice

    PubMed Central

    Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra; Liu, Jiahui; Pike, Christian J.; Sullivan, Patrick M.; Morgan, Todd E.; Dolzhenko, Egor; Charidimou, Andreas; Wahlund, Lars-Olaf; Wiberg, Maria Kristofferson; Shams, Sara; Chiang, Gloria Chia-Yi; Finch, Caleb E.

    2015-01-01

    The APOE4 allele confers greater risk of Alzheimer’s Disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment (MCI) and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in two clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes. At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy (CAA), plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and CAA increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds vs the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition. PMID:26686669

  12. Altered resistance to Trichinella spiralis infection following subchronic exposure of adult mice to chemicals of environmental concern

    SciTech Connect

    Luebke, R.W.

    1981-01-01

    The effects of subchronic chemical exposure on expulsion of adult Trichinella spiralis from the small intestine of mice and encystment of newborn larvae in the host's musculature were investigated. Exposure to diethylstilbestrol, benzo(a)pyrene, tris-(1,3-dichloro-2-propyl) phosphate, cyclophosphamide, phorbol myristate acetate, and dimethylvinylchloride prior to infection of mice with 200 infective larvae resulted in larger worm burdens in treated animals than in controls 14 days after infection. Worm expulsion was not affected by exposure to tris-(2,3-dibromopropyl)phosphate, orthophenylphenol, and indomethacin. Increased burdens of muscle-phase larvae were found in animals that maintained significant numbers of adult worms in the gut at 14 days, except in mice administered diethylstilbestrol and dimethylvinylchloride. Exposure to diethylstilbestrol and cyclophosphamide resulted in decreased inflammatory reactions in the tissues of the small intestine and development of bone marrow eosinophilia in infected mice. Marrow eosinophilia was likewise decreased in mice given tris-(1,3-dichloro-2-propyl)phosphate before infection. Additional studies with diethylstilbestrol administered either before, at the time of, or after infection showed inhibition of worm expulsion. Drug exposure during a primary infection inhibited the expulsion of a second T. spiralis infection, but did not affect worm elimination when given during a second infection. Treatment with diethylstilbestrol after artificial sensitization of mice with Trichinella antigens decreased delayed hypersensitivity responses to the sensitizing antigen. Immune functions, assessed by lymphoproliferative responses to mitogens and antibody responses to sheep red blood cells, generally correlated with altered host resistance to T. spiralis infection.

  13. Cardiac structure/function, protein expression, and DNA methylation are changed in adult female mice exposed to diethylstilbestrol in utero.

    PubMed

    Haddad, Rami; Kasneci, Amanda; Sebag, Igal A; Chalifour, Lorraine E

    2013-09-01

    The detrimental effects of in utero exposure to the non-steroidal estrogen diethylstilbestrol (DES) are particularly marked in women. Fetal hearts express estrogen receptors, making them potentially responsive to DES. To examine whether gestational exposure to DES would impact the heart, we exposed pregnant C57bl/6n dams to DES (0.1, 1.0, and 10.0 μg·(kg body mass)(-1)·day(-1)) on gestation days 11.5-14.5, and examined the measured cardiac structure/function and calcium homeostasis protein expression in adult females. At baseline, echocardiography revealed eccentric hypertrophy in mice treated with 10.0 μg·(kg body mass)(-1)·day(-1) DES, and immunoblots showed increased SERCA2a in all DES-treated mice. Mice were swim-trained to assess cardiac remodeling. Swim-trained vehicle-treated mice developed eccentric hypertrophy without changing SERCA2 or calsequestrin 2 expression. In contrast, no DES-treated mice hypertrophied, and all increased in SERCA2a and calsequestrin 2 expression after training. To determine whether DES-induced changes in DNA methylation is part of the mechanism for its long-term effects, we measured DNA methyltransferase expression and DNA methylation. Global DNA methylation and DNA methyltransferase 3a expression were unchanged. However, DES-treated mice had increased DNA methylation in the calsequestrin 2 promoter. Thus, gestational exposure to DES altered female ventricular DNA, cardiac structure/function, and calcium homeostasis protein expression. We conclude that gestational exposure to estrogenizing compounds may impact cardiac structure/function in adult females.

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

    EPA Science Inventory

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

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

    PubMed

    Shan, Tizhong; Xiong, Yan; Kuang, Shihuan

    2016-11-08

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

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

    PubMed Central

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

    2014-01-01

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

  17. A novel BET bromodomain inhibitor, RVX-208, shows reduction of atherosclerosis in hyperlipidemic ApoE deficient mice.

    PubMed

    Jahagirdar, Ravi; Zhang, Haiyan; Azhar, Salman; Tobin, Jennifer; Attwell, Sarah; Yu, Raymond; Wu, Jin; McLure, Kevin G; Hansen, Henrik C; Wagner, Gregory S; Young, Peter R; Srivastava, Rai Ajit K; Wong, Norman C W; Johansson, Jan

    2014-09-01

    Despite the benefit of statins in reducing cardiovascular risk, a sizable proportion of patients still remain at risk. Since HDL reduces CVD risk through a process that involves formation of pre-beta particles that facilitates the removal of cholesterol from the lipid-laden macrophages in the arteries, inducing pre-beta particles, may reduce the risk of CVD. A novel BET bromodomain antagonist, RVX-208, was reported to raise apoA-I and increase preβ-HDL particles in non-human primates and humans. In the present study, we investigated the effect of RVX-208 on aortic lesion formation in hyperlipidemic apoE(-/-) mice. Oral treatments of apoE(-/-) mice with 150 mg/kg b.i.d RVX-208 for 12 weeks significantly reduced aortic lesion formation, accompanied by 2-fold increases in the levels of circulating HDL-C, and ∼50% decreases in LDL-C, although no significant changes in plasma apoA-I were observed. Circulating adhesion molecules as well as cytokines also showed significant reduction. Haptoglobin, a proinflammatory protein, known to bind with HDL/apoA-I, decreased >2.5-fold in the RVX-208 treated group. With a therapeutic dosing regimen in which mice were fed Western diet for 10 weeks to develop lesions followed by switching to a low fat diet and concurrent treatment with RVX-208 for 14 weeks, RVX-208 similarly reduced lesion formation by 39% in the whole aorta without significant changes in the plasma lipid parameters. RVX-208 significantly reduced the proinflammatory cytokines IP-10, MIP1(®) and MDC. These results show that the antiatherogenic activity of BET inhibitor, RVX-208, occurs via a combination of lipid changes and anti-inflammatory activities.

  18. Loss of endothelial-ARNT in adult mice contributes to dampened circulating proangiogenic cells and delayed wound healing.

    PubMed

    Han, Yu; Tao, Jiayi; Gomer, Alla; Ramirez-Bergeron, Diana L

    2014-12-01

    The recruitment and homing of circulating bone marrow-derived cells include endothelial progenitor cells (EPCs) that are critical to neovascularization and tissue regeneration of various vascular pathologies. We report here that conditional inactivation of hypoxia-inducible factor's (HIF) transcriptional activity in the endothelium of adult mice (Arnt(ΔiEC) mice) results in a disturbance of infiltrating cells, a hallmark of neoangiogenesis, during the early phases of wound healing. Cutaneous biopsy punches show distinct migration of CD31(+) cells into wounds of control mice by 36 hours. However, a significant decline in numbers of infiltrating cells with immature vascular markers, as well as decreased transcript levels of genes associated with their expression and recruitment, were identified in wounds of Arnt(ΔiEC) mice. Matrigel plug assays further confirmed neoangiogenic deficiencies alongside a reduction in numbers of proangiogenic progenitor cells from bone marrow and peripheral blood samples of recombinant vascular endothelial growth factor-treated Arnt(ΔiEC) mice. In addition to HIF's autocrine requirements in endothelial cells, our data implicate that extrinsic microenvironmental cues provided by endothelial HIF are pivotal for early migration of proangiogenic cells, including those involved in wound healing.

  19. Dynamic studies of positron-emitting putative tumor marker /sup 132/Cs in mice show differential tumor and regional uptake

    SciTech Connect

    McKee, J.S.; Durocher, J.J.; Bose, R.; Gusdal, M.I.; Sharma, G.P.; Pinsky, C.; Gallop, D.

    1985-01-01

    Positron-emitting /sup 132/Cs (t1/2 = 6.47 days) was generated from stable /sup 133/CsCl via the /sup 133/Cs (p,pn) /sup 132/Cs reaction. BALB/c mice, bearing implanted MT296 mammary tumors, were given 4.6 mEq kg-1 of /sup 132/CsCl via a single intraperitoneal injection. Postinjection uptake of /sup 132/Cs into body regions was monitored in vivo with external detectors. Positron emission from the tumor region was continuously greater than that from the head, the numerical ratio of mean emission intensities being fourfold at 10 min postinjection. Tissues excised from these mice postmortem showed sequence of relative tissue cesium uptake rates to be kidney 1.8, small intestine 1.7, tumor 1.0, skin 0.75, liver 0.75, skeletal muscle 0.4, and brain 0.28. Comparative studies with multiple injections of stable cesium and rubidium showed this sequence to be ion-specific. These observations suggest that positron-emitting isotopes of cesium could provide useful markers for tumors of several tissues.

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

    PubMed Central

    2011-01-01

    Background Isoflurane, a volatile anesthetic widely used clinically, has been implicated to be both neuroprotective and neurotoxic. The claim about isoflurane causing neural apoptosis remains controversial. In this study, we investigated the effects of isoflurane exposures on apoptotic and anti-apoptotic signals, cell proliferation and neurogenesis, and astroglial processes in young adult mouse brains. Methods Sixty 6-week-old mice were randomly assigned to four anesthetic concentration groups (0 as control and 0.6%, 1.3%, and 2%) with four recovery times (2 h and 1, 6, and 14 d) after 2-h isoflurane exposure. Immunohistochemistry measurements of activated caspase-3 and Bcl-xl for apoptotic and anti-apoptotic signals, respectively, glial fibrillary acidic protein (GFAP) and vimentin for reactive astrocytosis, doublecortin (Dcx) for neurogenesis, and BrdU for cell proliferation were performed. Results Contrary to the previous conclusion derived from studies with neonatal rodents, we found no evidence of isoflurane-induced apoptosis in the adult mouse brain. Neurogenesis in the subgranule zone of the dentate gyrus was not affected by isoflurane. However, there is a tendency of reduced cell proliferation after 2% isoflurane exposure. VIM and GFAP staining showed that isoflurane exposure caused a delayed reduction of astroglial processes in the hippocampus and dentate gyrus. Conclusion Two-hour exposure to isoflurane did not cause neuroapoptosis in adult brains. The delayed reduction in astroglial processes after isoflurane exposure may explain why some volatile anesthetics can confer neuroprotection after experimental stroke because reduced glial scarring facilitates better long-term neuronal recoveries. PMID:22146123

  1. HIV-1 Nef mutations abrogating downregulation of CD4 affect other Nef functions and show reduced pathogenicity in transgenic mice

    SciTech Connect

    Hanna, Zaher . E-mail: Zaher.Hanna@ircm.qc.ca; Priceputu, Elena; Hu, Chunyan; Vincent, Patrick; Jolicoeur, Paul

    2006-03-01

    HIV-1 Nef has the ability to downmodulate CD4 cell surface expression. Several studies have shown that CD4 downregulation is required for efficient virus replication and high infectivity. However, the pathophysiological relevance of this phenomenon in vivo, independently of its role in sustaining high virus loads, remains unclear. We studied the impact of the CD4 downregulation function of Nef on its pathogenesis in vivo, in the absence of viral replication, in the CD4C/HIV transgenic (Tg) mouse model. Two independent Nef mutants (RD35/36AA and D174K), known to abrogate CD4 downregulation, were tested in Tg mice. Flow cytometry analysis showed that downregulation of murine CD4 was severely decreased or abrogated on Tg T cells expressing respectively Nef{sup RD35/36AA} and Nef{sup D174K}. Similarly, the severe depletion of double-positive CD4{sup +}CD8{sup +} and of single-positive CD4{sup +}CD8{sup -} thymocytes, usually observed with Nef{sup Wt}, was not detected in Nef{sup RD35/36AA} and Nef{sup D174K} Tg mice. However, both mutant Tg mice showed a partial depletion of peripheral CD4{sup +} T cells. This was accompanied, as previously reported for Net{sup Wt} Tg mice, by the presence of an activated/memory-like phenotype (CD69{sup +}, CD25{sup +}, CD44{sup +}, CD45RB{sup Low}, CD62{sup Low}) of CD4{sup +} T cells expressing Nef{sup RD35/36AA} and to a lesser extent Nef{sup D174K}. In addition, both mutants retained the ability to block CD4{sup +} T cell proliferation in vitro after anti-CD3 stimulation, but not to enhance apoptosis/death of CD4{sup +} T cells. Therefore, it appears that Nef-mediated CD4 downregulation is associated with thymic defects, but segregates independently of the activated/memory-like phenotype, of the partial depletion and of the impaired in vitro proliferation of peripheral CD4{sup +} T cells. Histopathological assessment revealed the total absence of or decrease severity and frequency of organ AIDS-like diseases (lung, heart and kidney

  2. HIV-1 Nef mutations abrogating downregulation of CD4 affect other Nef functions and show reduced pathogenicity in transgenic mice.

    PubMed

    Hanna, Zaher; Priceputu, Elena; Hu, Chunyan; Vincent, Patrick; Jolicoeur, Paul

    2006-03-01

    HIV-1 Nef has the ability to downmodulate CD4 cell surface expression. Several studies have shown that CD4 downregulation is required for efficient virus replication and high infectivity. However, the pathophysiological relevance of this phenomenon in vivo, independently of its role in sustaining high virus loads, remains unclear. We studied the impact of the CD4 downregulation function of Nef on its pathogenesis in vivo, in the absence of viral replication, in the CD4C/HIV transgenic (Tg) mouse model. Two independent Nef mutants (RD35/36AA and D174K), known to abrogate CD4 downregulation, were tested in Tg mice. Flow cytometry analysis showed that downregulation of murine CD4 was severely decreased or abrogated on Tg T cells expressing respectively Nef(RD35/36AA) and Nef(D174K). Similarly, the severe depletion of double-positive CD4+CD8+ and of single-positive CD4+CD8- thymocytes, usually observed with Nef(Wt), was not detected in Nef(RD35/36AA) and Nef(D174K) Tg mice. However, both mutant Tg mice showed a partial depletion of peripheral CD4+ T cells. This was accompanied, as previously reported for Net(Wt) Tg mice, by the presence of an activated/memory-like phenotype (CD69+, CD25+, CD44+, CD45RB(Low), CD62(Low)) of CD4+ T cells expressing Nef(RD35/36AA) and to a lesser extent Nef(D174K). In addition, both mutants retained the ability to block CD4+ T cell proliferation in vitro after anti-CD3 stimulation, but not to enhance apoptosis/death of CD4+ T cells. Therefore, it appears that Nef-mediated CD4 downregulation is associated with thymic defects, but segregates independently of the activated/memory-like phenotype, of the partial depletion and of the impaired in vitro proliferation of peripheral CD4+ T cells. Histopathological assessment revealed the total absence of or decrease severity and frequency of organ AIDS-like diseases (lung, heart and kidney pathologies) in respectively Nef(RD35/36AA) and Nef(D174K) Tg mice, relative to those developing in Nef(Wt) Tg

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

    PubMed

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

    2014-12-15

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

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

    SciTech Connect

    Fox, Donald A.; Hamilton, W. Ryan; Johnson, Jerry E.; Xiao, Weimin; Chaney, Shawntay; Mukherjee, Shradha; Miller, Diane B.; O'Callaghan, James P.

    2011-11-15

    Gestational lead exposure (GLE) produces supernormal scotopic electroretinograms (ERG) in children, monkeys and rats, and a novel retinal phenotype characterized by an increased number of rod photoreceptors and bipolar cells in adult mice and rats. Since the loss of dopaminergic amacrine cells (DA ACs) in GLE monkeys and rats contributes to supernormal ERGs, the retinal DA system was analyzed in mice following GLE. C57BL/6 female mice were exposed to low (27 ppm), moderate (55 ppm) or high (109 ppm) lead throughout gestation and until postnatal day 10 (PN10). Blood [Pb] in control, low-, moderate- and high-dose GLE was {<=} 1, {<=} 10, {approx} 25 and {approx} 40 {mu}g/dL, respectively, on PN10 and by PN30 all were {<=} 1 {mu}g/dL. At PN60, confocal-stereology studies used vertical sections and wholemounts to characterize tyrosine hydroxylase (TH) expression and the number of DA and other ACs. GLE dose-dependently and selectively decreased the number of TH-immunoreactive (IR) DA ACs and their synaptic plexus without affecting GABAergic, glycinergic or cholinergic ACs. Immunoblots and confocal revealed dose-dependent decreases in retinal TH protein expression and content, although monoamine oxidase-A protein and gene expression were unchanged. High-pressure liquid chromatography showed that GLE dose-dependently decreased retinal DA content, its metabolites and DA utilization/release. The mechanism of DA selective vulnerability is unknown. However, a GLE-induced loss/dysfunction of DA ACs during development could increase the number of rods and bipolar cells since DA helps regulate neuronal proliferation, whereas during adulthood it could produce ERG supernormality as well as altered circadian rhythms, dark/light adaptation and spatial contrast sensitivity. -- Highlights: Black-Right-Pointing-Pointer Peak [BPb] in control, low-, moderate- and high-dose newborn mice with gestational lead exposure: {<=} 1, {<=} 10, 25 and 40 {mu}g/dL Black

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

    PubMed Central

    Janus, Christopher; Golde, Todd

    2013-01-01

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

  6. Type 1 inositol trisphosphate receptor regulates cerebellar circuits by maintaining the spine morphology of purkinje cells in adult mice.

    PubMed

    Sugawara, Takeyuki; Hisatsune, Chihiro; Le, Tung Dinh; Hashikawa, Tsutomu; Hirono, Moritoshi; Hattori, Mitsuharu; Nagao, Soichi; Mikoshiba, Katsuhiko

    2013-07-24

    The structural maintenance of neural circuits is critical for higher brain functions in adulthood. Although several molecules have been identified as regulators for spine maintenance in hippocampal and cortical neurons, it is poorly understood how Purkinje cell (PC) spines are maintained in the mature cerebellum. Here we show that the calcium channel type 1 inositol trisphosphate receptor (IP3R1) in PCs plays a crucial role in controlling the maintenance of parallel fiber (PF)-PC synaptic circuits in the mature cerebellum in vivo. Significantly, adult mice lacking IP3R1 specifically in PCs (L7-Cre;Itpr1(flox/flox)) showed dramatic increase in spine density and spine length of PCs, despite having normal spines during development. In addition, the abnormally rearranged PF-PC synaptic circuits in mature cerebellum caused unexpectedly severe ataxia in adult L7-Cre;Itpr1(flox/flox) mice. Our findings reveal a specific role for IP3R1 in PCs not only as an intracellular mediator of cerebellar synaptic plasticity induction, but also as a critical regulator of PF-PC synaptic circuit maintenance in the mature cerebellum in vivo; this mechanism may underlie motor coordination and learning in adults.

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

    PubMed

    Dagnas, Malorie; Micheau, Jacques; Decorte, Laurence; Beracochea, Daniel; Mons, Nicole

    2015-07-01

    Converging evidence indicates that pharmacologically elevating histone acetylation using post-training, systemic or intrahippocampal, administration of histone deacetylase inhibitor (HDACi) can enhance memory consolidation processes in young rodents but it is not yet clear, whether such treatment is sufficient to prevent memory impairments associated with aging. To address this question, we used a 1-day massed spatial learning task in the water maze to investigate the effects of immediate post-training injection of the HDACi trichostatin A (TSA) into the dorsal hippocampus on long-term memory consolidation in 3-4 and 18-20 month-old mice. We show that TSA improved the 24 h-memory retention for the hidden platform location in young-adults, but failed to rescue memory impairments in older mice. The results further indicate that Young-TSA mice sacrificed 1 h after training had a robust increase in histone H4 acetylation in the dorsal hippocampal CA1 region (dCA1) and the dorsomedial part of the striatum (DMS), a structure important for spatial information processing. Importantly, TSA infusion in aged mice completely rescued altered H4 acetylation in the dCA1 but failed to alleviate age-associated decreased H4 acetylation in the DMS. Moreover, intrahippocampal TSA infusion produced concomitant decreases (in adults) or increases (in older mice) of acetylated histone levels in the ventral hippocampus (vCA1 and vCA3) and the lateral amygdala, two structures critically involved in stress and emotional responses. These data suggest that the failure of post-training, intrahippocampal TSA injection to reverse age-associated memory impairments may be related to an inability to recruit appropriate circuit-specific epigenetic patterns during early consolidation processes.

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

    PubMed Central

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

    2013-01-01

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

  9. Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

    PubMed Central

    Mingote, Susana; Masson, Justine; Gellman, Celia; Thomsen, Gretchen M.; Lin, Chyuan-Sheng; Merker, Robert J.; Gaisler-Salomon, Inna; Wang, Yvonne; Ernst, Rachel; Hen, René; Rayport, Stephen

    2016-01-01

    Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAGERT2cre∕+ mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction—mimicking pharmacological inhibition—strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel

  10. Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice.

    PubMed

    Mingote, Susana; Masson, Justine; Gellman, Celia; Thomsen, Gretchen M; Lin, Chyuan-Sheng; Merker, Robert J; Gaisler-Salomon, Inna; Wang, Yvonne; Ernst, Rachel; Hen, René; Rayport, Stephen

    2015-01-01

    Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG(ERT2cre∕+) mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction-mimicking pharmacological inhibition-strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2005-01-01

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

  13. Mice overexpressing 70-kDa heat shock protein show increased resistance to malonate and 3-nitropropionic acid.

    PubMed

    Dedeoglu, Alpaslan; Ferrante, Robert J; Andreassen, Ole A; Dillmann, Wolfgang H; Beal, M Flint

    2002-07-01

    Heat shock proteins (HSPs) are induced in response to oxidative stress, hypoxia-ischemia, and neuronal injury and play a protective role. Malonate and 3-nitropropionic acid (3-NP) are well-characterized animal models of Huntington's Disease (HD). They inhibit succinate dehydrogenase, inducing mitochondrial dysfunction, which triggers the generation of superoxide radicals, secondary excitotoxicity, and apoptosis. In this study, we examined whether the 70-kDa heat shock protein (HSP-70) is protective against neurotoxicity induced by malonate and 3-NP. Homozygous and heterozygous HSP-70 overexpressing mice (HSP-70+/+, HSP-70+/-) and wild-type controls received 3-NP or malonate and striatal lesion sizes were evaluated by stereology. Compared to HSP-70+/+ and HSP-70+/-, wild-type controls showed significantly larger striatal lesions following 3-NP or malonate injections. These findings support the idea that HSP-70 has a neuroprotective role that may be useful in the treatment of neurodegenerative diseases.

  14. Effects of tamoxifen on autosomal genes regulating ovary maintenance in adult mice.

    PubMed

    Yu, Mingxi; Liu, Wei; Wang, Jingyun; Qin, Junwen; Wang, Yongan; Wang, Yu

    2015-12-01

    Environmental endocrine-disrupting chemicals (EDCs), known to bind to estrogen/androgen receptors and mimic native estrogens, have been implicated as a main source for increasing human reproductive and developmental deficiencies and diseases. Tamoxifen (TAM) is one of the most well-known antiestrogens with defined adverse effects on the female reproductive tract, but the mechanisms related to autosomal gene regulation governing ovary maintenance in mammals remain unclear. The expression pattern and levels of key genes and proteins involved in maintaining the ovarian phenotype in mice were analyzed. The results showed that TAM induced significant upregulation of Sox9, which is the testis-determining factor gene. The results showed that TAM induced significant upregulation of Sox9, the testis-determining factor gene, and the expression level of Sox9 mRNA in the ovaries of mice exposed to 75 or 225 mg/kg bw TAM was 2- and 10-fold that in the control group, respectively (p < 0.001). Furthermore, the testicular fibroblast growth factor gene, Fgf9, was also elevated in TAM-treated ovaries. Accordingly, expression of the ovary development marker, forkhead transcription factor (FOXL2), and WNT4/FST signaling, were depressed. The levels of protein expression changed consistently with the target genes. Moreover, the detection of platelet/endothelial cell adhesion molecule 1 (PECAM-1) in TAM-treated ovaries suggested the formation of vascular endothelial cells, which is a further evidence for the differentiation of the ovaries to a testis-like phenotype. During this period, the level of 17β-estradiol, progesterone, and luteinizing hormone decreased, while that of testosterone increased by 3.3-fold (p = 0.013). The activation of a testis-specific molecular signaling cascade was a potentially important mechanism contributing to the gender disorder induced by TAM, which resulted in the differentiation of the ovaries to a testis-like phenotype in adult mice. Limited with

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

    PubMed

    Nath, Amar; Hakim, Bilal Ahmad; Rajender, Singh; Singh, Kavita; Sachdev, Monika; Konwar, Rituraj

    2016-05-01

    This study was aimed to determine the impact of insulin concentrations on in vitro pre-antral follicle growth, survival, antrum formation rate, and retrieval of mature oocytes in mice. Mice pre-antral follicle growth were recorded on days 2, 4, 6, 8, 10, and 12 in α-modified essential media (α-MEM) supplemented with insulin concentrations of 6, 8, and 10 μg/ml along with 10% FBS, 100 mIU/ml follicle stimulating hormone, 10 mIU/ml luteinizing hormone, 100 μg/ml penicillin, and 50 μg/ml streptomycin. After 12 d of growth in vitro, follicles were allowed to mature for 16-18 h in α-MEM supplemented with 1.5 IU/ml human chorionic gonadotrophin (hCG) and 5 ng/ml epidermal growth factor (EGF). The initial diameter (54.86 ± 2.5 μm) of mice oocyte progressively increased in all the three insulin concentration groups and attained a maximum size on day 12 (71.90 ± 2.8 μm). Supplementation with higher concentrations of insulin (both 8 and 10 μg/ml) significantly enhanced antrum formation without effecting the oocyte diameter and percent retrieval of mature oocyte in all the three concentration groups. Both in vitro cultured as well as in vivo collected follicles and oocytes showed similar localization and expression of oocyte maturation markers SAS1B and GDF9. Insulin concentration of 8 μg/ml was found to be optimal for in vitro follicle culture of adult mice (42-49 d). Optimized follicle culture conditions were also assessed successfully with pre-pubertal mice (12-14 d); however, adult mice showed higher follicle survival, antrum formation, and more mature oocytes production in comparison to pre-pubertal mice.

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    2012-01-01

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

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

    NASA Technical Reports Server (NTRS)

    Ronca, April E.

    2016-01-01

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

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

    SciTech Connect

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

    1982-01-01

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

  20. Preterm birth and unintentional injuries: risks to children, adolescents and young adults show no consistent pattern

    PubMed Central

    Calling, Susanna; Palmér, Karolina; Jönsson, Lena; Sundquist, Jan; Winkleby, Marilyn; Sundquist, Kristina

    2012-01-01

    Aim Preterm birth is associated with a number of physical and mental health issues. The aim of this study was to find out if there was also any association between individuals born preterm in Sweden between 1984 and 2006 and the risk of unintentional injuries during childhood, adolescence and young adulthood. Methods The study followed 2,297,134 individuals, including 5.9% born preterm, from 1985 to 2007 for unintentional injuries leading to hospitalisation or death (n=244,021). The males and females were divided into four age groups: 1–5 years, 6–12 years, 13–18 years and 19–23 years. Hazard ratios were calculated for falls, transport injuries and other injuries. Results After adjusting for a comprehensive set of covariates, some of the preterm subgroups demonstrated slightly increased risks of unintentional injuries, while others showed slightly decreased risks. However, most of the estimates were borderline or non-significant in both males and females. In addition, the absolute risk differences between individuals born preterm and full term were small. Conclusion Despite the association between preterm birth and a variety of physical and mental health consequences, this study shows that there is no consistent risk pattern between preterm birth and unintentional injuries in childhood, adolescence and young adulthood. PMID:23181809

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

    PubMed

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

    2016-07-29

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

  2. ERK1/2 Activation in Preexisting Oligodendrocytes of Adult Mice Drives New Myelin Synthesis and Enhanced CNS Function

    PubMed Central

    Jeffries, Marisa A.; Urbanek, Kelly; Torres, Lester; Wendell, Stacy Gelhaus; Rubio, Maria E.

    2016-01-01

    Growing evidence shows that mechanisms controlling CNS plasticity extend beyond the synapse and that alterations in myelin can modify conduction velocity, leading to changes in neural circuitry. Although it is widely accepted that newly generated oligodendrocytes (OLs) produce myelin in the adult CNS, the contribution of preexisting OLs to functional myelin remodeling is not known. Here, we show that sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in preexisting OLs of adult mice is sufficient to drive increased myelin thickness, faster conduction speeds, and enhanced hippocampal-dependent emotional learning. Although preexisting OLs do not normally contribute to remyelination, we show that sustained activation of ERK1/2 renders them able to do so. These data suggest that strategies designed to push mature OLs to reinitiate myelination may be beneficial both for enhancing remyelination in demyelinating diseases and for increasing neural plasticity in the adult CNS. SIGNIFICANCE STATEMENT Myelin is a crucial regulator of CNS plasticity, function, and repair. Although it is generally accepted that new myelin production in the adult CNS is initiated by newly generated oligodendrocytes (OLs), great interest remains in additionally driving mature preexisting OLs to make myelin. The ability to induce myelination by the larger population of preexisting OLs carries the potential for enhanced remyelination in demyelinating diseases and increased neural plasticity in the adult CNS. Here, we show that sustained activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway is sufficient to drive mature OLs in the adult mouse CNS to reinitiate myelination, leading to new myelin wraps and functional changes. PMID:27581459

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

    PubMed

    Hu, Lili; Han, Bo; Zhao, Xiaoge; Mi, Lihua; Song, Qiang; Wang, Jue; Song, Tusheng; Huang, Chen

    2016-04-13

    Chronic scream sounds during adulthood affect spatial learning and memory, both of which are sexually dimorphic. The long-term effects of chronic early postnatal scream sound stress (SSS) during postnatal days 1-21 (P1-P21) on spatial learning and memory in adult mice as well as whether or not these effects are sexually dimorphic are unknown. Therefore, the present study examines the performance of adult male and female mice in the Morris water maze following exposure to chronic early postnatal SSS. Hippocampal NR2A and NR2B levels as well as NR2A/NR2B subunit ratios were tested using immunohistochemistry. In the Morris water maze, stress males showed greater impairment in spatial learning and memory than background males; by contrast, stress and background females performed equally well. NR2B levels in CA1 and CA3 were upregulated, whereas NR2A/NR2B ratios were downregulated in stressed males, but not in females. These data suggest that chronic early postnatal SSS influences spatial learning and memory ability, levels of hippocampal NR2B, and NR2A/NR2B ratios in adult males. Moreover, chronic early stress-induced alterations exert long-lasting effects and appear to affect performance in a sex-specific manner.

  4. Self-compassionate young adults show lower salivary alpha-amylase responses to repeated psychosocial stress

    PubMed Central

    Breines, Juliana G.; McInnis, Christine M.; Kuras, Yuliya I.; Thoma, Myriam V.; Gianferante, Danielle; Hanlin, Luke; Chen, Xuejie; Rohleder, Nicolas

    2015-01-01

    In this study we tested the hypothesis that participants higher in dispositional self-compassion would show lower stress-induced reactivity of salivary alpha-amylase (sAA), a marker of sympathetic nervous system activation. Thirty-three healthy participants (18–34 years old) were exposed to a standardized laboratory stressor on two consecutive days. Self-compassion, self-esteem, and demographic factors were assessed by questionnaire and sAA was assessed at baseline and at 1, 10, 30, and 60 minutes following each stressor. Self-compassion was a significant negative predictor of sAA responses on both days. This relationship remained significant when controlling for self-esteem, subjective distress, age, gender, ethnicity, and Body Mass Index (BMI). These results suggest that self-compassion may serve as a protective factor against stress-induced physiological changes that have implications for health. PMID:26005394

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

    PubMed

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

    2014-01-01

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

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

    PubMed

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

    2011-09-01

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

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

    PubMed Central

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

    2010-01-01

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

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

    SciTech Connect

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

    1986-03-01

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

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

    PubMed

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

    2012-01-01

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

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

    PubMed

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

    2014-08-01

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

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

    2012-01-01

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

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

    PubMed

    Lei, Lei; Spradling, Allan C

    2013-05-21

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

  14. Salidroside, a Bioactive Compound of Rhodiola Rosea, Ameliorates Memory and Emotional Behavior in Adult Mice.

    PubMed

    Palmeri, Agostino; Mammana, Leonardo; Tropea, Maria Rosaria; Gulisano, Walter; Puzzo, Daniela

    2016-02-26

    Rhodiola Rosea (R. Rosea) is a plant used in traditional popular medicine to enhance cognition and physical performance. R. Rosea medicinal properties have been related to its capability to act as an adaptogen, i.e., a substance able to increase the organism's resistance to a variety of chemical, biological, and physical stressors in a non-specific way. These adaptogen properties have been mainly attributed to the glycoside salidroside, one of the bioactive compounds present in the standardized extracts of R. Rosea. Here, we aimed to investigate whether a single dose of salidroside is able to affect memory and emotional behavior in wild type adult mice. We performed fear conditioning to assess cued and contextual memory, elevated plus maze and open field to evaluate anxiety, and tail suspension test to evaluate depression. Our results showed that a single i.p. administration of salidroside was able to enhance fear memory and exerted an anxiolytic and antidepressant effect. These data confirmed the adaptogenic effect of R. Rosea bioactive compounds in animal models and suggest that salidroside might represent an interesting pharmacological tool to ameliorate cognition and counteract mood disorders.

  15. Clone-forming activity of embryonal stem hemopoietic cells after transplantation to newborn or adult sublethally irradiated mice.

    PubMed

    Drize, N I; Chertkov, I L

    2000-07-01

    Hemopoietic activity of stem hemopoietic cells from the liver of embryos was studied at different terms of intrauterine development. The fate of individual clones of hemopoietic cells marked by human adenosine deaminase gene was followed up in sublethally irradiated or newborn recipients. The efficiency of marker gene incorporation in primitive stem hemopoietic cells from the liver of 12-, 13-, and 17-day embryos was not high. Gene transfer was performed without cell prestimulation to division, and hence, these data show that primitive stem cells proliferate even in 17-day embryos. Cells from embryonal liver in all terms maintain hemopoiesis both in newborn and adult microenvironment, hemopoiesis being realized according to the clonal succession model, i. e. in the some way after transplantation of the bone marrow from adult mice.

  16. Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585.

    PubMed

    Schreml, Julia; Riessland, Markus; Paterno, Mario; Garbes, Lutz; Roßbach, Kristina; Ackermann, Bastian; Krämer, Jan; Somers, Eilidh; Parson, Simon H; Heller, Raoul; Berkessel, Albrecht; Sterner-Kock, Anja; Wirth, Brunhilde

    2013-06-01

    Spinal muscular atrophy (SMA) is the leading genetic cause of early childhood death worldwide and no therapy is available today. Many drugs, especially histone deacetylase inhibitors (HDACi), increase SMN levels. As all HDACi tested so far only mildly ameliorate the SMA phenotype or are unsuitable for use in humans, there is still need to identify more potent drugs. Here, we assessed the therapeutic power of the pan-HDACi JNJ-26481585 for SMA, which is currently used in various clinical cancer trials. When administered for 64 h at 100 nM, JNJ-26481585 upregulated SMN levels in SMA fibroblast cell lines, including those from non-responders to valproic acid. Oral treatment of Taiwanese SMA mice and control littermates starting at P0 showed no overt extension of lifespan, despite mild improvements in motor abilities and weight progression. Many treated and untreated animals showed a very rapid decline or unexpected sudden death. We performed exploratory autopsy and histological assessment at different disease stages and found consistent abnormalities in the intestine, heart and lung and skeletal muscle vasculature of SMA animals, which were not prevented by JNJ-26481585 treatment. Interestingly, some of these features may be only indirectly caused by α-motoneuron function loss but may be major life-limiting factors in the course of disease. A better understanding of - primary or secondary - non-neuromuscular organ involvement in SMA patients may improve standard of care and may lead to reassessment of how to investigate SMA patients clinically.

  17. The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice.

    PubMed

    Wen, Paul H; Hof, Patrick R; Chen, Xiaoping; Gluck, Karen; Austin, Gregory; Younkin, Steven G; Younkin, Linda H; DeGasperi, Rita; Gama Sosa, Miguel A; Robakis, Nikolaos K; Haroutunian, Vahram; Elder, Gregory A

    2004-08-01

    The functions of presenilin 1 (PS1) and how PS1 mutations cause familial Alzheimer's disease (FAD) are incompletely understood. PS1 expression is essential for neurogenesis during embryonic development and may also influence neurogenesis in adult brain. We examined how increasing PS1 expression or expressing an FAD mutant would affect neurogenesis in the adult hippocampus. A neuron-specific enolase (NSE) promoter was used to drive neuronal overexpression of either wild-type human PS1 or the FAD mutant P117L in transgenic mice, and the animals were studied under standard-housing conditions or after environmental enrichment. As judged by bromodeoxyuridine (BrdU) labeling, neural progenitor proliferation rate was mostly unaffected by increasing expression of either wild-type or FAD mutant PS1. However, in both housing conditions, the FAD mutant impaired the survival of BrdU-labeled neural progenitor cells leading to fewer new beta-III-tubulin-immunoreactive neurons being generated in FAD mutant animals during the 4-week postlabeling period. The effect was FAD mutant specific in that neural progenitor survival and differentiation in mice overexpressing wild-type human PS1 were similar to nontransgenic controls. Two additional lines of PS1 wild-type and FAD mutant transgenic mice showed similar changes indicating that the effects were not integration site-dependent. These studies demonstrate that a PS1 FAD mutant impairs new neuron production in adult hippocampus by decreasing neural progenitor survival. They also identify a new mechanism whereby PS1 FAD mutants may impair normal neuronal function and may have implications for the physiological functioning of the hippocampus in FAD.

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

    PubMed

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

    2013-11-27

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

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

    PubMed Central

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

    2015-01-01

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

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

    EPA Science Inventory

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

  1. T cells from baxalpha transgenic mice show accelerated apoptosis in response to stimuli but do not show restored DNA damage-induced cell death in the absence of p53.

    PubMed Central

    Brady, H J; Salomons, G S; Bobeldijk, R C; Berns, A J

    1996-01-01

    Baxalpha was isolated due to its interaction with Bcl-2. Baxalpha overexpression in an interleukin (IL)-3 dependent cell line accelerates apoptosis upon removal of the cytokine. The ratio of Baxalpha to Bcl-2 appears to be crucial for the effect. To study the action of the bax gene product in vivo, we have generated transgenic mice overexpressing Baxalpha specifically in T cells. Such T cells show accelerated apoptosis in response to gamma-radiation, dexamethasone and etoposide. By crossing baxalpha mice with bcl-2 transgenics we show that the critical nature of the Baxalpha:Bcl-2 ratio holds in primary T cells and that it can be manipulated to elicit a strong response to previously resisted stimuli. p53 has a role in the regulation of apoptosis in response to DNA-damaging agents. p53 directly activates transcription of the bax gene. The presence of the baxalpha transgene accelerated apoptosis in thymocytes from both p53-l- and p53+l- mice in response to dexamethasone. Thymocytes from p53-l- mice with the baxalpha transgene showed similar resistance to apoptosis by DNA-damaging agents as did p53-l- mice without the transgene. Baxalpha overexpression alone cannot restore the DNA damage apoptosis pathway, suggesting that p53 is required to induce or activate other factor(s) to reconstitute the response fully. Images PMID:8635454

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

    PubMed

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

    2016-01-01

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

  3. THE ANABOLIC STEROIDS TESTOSTERONE PROPIONATE AND NANDROLONE, BUT NOT 17α-METHYLTESTOSTERONE, INDUCE CONDITIONED PLACE PREFERENCE IN ADULT MICE

    PubMed Central

    Parrilla-Carrero, Jeffrey; Figueroa, Orialis; Lugo, Alejandro; García-Sosa, Rebecca; Brito-Vargas, Paul; Cruz, Beatriz; Rivera, Melanis; Barreto-Estrada, Jennifer L.

    2009-01-01

    Anabolic androgenic steroids (AAS) are often misused by adolescents and athletes. Their effects vary according to chemical structure and metabolism, route of administration, and AAS regimen. In this study, adult C57Bl/6 male mice were systemically exposed to testosterone propionate (TP), nandrolone or 17α-methyltestosterone (17α-meT), type I, type II and type III AAS, respectively, in order to determine the hedonic or aversive properties of each drug. For this purpose, the conditioned place preference (CPP) test was employed at three different AAS doses (0.075, 0.75 and 7.5 mg/kg). Other behavioral domains monitored were light-dark transitions (side changes) and general activity. TP shifted place preference at all doses tested, and nandrolone shifted place preference at 0.75 and 7.5mg/kg, but not at 0.075 mg/kg, the lower dose tested. Conversely, mice receiving 17α-meT did not show alteration in the preference score. The lower dose of nandrolone did modify exploratory based-anxiety showing a decrease in light-dark transitions if compared to vehicle-treated animals, while mice treated with TP or 17α-meT were not affected. Our data suggest that when studying hedonic and rewarding properties of synthetic androgens, distinction has to be made based on type of AAS and metabolism. PMID:19028026

  4. The anabolic steroids testosterone propionate and nandrolone, but not 17alpha-methyltestosterone, induce conditioned place preference in adult mice.

    PubMed

    Parrilla-Carrero, Jeffrey; Figueroa, Orialis; Lugo, Alejandro; García-Sosa, Rebecca; Brito-Vargas, Paul; Cruz, Beatriz; Rivera, Mélanis; Barreto-Estrada, Jennifer L

    2009-02-01

    Anabolic androgenic steroids (AAS) are often misused by adolescents and athletes. Their effects vary according to chemical structure and metabolism, route of administration, and AAS regimen. In this study, adult C57Bl/6 male mice were systemically exposed to testosterone propionate (TP), nandrolone or 17alpha-methyltestosterone (17alpha-meT), type I, type II and type III AAS, respectively, in order to determine the hedonic or aversive properties of each drug. For this purpose, the conditioned place preference (CPP) test was employed at three different AAS doses (0.075, 0.75 and 7.5 mg/kg). Other behavioral domains monitored were light-dark transitions (side changes) and general activity. TP shifted place preference at all doses tested, and nandrolone shifted place preference at 0.75 and 7.5 mg/kg, but not at 0.075 mg/kg, the lower dose tested. Conversely, mice receiving 17alpha-meT did not show alteration in the preference score. The lower dose of nandrolone did modify exploratory-based anxiety showing a decrease in light-dark transitions if compared to vehicle-treated animals, while mice treated with TP or 17alpha-meT were not affected. Our data suggest that when studying hedonic and rewarding properties of synthetic androgens, distinction has to be made based on type of AAS and metabolism.

  5. Protocol to Isolate a Large Amount of Functional Oligodendrocyte Precursor Cells from the Cerebral Cortex of Adult Mice and Humans

    PubMed Central

    Medina-Rodríguez, Eva María; Arenzana, Francisco Javier; Bribián, Ana; de Castro, Fernando

    2013-01-01

    During development, oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), a cell type that is a significant proportion of the total cells (3-8%) in the adult central nervous system (CNS) of both rodents and humans. Adult OPCs are responsible for the spontaneous remyelination that occurs in demyelinating diseases like Multiple Sclerosis (MS) and they constitute an interesting source of cells for regenerative therapy in such conditions. However, there is little data regarding the neurobiology of adult OPCs isolated from mice since an efficient method to isolate them has yet to be established. We have designed a protocol to obtain viable adult OPCs from the cerebral cortex of different mouse strains and we have compared its efficiency with other well-known methods. In addition, we show that this protocol is also useful to isolate functional OPCs from human brain biopsies. Using this method we can isolate primary cortical OPCs in sufficient quantities so as to be able to study their survival, maturation and function, and to facilitate an evaluation of their utility in myelin repair. PMID:24303061

  6. Properties of doublecortin-(DCX)-expressing cells in the piriform cortex compared to the neurogenic dentate gyrus of adult mice.

    PubMed

    Klempin, Friederike; Kronenberg, Golo; Cheung, Giselle; Kettenmann, Helmut; Kempermann, Gerd

    2011-01-01

    The piriform cortex receives input from the olfactory bulb and (via the entorhinal cortex) sends efferents to the hippocampus, thereby connecting the two canonical neurogenic regions of the adult rodent brain. Doublecortin (DCX) is a cytoskeleton-associated protein that is expressed transiently in the course of adult neurogenesis. Interestingly, the adult piriform cortex, which is usually considered non-neurogenic (even though some reports exist that state otherwise), also contains an abundant population of DCX-positive cells. We asked how similar these cells would be to DCX-positive cells in the course of adult hippocampal neurogenesis. Using BAC-generated transgenic mice that express GFP under the DCX promoter, we studied DCX-expression and electrophysiological properties of DCX-positive cells in the mouse piriform cortex in comparison with the dentate gyrus. While one class of cells in the piriform cortex indeed showed features similar to newly generated immature granule neurons, the majority of DCX cells in the piriform cortex was mature and revealed large Na+ currents and multiple action potentials. Furthermore, when proliferative activity was assessed, we found that all DCX-expressing cells in the piriform cortex were strictly postmitotic, suggesting that no DCX-positive "neuroblasts" exist here as they do in the dentate gyrus. We conclude that DCX in the piriform cortex marks a unique population of postmitotic neurons with a subpopulation that retains immature characteristics associated with synaptic plasticity. DCX is thus, per se, no marker of neurogenesis but might be associated more broadly with plasticity.

  7. Young adult donor bone marrow infusions into female mice postpone age-related reproductive failure and improve offspring survival.

    PubMed

    Selesniemi, Kaisa; Lee, Ho-Joon; Niikura, Teruko; Tilly, Jonathan L

    2008-11-14

    The female reproductive axis is the first major organ system of the body to fail with advancing age. In addition to a permanent cessation of fertile potential, the loss of cyclic ovarian function in humans heralds the onset of menopause, which in turn underlies the emergence of a diverse spectrum of health issues in aging women. Recently, it was reported that bone marrow (BM) transplantation (BMT) into adult female mice conditioned a week earlier with highly cytotoxic drugs rescues ovarian function and fertility. Herein we show in mice receiving no prior conditioning regimen that once-monthly infusions of BM-derived cells retrieved from young adult female donors bearing an enhanced green fluorescent protein (EGFP) transgene sustain the fertile potential of aging wild-type females long past their time of normal reproductive senescence. The fertility-promoting effects of female donor BM are observed regardless whether the infusions are initiated in young adult or middle-aged females. Although the mechanism by which BM infusions benefit the reproductive performance of aging females remains to be elucidated, the absence of EGFP-expressing offspring suggests that it does not depend on development of mature eggs derived from germline-committed cells in the donor marrow. However, donor BM-derived somatic cells accumulate in the recipients, indicating efficient donor cell engraftment without prior conditioning. These findings provide a strong impetus to further explore development of adult stem cell-based technologies to safely extend function of the female reproductive axis into advanced age without the need for toxic pre-conditioning protocols routinely used in other models of stem cell delivery.

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

    PubMed Central

    Capilla-Gonzalez, Vivian; Gil-Perotin, Sara; Ferragud, Antonio; Bonet-Ponce, Luis; Canales, Juan Jose; Garcia-Verdugo, Jose Manuel

    2012-01-01

    Background Previous studies have shown that prenatal exposure to the mutagen N-ethyl-N-nitrosourea (ENU), a N-nitroso compound (NOC) found in the environment, disrupts developmental neurogenesis and alters memory formation. Previously, we showed that postnatal ENU treatment induced lasting deficits in proliferation of neural progenitors in the subventricular zone (SVZ), the main neurogenic region in the adult mouse brain. The present study is aimed to examine, in mice exposed to ENU, both the structural features of adult neurogenic sites, incorporating the dentate gyrus (DG), and the behavioral performance in tasks sensitive to manipulations of adult neurogenesis. Methodology/Principal Findings 2-month old mice received 5 doses of ENU and were sacrificed 45 days after treatment. Then, an ultrastructural analysis of the SVZ and DG was performed to determine cellular composition in these regions, confirming a significant alteration. After bromodeoxyuridine injections, an S-phase exogenous marker, the immunohistochemical analysis revealed a deficit in proliferation and a decreased recruitment of newly generated cells in neurogenic areas of ENU-treated animals. Behavioral effects were also detected after ENU-exposure, observing impairment in odor discrimination task (habituation-dishabituation test) and a deficit in spatial memory (Barnes maze performance), two functions primarily related to the SVZ and the DG regions, respectively. Conclusions/Significance The results demonstrate that postnatal exposure to ENU produces severe disruption of adult neurogenesis in the SVZ and DG, as well as strong behavioral impairments. These findings highlight the potential risk of environmental NOC-exposure for the development of neural and behavioral deficits. PMID:22238669

  9. Characterization of juvenile and adult leaves of Eucalyptus globulus showing distinct heteroblastic development: photosynthesis and volatile isoprenoids.

    PubMed

    Velikova, V; Loreto, F; Brilli, F; Stefanov, D; Yordanov, I

    2008-01-01

    Heteroblastic Eucalyptus (Eucalyptus globulus L.) leaves were characterized for their functional diversity examining photosynthesis and photosynthesis limitations, transpiration, and the emission of isoprene and monoterpenes. In vivo and combined analyses of gas-exchange, chlorophyll fluorescence, and light absorbance at 830 nm were made on the adaxial and abaxial sides of juvenile and adult leaves. When adult leaves were reversed to illuminate the abaxial side, photosynthesis and isoprene emission were significantly lower than when the adaxial side was illuminated. Monoterpene emission, however, was independent on the side illuminated and similarly partitioned between the two leaf sides. The abaxial side of adult leaves showed less diffusive resistance to CO(2) acquisition by chloroplasts, but also lower ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) activity, than the adaxial leaf side. In juvenile leaves, photosynthesis, isoprene, and monoterpene emissions were similar when the adaxial or abaxial side was directly illuminated. In the abaxial side of juvenile leaves, photosynthesis did not match the rates attained by the other leaf types when exposed to elevated CO(2), which suggests the occurrence of a limitation of photosynthesis by ribulose bisphosphate (RuBP) regeneration. Accordingly, a reduced efficiency of both photosystems and a high non-radiative dissipation of energy was observed in the abaxial side of juvenile leaves. During light induction, the adaxial side of juvenile leaves also showed a reduced efficiency of photosystem II and a large non-radiative energy dissipation. Our report reveals distinct functional properties in Eucalyptus leaves. Juvenile leaves invest more carbon in isoprene, but not in monoterpenes, and have a lower water use efficiency than adult leaves. Under steady-state conditions, in adult leaves the isobilateral anatomy does not correspond to an equal functionality of the two sides, while in juvenile leaves the

  10. Improved function and proliferation of adult human beta cells engrafted in diabetic immunodeficient NOD-scid IL2rγnull mice treated with alogliptin

    PubMed Central

    Jurczyk, Agata; diIorio, Philip; Brostowin, Dean; Leehy, Linda; Yang, Chaoxing; Urano, Fumihiko; Harlan, David M; Shultz, Leonard D; Greiner, Dale L; Bortell, Rita

    2013-01-01

    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 treated with alogliptin show improved human insulin secretion and beta cell proliferation compared to control mice engrafted with the same donor islets. Immunodeficient mice transplanted with human islets provide a useful model to interrogate potential therapies to improve human islet function and survival in vivo. PMID:24376359

  11. Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence.

    PubMed

    Long, Leonora E; Chesworth, Rose; Huang, Xu-Feng; McGregor, Iain S; Arnold, Jonathon C; Karl, Tim

    2013-02-01

    Heavy cannabis abuse increases the risk of developing schizophrenia. Adolescents appear particularly vulnerable to the development of psychosis-like symptoms after cannabis use. To test whether the schizophrenia candidate gene neuregulin 1 (NRG1) modulates the effects of cannabinoids in adolescence, we tested male adolescent heterozygous transmembrane domain Nrg1 mutant (Nrg1 TM HET) mice and wild type-like littermates (WT) for their neurobehavioural response to repeated Δ(9)-tetrahydrocannabinol (THC, 10 mg/kg i.p. for 21 d starting on post-natal day 31). During treatment and 48 h after treatment withdrawal, we assessed several behavioural parameters relevant to schizophrenia. After behavioural testing we measured autoradiographic CB(1), 5-HT(2A) and NMDA receptor binding. The hyperlocomotor phenotype typical of Nrg1 mutants emerged after drug withdrawal and was more pronounced in vehicle than THC-treated Nrg1 TM HET mice. All mice were equally sensitive to THC-induced suppression of locomotion. However, mutant mice appeared protected against inhibiting effects of repeated THC on investigative social behaviours. Neither THC nor Nrg1 genotype altered prepulse inhibition. Repeated adolescent THC promoted differential effects on CB(1) and 5-HT(2A) receptor binding in the substantia nigra and insular cortex respectively, decreasing binding in WT while increasing it in Nrg1 TM HET mice. THC also selectively affected 5-HT(2A) receptor binding in several other regions in WT mice, whereas NMDA receptor binding was only affected in mutant mice. Overall, Nrg1 mutation does not appear to increase the induction of psychotomimetic symptoms by repeated adolescent THC exposure but may attenuate some of its actions on social behaviour and schizophrenia-relevant neurotransmitter receptor profiles.

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

    PubMed Central

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

    2014-01-01

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

  13. Cerebral Cell Renewal in Adult Mice Controls the Onset of Obesity

    PubMed Central

    Gouazé, Alexandra; Brenachot, Xavier; Rigault, Caroline; Krezymon, Alice; Rauch, Camille; Nédélec, Emmanuelle; Lemoine, Aleth; Gascuel, Jean; Bauer, Sylvian; Pénicaud, Luc; Benani, Alexandre

    2013-01-01

    The hypothalamus plays a crucial role in the control of the energy balance and also retains neurogenic potential into adulthood. Recent studies have reported the severe alteration of the cell turn-over in the hypothalamus of obese animals and it has been proposed that a neurogenic deficiency in the hypothalamus could be involved in the development of obesity. To explore this possibility, we examined hypothalamic cell renewal during the homeostatic response to dietary fat in mice, i.e., at the onset of diet-induced obesity. We found that switching to high-fat diet (HFD) accelerated cell renewal in the hypothalamus through a local, rapid and transient increase in cell proliferation, peaking three days after introducing the HFD. Blocking HFD-induced cell proliferation by central delivery of an antimitotic drug prevented the food intake normalization observed after HFD introduction and accelerated the onset of obesity. This result showed that HFD-induced dividing brain cells supported an adaptive anorectic function. In addition, we found that the percentage of newly generated neurons adopting a POMC-phenotype in the arcuate nucleus was increased by HFD. This observation suggested that the maturation of neurons in feeding circuits was nutritionally regulated to adjust future energy intake. Taken together, these results showed that adult cerebral cell renewal was remarkably responsive to nutritional conditions. This constituted a physiological trait required to prevent severe weight gain under HFD. Hence this report highlighted the amazing plasticity of feeding circuits and brought new insights into our understanding of the nutritional regulation of the energy balance. PMID:23967273

  14. Transgenic mice overexpressing glia maturation factor-β, an oxidative stress inducible gene, show premature aging due to Zmpste24 down-regulation.

    PubMed

    Imai, Rika; Asai, Kanae; Hanai, Jun-ichi; Takenaka, Masaru

    2015-07-01

    Glia Maturation Factor-β (GMF), a brain specific protein, is induced by proteinuria in renal tubules. Ectopic GMF overexpression causes apoptosisin vitro via cellular vulnerability to oxidative stress. In order to examine the roles of GMF in non-brain tissue, we constructed transgenic mice overexpressing GMF (GMF-TG). The GMF-TG mice exhibited appearance phenotypes associated with premature aging. The GMF-TG mice also demonstrated short lifespans and reduced hair regrowth, suggesting an accelerated aging process. The production of an abnormal lamin A, a nuclear envelope protein, plays a causal role in both normal aging and accelerated aging diseases, known as laminopathies. Importantly, we identified the abnormal lamin A (prelamin A), accompanied by a down-regulation of a lamin A processing enzyme (Zmpste24) in the kidney of the GMF-TG mice. The GMF-TG mice showed accelerated aging in the kidney, compared with wild-type mice, showing increased TGF-β1, CTGF gene and serum creatinine. The gene expression of p21/waf1 was increased at an earlier stage of life, at 10 weeks, which was in turn down-regulated at a later stage, at 60 weeks. In conclusion, we propose that GMF-TG mice might be a novel mouse model of accelerated aging, due to the abnormal lamin A.

  15. Lectin-like, oxidized low-density lipoprotein receptor-1-deficient mice show resistance to age-related knee osteoarthritis

    PubMed Central

    Hashimoto, Kazuhiko; Oda, Yutaka; Nakamura, Fumihisa; Kakinoki, Ryosuke; Akagi, Masao

    2017-01-01

    The lectin-like, oxidized low-density lipoprotein (ox-LDL) receptor-1 (LOX-1)/ox-LDL system contributes to atherosclerosis and may be involved in cartilage degeneration. The purpose of this study was to determine whether the LOX-1/ox-LDL system contributes to age-related osteoarthritis (OA) in vivo, using LOX-1 knockout (LOX-1 KO) mice. Knee cartilage from 6, 12, and 18-month old (n = 10/group) C57Bl/6 wild-type (WT) and LOX-1 KO mice was evaluated by determining the Osteoarthritis Research Society International (OARSI) score of Safranin-O stained samples. The prevalence of knee OA in both mouse strains was also investigated. Expression levels of LOX-1, ox-LDL, runt-related transcription factor-2 (Runx2), type-X collagen (COL X), and matrix metalloproteinase-13 (MMP-13) in the articular chondrocytes were analyzed immunohistologically. No significant difference was observed in the mean scores of WT (2.00±0.61) and LOX-1 KO mice (2.00±0.49) at 6 months of age (P=1.00, n=10). At 12 and 18 months of age, the mean scores of LOX-1 KO mice (3.75±0.93 and 5.50±0.78) were significantly lower than those of WT mice (5.25±1.14 and 9.00±1.01; P<0.001 in both cases; n=10). The prevalence of OA in LOX-1 KO mice was lower than that in WT mice at 12 and 18 months of age (40 vs 70%, 70 vs 90%, respectively; n=10). The expression levels of Runx2, COL X, and MMP-13 in articular chondrocytes significantly decreased in LOX-1 KO, mice compared with those in WT mice. The study indicated that the LOX-1/ox-LDL system in chondrocytes plays a role in the pathogenesis of age-related knee OA, which is potentially a target for preventing OA progression. PMID:28348422

  16. Repeated dose liver micronucleus assay using adult mice with multiple genotoxicity assays concurrently performed as a combination test.

    PubMed

    Hagio, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Ogawa, Izumi

    2014-06-01

    Recently, the liver micronucleus (MN) assay using young adult rats with repeated administrations has been investigated by employing a new method without partial hepatectomy or in situcollagenase perfusion as the repeated dose liver MN (RDLMN) assay by Narumi et al. (2012). In our study, in order to investigate the possibility of the RDLMN assay using young adult mice instead of rats and the feasibility of employing some genotoxicity assays along with the RDLMN assay as a combination test, two genotoxic carcinogens (N,N-diethylnitrosoamine (DEN) and cisplatin (CIS)) and a nongenotoxic carcinogen (phenobarbital sodium (PHE)) were administered to mice for 15 or 29 days. Then, the liver MN assay, peripheral blood (PB) MN assay and comet assay using the liver and kidney were concurrently performed as a combination test. DEN showed positive responses to all endpoints except MN induction in PB after 15 days of repeat administration. A cross-linking agent, CIS, showed MN induction in liver after 29 days of repeat administration, and in PB after 15 and 29 days of repeat administration, although the comet assay yielded negative responses for both organs at both sampling times. PHE yielded negative responses for all endpoints. In conclusion, it is suggested that the RDLMN assay using mice is a feasible method to be integrated into the general repeated toxicity test along with the combination assays, i.e., comet assay or PB MN assay, which would help in risk assessment for carcinogenicity by comparing the results of combination assays with each other.

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

    PubMed Central

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

    1988-01-01

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

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

    PubMed Central

    Schellino, Roberta; Trova, Sara; Cimino, Irene; Farinetti, Alice; Jongbloets, Bart C.; Pasterkamp, R. Jeroen; Panzica, Giancarlo; Giacobini, Paolo; De Marchis, Silvia; Peretto, Paolo

    2016-01-01

    Opposite-sex attraction in most mammals depends on the fine-tuned integration of pheromonal stimuli with gonadal hormones in the brain circuits underlying sexual behaviour. Neural activity in these circuits is regulated by sensory processing in the accessory olfactory bulb (AOB), the first central station of the vomeronasal system. Recent evidence indicates adult neurogenesis in the AOB is involved in sex behaviour; however, the mechanisms underlying this function are unknown. By using Semaphorin 7A knockout (Sema7A ko) mice, which show a reduced number of gonadotropin-releasing-hormone neurons, small testicles and subfertility, and wild-type males castrated during adulthood, we demonstrate that the level of circulating testosterone regulates the sex-specific control of AOB neurogenesis and the vomeronasal system activation, which influences opposite-sex cue preference/attraction in mice. Overall, these data highlight adult neurogenesis as a hub for the integration of pheromonal and hormonal cues that control sex-specific responses in brain circuits. PMID:27782186

  19. Embryonic interneurons from the medial, but not the caudal ganglionic eminence trigger ocular dominance plasticity in adult mice.

    PubMed

    Isstas, Marcel; Teichert, Manuel; Bolz, Jürgen; Lehmann, Konrad

    2017-01-01

    The maturation of cortical inhibition provided by parvalbumin-containing basket cells derived from the medial ganglionic eminence (MGE) is a key event in starting the enhanced visual cortical plasticity during the critical period. Although it is generally assumed that a further increase in inhibition closes the critical period again, it was recently shown that embryonic interneurons derived from the MGE can induce an additional, artificial critical period when injected into the visual cortex of young mice. It has, however, remained open whether this effect was indeed specific for MGE-derived cells, and whether critical period-like plasticity could also be induced in fully adult animals. To clarify these issues, we injected explants from either the MGE or the caudal ganglionic eminence (CGE) into the visual cortices of fully adult mice, and performed monocular deprivation 33 days later for 4 days. Animals implanted with MGE cells, but not with CGE cells, showed marked ocular dominance plasticity. Immunohistochemistry confirmed that the injected cells from both sources migrated far in the host cortex, that most developed into neurons producing GABA, and that only cells from the MGE expressed parvalbumin. Thus, our results confirm that the plasticity-inducing effect of embryonic interneurons is specific for cells from the MGE, and is independent of the host animal's age.

  20. Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice.

    PubMed

    Nomura, J; Jaaro-Peled, H; Lewis, E; Nuñez-Abades, P; Huppe-Gourgues, F; Cash-Padgett, T; Emiliani, F; Kondo, M A; Furuya, A; Landek-Salgado, M A; Ayhan, Y; Kamiya, A; Takumi, T; Huganir, R; Pletnikov, M; O'Donnell, P; Sawa, A

    2016-03-01

    NMDA glutamate receptors have key roles in brain development, function and dysfunction. Regulatory roles of D-serine in NMDA receptor-mediated synaptic plasticity have been reported. Nonetheless, it is unclear whether and how neonatal deficits in NMDA-receptor-mediated neurotransmission affect adult brain functions and behavior. Likewise, the role of D-serine during development remains elusive. Here we report behavioral and electrophysiological deficits associated with the frontal cortex in Pick1 knockout mice, which show D-serine deficits in a neonatal- and forebrain-specific manner. The pathological manifestations observed in adult Pick1 mice are rescued by transient neonatal supplementation of D-serine, but not by a similar treatment in adulthood. These results indicate a role for D-serine in neurodevelopment and provide novel insights on how we interpret data of psychiatric genetics, indicating the involvement of genes associated with D-serine synthesis and degradation, as well as how we consider animal models with neonatal application of NMDA receptor antagonists.

  1. Pharmacological and Genetic Manipulation of p53 in Brown Fat at Adult But Not Embryonic Stages Regulates Thermogenesis and Body Weight in Male Mice.

    PubMed

    Al-Massadi, Omar; Porteiro, Begoña; Kuhlow, Doreen; Köhler, Markus; Gonzalez-Rellan, María J; Garcia-Lavandeira, Montserrat; Díaz-Rodríguez, Esther; Quiñones, Mar; Senra, Ana; Alvarez, Clara V; López, Miguel; Diéguez, Carlos; Schulz, Tim J; Nogueiras, Rubén

    2016-07-01

    p53 is a well-known tumor suppressor that plays multiple biological roles, including the capacity to modulate metabolism at different levels. However, its metabolic role in brown adipose tissue (BAT) remains largely unknown. Herein we sought to investigate the physiological role of endogenous p53 in BAT and its implication on BAT thermogenic activity and energy balance. To this end, we generated and characterized global p53-null mice and mice lacking p53 specifically in BAT. Additionally we performed gain-and-loss-of-function experiments in the BAT of adult mice using virogenetic and pharmacological approaches. BAT was collected and analyzed by immunohistochemistry, thermography, real-time PCR, and Western blot. p53-deficient mice were resistant to diet-induced obesity due to increased energy expenditure and BAT activity. However, the deletion of p53 in BAT using a Myf5-Cre driven p53 knockout did not show any changes in body weight or the expression of thermogenic markers. The acute inhibition of p53 in the BAT of adult mice slightly increased body weight and inhibited BAT thermogenesis, whereas its overexpression in the BAT of diet-induced obese mice reduced body weight and increased thermogenesis. On the other hand, pharmacological activation of p53 improves body weight gain due to increased BAT thermogenesis by sympathetic nervous system in obese adult wild-type mice but not in p53(-/-) animals. These results reveal that p53 regulates BAT metabolism by coordinating body weight and thermogenesis, but these metabolic actions are tissue specific and also dependent on the developmental stage.

  2. Early-life stress-induced anxiety-related behavior in adult mice partially requires forebrain corticotropin-releasing hormone receptor 1.

    PubMed

    Wang, Xiao-Dong; Labermaier, Christiana; Holsboer, Florian; Wurst, Wolfgang; Deussing, Jan M; Müller, Marianne B; Schmidt, Mathias V

    2012-08-01

    Early-life stress may lead to persistent changes in central corticotropin-releasing hormone (CRH) and the CRH receptor 1 (CRHR1) system that modulates anxiety-related behavior. However, it remains unknown whether CRH-CRHR1 signaling is involved in early-life stress-induced anxiety-related behavior in adult animals. In the present study, we used conditional forebrain CRHR1 knockout (CRHR1-CKO) mice and examined the potential role of forebrain CRHR1 in the anxiogenic effects of early-life stress. As adults, wild-type mice that received unstable maternal care during the first postnatal week showed reduced body weight gain and increased anxiety levels in the open field test, which were prevented in stressed CRHR1-CKO mice. In the light-dark box test, control CRHR1-CKO mice were less anxious, but early-life stress increased anxiety levels in both wild-type and CRHR1-CKO mice. In the elevated plus maze test, early-life stress had only subtle effects on anxiety-related behavior. Moreover, early-life stress did not alter the basal home cage activity and gene expression levels of key hypothalamic-pituitary-adrenal axis regulators in adult wild-type and CRHR1-CKO mice, but enhanced neuroendocrine reactivity to acute immobilization stress in CRHR1-CKO mice. Our findings highlight the importance of forebrain CRHR1 in modulating some of the anxiogenic effects of early-life stress, and suggest that other neural circuits are also involved in the programming effects of early-life stress on anxiety-related behavior.

  3. The ependymal region of the adult human spinal cord differs from other species and shows ependymoma-like features.

    PubMed

    Garcia-Ovejero, Daniel; Arevalo-Martin, Angel; Paniagua-Torija, Beatriz; Florensa-Vila, José; Ferrer, Isidro; Grassner, Lukas; Molina-Holgado, Eduardo

    2015-06-01

    Several laboratories have described the existence of undifferentiated precursor cells that may act like stem cells in the ependyma of the rodent spinal cord. However, there are reports showing that this region is occluded and disassembled in humans after the second decade of life, although this has been largely ignored or interpreted as a post-mortem artefact. To gain insight into the patency, actual structure, and molecular properties of the adult human spinal cord ependymal region, we followed three approaches: (i) with MRI, we estimated the central canal patency in 59 control subjects, 99 patients with traumatic spinal cord injury, and 26 patients with non-traumatic spinal cord injuries. We observed that the central canal is absent from the vast majority of individuals beyond the age of 18 years, gender-independently, throughout the entire length of the spinal cord, both in healthy controls and after injury; (ii) with histology and immunohistochemistry, we describe morphological properties of the non-lesioned ependymal region, which showed the presence of perivascular pseudorosettes, a common feature of ependymoma; and (iii) with laser capture microdissection, followed by TaqMan® low density arrays, we studied the gene expression profile of the ependymal region and found that it is mainly enriched in genes compatible with a low grade or quiescent ependymoma (53 genes); this region is enriched only in 14 genes related to neurogenic niches. In summary, we demonstrate here that the central canal is mainly absent in the adult human spinal cord and is replaced by a structure morphologically and molecularly different from that described for rodents and other primates. The presented data suggest that the ependymal region is more likely to be reminiscent of a low-grade ependymoma. Therefore, a direct translation to adult human patients of an eventual therapeutic potential of this region based on animal models should be approached with caution.

  4. The ependymal region of the adult human spinal cord differs from other species and shows ependymoma-like features

    PubMed Central

    Arevalo-Martin, Angel; Paniagua-Torija, Beatriz; Florensa-Vila, José; Ferrer, Isidro; Grassner, Lukas; Molina-Holgado, Eduardo

    2015-01-01

    Several laboratories have described the existence of undifferentiated precursor cells that may act like stem cells in the ependyma of the rodent spinal cord. However, there are reports showing that this region is occluded and disassembled in humans after the second decade of life, although this has been largely ignored or interpreted as a post-mortem artefact. To gain insight into the patency, actual structure, and molecular properties of the adult human spinal cord ependymal region, we followed three approaches: (i) with MRI, we estimated the central canal patency in 59 control subjects, 99 patients with traumatic spinal cord injury, and 26 patients with non-traumatic spinal cord injuries. We observed that the central canal is absent from the vast majority of individuals beyond the age of 18 years, gender-independently, throughout the entire length of the spinal cord, both in healthy controls and after injury; (ii) with histology and immunohistochemistry, we describe morphological properties of the non-lesioned ependymal region, which showed the presence of perivascular pseudorosettes, a common feature of ependymoma; and (iii) with laser capture microdissection, followed by TaqMan® low density arrays, we studied the gene expression profile of the ependymal region and found that it is mainly enriched in genes compatible with a low grade or quiescent ependymoma (53 genes); this region is enriched only in 14 genes related to neurogenic niches. In summary, we demonstrate here that the central canal is mainly absent in the adult human spinal cord and is replaced by a structure morphologically and molecularly different from that described for rodents and other primates. The presented data suggest that the ependymal region is more likely to be reminiscent of a low-grade ependymoma. Therefore, a direct translation to adult human patients of an eventual therapeutic potential of this region based on animal models should be approached with caution. PMID:25882650

  5. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice.

    PubMed

    Han, Xiaoning; Chen, Michael; Wang, Fushun; Windrem, Martha; Wang, Su; Shanz, Steven; Xu, Qiwu; Oberheim, Nancy Ann; Bekar, Lane; Betstadt, Sarah; Silva, Alcino J; Takano, Takahiro; Goldman, Steven A; Nedergaard, Maiken

    2013-03-07

    Human astrocytes are larger and more complex than those of infraprimate mammals, suggesting that their role in neural processing has expanded with evolution. To assess the cell-autonomous and species-selective properties of human glia, we engrafted human glial progenitor cells (GPCs) into neonatal immunodeficient mice. Upon maturation, the recipient brains exhibited large numbers and high proportions of both human glial progenitors and astrocytes. The engrafted human glia were gap-junction-coupled to host astroglia, yet retained the size and pleomorphism of hominid astroglia, and propagated Ca2+ signals 3-fold faster than their hosts. Long-term potentiation (LTP) was sharply enhanced in the human glial chimeric mice, as was their learning, as assessed by Barnes maze navigation, object-location memory, and both contextual and tone fear conditioning. Mice allografted with murine GPCs showed no enhancement of either LTP or learning. These findings indicate that human glia differentially enhance both activity-dependent plasticity and learning in mice.

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    Mahmoud, Yomna Ibrahim

    2012-07-01

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

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

    PubMed

    Angelucci, Francesco; Fiore, Marco; Ricci, Enzo; Padua, Luca; Sabino, Andrea; Tonali, Pietro Attilio

    2007-09-01

    It has been shown that music might be able to improve mood state in people affected by psychiatric disorders, ameliorate cognitive deficits in people with dementia and increase motor coordination in Parkinson patients. Robust experimental evidence explaining the central effects of music, however, is missing. This study was designed to investigate the effect of music on brain neurotrophin production and behavior in the mouse. We exposed young adult mice to music with a slow rhythm (6 h/day; mild sound pressure levels, between 50 and 60 db) for 21 consecutive days. At the end of the treatment, mice were tested for passive avoidance learning and then killed for analysis of brain-derived neurotrophic factor (BDNF) and nerve growth factor with enzyme-linked immunosorbent assay (ELISA) in selected brain regions. We found that music-exposed mice showed increased BDNF, but not nerve growth factor in the hippocampus. Furthermore, we observed that music exposure significantly enhanced learning performance, as measured by the passive avoidance test. Our results demonstrate that exposure to music can modulate the activity of the hippocampus by influencing BDNF production. Our findings also suggest that music exposure might be of help in several central nervous system pathologies.

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

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  11. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan

    PubMed Central

    Weismann, Cara M.; Ferreira, Jennifer; Keeler, Allison M.; Su, Qin; Qui, Linghua; Shaffer, Scott A.; Xu, Zuoshang; Gao, Guangping; Sena-Esteves, Miguel

    2015-01-01

    GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease where GLB1 gene mutations result in a reduction or absence of lysosomal acid β-galactosidase (βgal) activity. βgal deficiency leads to accumulation of GM1-ganglioside in the central nervous system (CNS). GM1 is characterized by progressive neurological decline resulting in generalized paralysis, extreme emaciation and death. In this study, we assessed the therapeutic efficacy of an adeno-associated virus (AAV) 9-mβgal vector infused systemically in adult GM1 mice (βGal−/−) at 1 × 1011 or 3 × 1011 vector genomes (vg). Biochemical analysis of AAV9-treated GM1 mice showed high βGal activity in liver and serum. Moderate βGal levels throughout CNS resulted in a 36–76% reduction in GM1-ganglioside content in the brain and 75–86% in the spinal cord. Histological analyses of the CNS of animals treated with 3 × 1011 vg dose revealed increased presence of βgal and clearance of lysosomal storage throughout cortex, hippocampus, brainstem and spinal cord. Storage reduction in these regions was accompanied by a marked decrease in astrogliosis. AAV9 treatment resulted in improved performance in multiple tests of motor function and behavior. Also the majority of GM1 mice in the 3 × 1011 vg cohort retained ambulation and rearing despite reaching the humane endpoint due to weight loss. Importantly, the median survival of AAV9 treatment groups (316–576 days) was significantly increased over controls (250–264 days). This study shows that moderate widespread expression of βgal in the CNS of GM1 gangliosidosis mice is sufficient to achieve significant biochemical impact with phenotypic amelioration and extension in lifespan. PMID:25964428

  12. Systemic AAV9 gene transfer in adult GM1 gangliosidosis mice reduces lysosomal storage in CNS and extends lifespan.

    PubMed

    Weismann, Cara M; Ferreira, Jennifer; Keeler, Allison M; Su, Qin; Qui, Linghua; Shaffer, Scott A; Xu, Zuoshang; Gao, Guangping; Sena-Esteves, Miguel

    2015-08-01

    GM1 gangliosidosis (GM1) is an autosomal recessive lysosomal storage disease where GLB1 gene mutations result in a reduction or absence of lysosomal acid β-galactosidase (βgal) activity. βgal deficiency leads to accumulation of GM1-ganglioside in the central nervous system (CNS). GM1 is characterized by progressive neurological decline resulting in generalized paralysis, extreme emaciation and death. In this study, we assessed the therapeutic efficacy of an adeno-associated virus (AAV) 9-mβgal vector infused systemically in adult GM1 mice (βGal(-/-)) at 1 × 10(11) or 3 × 10(11) vector genomes (vg). Biochemical analysis of AAV9-treated GM1 mice showed high βGal activity in liver and serum. Moderate βGal levels throughout CNS resulted in a 36-76% reduction in GM1-ganglioside content in the brain and 75-86% in the spinal cord. Histological analyses of the CNS of animals treated with 3 × 10(11) vg dose revealed increased presence of βgal and clearance of lysosomal storage throughout cortex, hippocampus, brainstem and spinal cord. Storage reduction in these regions was accompanied by a marked decrease in astrogliosis. AAV9 treatment resulted in improved performance in multiple tests of motor function and behavior. Also the majority of GM1 mice in the 3 × 10(11) vg cohort retained ambulation and rearing despite reaching the humane endpoint due to weight loss. Importantly, the median survival of AAV9 treatment groups (316-576 days) was significantly increased over controls (250-264 days). This study shows that moderate widespread expression of βgal in the CNS of GM1 gangliosidosis mice is sufficient to achieve significant biochemical impact with phenotypic amelioration and extension in lifespan.

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

    PubMed Central

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

    2008-01-01

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

  14. Forebrain-specific constitutively active CaMKKα transgenic mice show deficits in hippocampus-dependent long-term memory.

    PubMed

    Kaitsuka, Taku; Li, Sheng-Tian; Nakamura, Kenji; Takao, Keizo; Miyakawa, Tsuyoshi; Matsushita, Masayuki

    2011-09-01

    The Ca(2+)/calmodulin (CaM) kinase cascade is activated by Ca(2+) influx through the voltage-dependent Ca(2+) channels and the NMDA receptor. CaM kinase kinase (CaMKK), the most upstream kinase of the CaM kinase cascade, phosphorylates and activates both CaM kinase I (CaMKI) and CaMKIV, resulting in activation of cyclic AMP-responsive element binding protein (CREB)-dependent gene transcription. Using transgenic techniques, we created mutant mice in which a constitutively active form of CaMKK1, the autoinhibitory domain truncated protein, is over-expressed specifically in the forebrain. In these mice, although performance was normal in basal activity and short-term memory, specific impairments were shown in hippocampus-dependent long-term memory after training in spatial memory tasks and after contextual fear conditioning. In cultured neurons of these mice, phosphorylation of CaMKI was significantly increased in basal states, whereas the activity range of CaMKI phosphorylation by brain-derived neurotrophic factor (BDNF) and KCl stimulation was significantly diminished in mutant mice. Our results define a critical role for CaMKKα in synaptic plasticity and the retention of hippocampus-dependent long-term memory.

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

    PubMed Central

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

    2016-01-01

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

  16. Adult female wildtype, but not oestrogen receptor β knockout, mice have decreased depression-like behaviour during pro-oestrus and following administration of oestradiol or diarylpropionitrile

    PubMed Central

    Walf, AA; Koonce, CJ; Frye, CA

    2013-01-01

    Studies in people and animal models suggest that depression is influenced by natural, fluctuations in the levels of 17β-oestradiol (E2), as well as administration of E2-based therapies, such as selective oestrogen receptor modulators (SERMs). Elucidating the effects and mechanisms of E2 is important to improve future E2-based therapeutics. An important question is whether effects of E2 or SERMs for mood regulation act at the α or β isoform of the oestrogen receptor (ER) because some of the unwanted trophic effects of E2-based therapies may involve actions at ERα, rather than ERβ. In the present study, whether there are sex differences in depression-like behaviour of adult mice (experiment 1), and the effects of natural fluctuations in E2 (experiment 2), or administration of E2 or a SERM that has higher affinity for ERβ than for ERα (diarylpropionitrile; DPN) to ovariectomised (experiment 3) wildtype and ERβ knockout (βERKO) mice were investigated. Results of this study supported our hypotheses that: there would be sex differences favouring males for depression-like behaviour and endogenous increases in, or exogenous administration of, E2 or administration of an ERβ SERM would decrease depression-like behaviour in wildtype, but not βERKO, mice. In experiment 1, adult male mice spent less time immobile in the forced swim test (i.e., showed less depression-like behaviour) compared with female mice. In experiment 2, pro-oestrous (higher circulating E2 levels), compared with dioestrous (lower circulating E2 levels), mice had reduced immobility in the forced swim test; this effect was not observed in βERKO mice. In experiment 3, administration of E2 or DPN to ovariectomised wildtype, but not βERKO, mice decreased immobility compared with vehicle administration, these data suggest that ERβ may be required for some of the anti–depressant-like effects of E2. PMID:18562442

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

    SciTech Connect

    Haddad, Rami; Kasneci, Amanda; Mepham, Kathryn; Sebag, Igal A.; and others

    2013-01-01

    Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0 μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5–14.5. At 3 months, male progeny were left sedentary or were swim trained for 4 weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. -- Highlights: ► Gestational DES changes cardiac SERCA2a and CASQ2 expression. ► Echocardiography identified systolic dysfunction and increased diastolic relaxation. ► DES

  18. C3 glomerulopathy in adults: a distinct patient subset showing frequent association with monoclonal gammopathy and poor renal outcome

    PubMed Central

    Lloyd, Isaac E.; Gallan, Alexander; Huston, Hunter K.; Raphael, Kalani L.; Miller, Dylan V.; Revelo, Monica P.

    2016-01-01

    Background C3 glomerulopathy (C3G) includes both C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) and is defined by C3-dominant deposits on immunofluorescence. Dysfunction of the alternative pathway (AP) of complement is central to the pathophysiology of C3G and young patients often harbor genetic alterations of AP mediators. Recently, a link between C3G and paraproteinemia has been established. We performed this study to better characterize older patients with C3G where this association is more frequently seen. Methods Fourteen biopsies from 12 patients meeting diagnostic criteria for C3G were identified in patients > 49 years of age from 2005 to 2015 after exclusion of cases containing masked monotypic immunoglobulin deposits. Pathologic and clinical features were reviewed. Results The median age was 63.5 years and 75% of patients were male. All had renal insufficiency at presentation. Kidney biopsy showed DDD in three patients and C3GN in the remainder. Serum protein electrophoresis revealed a paraprotein in 10 patients, 8 of which had a plasma cell dyscrasia on bone marrow biopsy. A membranoproliferative pattern of glomerular injury was seen in 64% of biopsies, while mesangial proliferative and endocapillary proliferative patterns were seen less frequently. Among patients with at least 1 year of follow-up (n = 9), five were on renal replacement therapy, three showed stable (but impaired) kidney function and one demonstrated improvement. Conclusions C3G is an uncommon but important cause of kidney injury in older adults and associates with a high prevalence of paraproteinemia. In adult patients with C3G, prognosis is guarded as most patients showed either progression to end-stage kidney disease or stable but impaired kidney function. PMID:27994856

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

    PubMed

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

    2014-05-01

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

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

    PubMed Central

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

    2015-01-01

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

  1. Similar L-dopa-stimulated motor activity in mice with adult-onset 6-hydroxydopamine-induced symmetric dopamine denervation and in transcription factor Pitx3 null mice with perinatal-onset symmetric dopamine denervation.

    PubMed

    Li, Li; Sagot, Ben; Zhou, Fu-Ming

    2015-07-30

    The transcription factor Pitx3 null mutant (Pitx3Null) mice have a constitutive perinatal-onset and symmetric bilateral dopamine (DA) loss in the striatum. In these mice l-3,4-dihydroxyphenylalanine (l-dopa) induces apparently normal horizontal movements (walking) but also upward movements consisting of the vertical body trunk and waving paws that are absent in normal animals and in animals with the classic unilateral 6-hydroxydopamine (6-OHDA) lesion-induced DA denervation. Thus, a concern is that the perinatal timing of the DA loss and potential developmental abnormalities in Pitx3Null mice may underlie these upward movements, thus reducing the usefulness as a DA denervation model. Here we show that in normal wild-type (Pitx3WT) mice with adult-onset symmetric, bilateral 6-OHDA-induced DA lesion in the dorsal striatum, l-dopa induces normal horizontal movements and upward movements that are qualitatively identical to those in Pitx3Null mice. Furthermore, after unilateral 6-OHDA lesion of the residual DA innervation in the striatum in Pitx3Null mice, l-dopa induces contraversive rotation that is similar to that in Pitx3WT mice with the classic unilateral 6-OHDA lesion. These results indicate that in Pitx3Null mice, the bilateral symmetric DA denervation in the dorsal striatum is sufficient for expressing the l-dopa-induced motor phenotype and the perinatal timing of their DA loss is not a determining factor, providing further evidence that Pitx3Null mice are a convenient and suitable mouse model to study the consequences of DA loss and dopaminergic replacement therapy in Parkinson's disease.

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

    PubMed Central

    Chugh, Deepti; Ali, Idrish; Bakochi, Anahita; Bahonjic, Elma; Etholm, Lars; Ekdahl, Christine T.

    2015-01-01

    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. PMID:26177381

  3. Male mice retain a metabolic memory of improved glucose tolerance induced during adult onset, short-term dietary restriction

    PubMed Central

    2012-01-01

    Background Chronic dietary restriction (DR) has been shown to have beneficial effects on glucose homeostasis and insulin sensitivity. These factors show rapid and robust improvements when rodents were crossed over from an ad libitum (AL) diet to DR in mid life. We aimed to determine whether the beneficial effects induced by short-term exposure to DR can be retained as a ‘metabolic memory’ when AL feeding is resumed (AL-DR-AL) and vice versa: whether the effects of long-term DR can be reversed by a period of AL feeding (DR-AL-DR). C57BL/6 male and female mice were used to examine sex differences (N = 10/sex/group). Mice were fed AL or DR from 3 until 15 months (baseline) and each dietary crossover lasted approximately 5 months. Results In females, body and fat mass were proportional to the changes in feeding regime and plasma insulin and glucose tolerance were unaffected by the crossovers. However, in male mice, glucose tolerance and plasma insulin levels were reversed within 6 to 12 weeks. When males returned to AL intake following 5 months DR (AL-DR-AL), body mass was maintained below baseline, proportional to changes in fat mass. Glucose tolerance was also significantly better compared to baseline. Conclusions Male mice retained a metabolic memory of 5 months of DR feeding in terms of reduced body mass and improved glucose tolerance. This implies that some of the beneficial effects induced by a period of DR in adult life may be beneficial, even when free feeding is resumed at least in males. However, under continuous DR, lifespan extension was more prominent in females than in males. PMID:24764509

  4. Precocious obesity predisposes the development of more severe cisplatin-induced acute kidney injury in young adult mice

    PubMed Central

    Ribeiro, Rosemara S.; Passos, Clevia S.; Novaes, Antônio S.; Maquigussa, Edgar; Glória, Maria A.; Visoná, Iria; Ykuta, Olinda; Oyama, Lila M.

    2017-01-01

    Obesity and its consequences can damage the kidney over time. However, less is known about the impact of developing overweight/obesity during childhood on the kidney in adulthood and the renal impact of a superimposed acute kidney injury (AKI). This study evaluated the effect of obesity induced by a high-fat diet initiated soon after weaning on the adult life of mice and their response to superimposed nephrotoxic effects of cisplatin. C57BL/6 post-weaning mice (3 weeks old) were divided into a control group (CT, n = 12) and a high-fat diet group (HF, n = 12). After 9 weeks, animals were further divided into the following groups: CT, CT treated with a single dose of cisplatin (CTCis, 20 mg/kg, i.p.), HF and HF treated with cisplatin (HFCis). The HF group exhibited higher body weight gain compatible with a moderate obesity. Obese mice presented increased visceral adiposity, hyperkalemia, sodium retention, glomerular hyperfiltration and proteinuria, without any significant changes in blood pressure and glycemia. AKI induced by cisplatin was exacerbated in obese animals with a 92% reduction in the GFR versus a 31% decrease in the CTCis group; this sharp decline resulted in severely elevated serum creatinine and urea levels. Acute tubular necrosis induced by cisplatin was worsened in obese mice. The HFCis group exhibited robust systemic and intrarenal inflammation that was significantly higher than that in the CTCis group; the HFCis group also showed a higher degree of renal oxidative stress. In conclusion, the moderate degree of obesity induced shortly after weaning resulted in mild early renal alterations, however, obese young animals were prone to develop a much more severe AKI induced by cisplatin. PMID:28358868

  5. Enzyme-treated Asparagus officinalis extract shows neuroprotective effects and attenuates cognitive impairment in senescence-accelerated mice.

    PubMed

    Sakurai, Takuya; Ito, Tomohiro; Wakame, Koji; Kitadate, Kentaro; Arai, Takashi; Ogasawara, Junetsu; Kizaki, Takako; Sato, Shogo; Ishibashi, Yoshinaga; Fujiwara, Tomonori; Akagawa, Kimio; Ishida, Hitoshi; Ohno, Hideki

    2014-01-01

    Increases in the number of patients with dementia involving Alzheimer's disease (AD) are seen as a grave public health problem. In neurodegenerative disorders involving AD, biological stresses, such as oxidative and inflammatory stress, induce neural cell damage. Asparagus (Asparagus officinalis) is a popular vegetable, and an extract prepared from this reportedly possesses various beneficial biological activities. In the present study, we investigated the effects of enzyme-treated asparagus extract (ETAS) on neuronal cells and early cognitive impairment of senescence-accelerated mouse prone 8 (SAMP8) mice. The expression of mRNAs for factors that exert cytoprotective and anti-apoptotic functions, such as heat-shock protein 70 and heme oxygenase-1, was upregulated in NG108-15 neuronal cells by treatment with ETAS. Moreover, when release of lactate dehydrogenase from damaged NG108-15 cells was increased for cells cultured in medium containing either the nitric oxide donor sodium nitroprusside or the hypoxia mimic reagent cobalt chloride, ETAS significantly attenuated this cell damage. Also, when contextual fear memory, which is considered to be a hippocampus-dependent memory, was significantly impaired in SAMP8 mice, ETAS attenuated the cognitive impairment. These results suggest that ETAS produces cytoprotective effects in neuronal cells and attenuates the effects on the cognitive impairment of SAMP8 mice.

  6. Mice Deficient in GEM GTPase Show Abnormal Glucose Homeostasis Due to Defects in Beta-Cell Calcium Handling

    PubMed Central

    Gunton, Jenny E.; Sisavanh, Mary; Stokes, Rebecca A.; Satin, Jon; Satin, Leslie S.; Zhang, Min; Liu, Sue M.; Cai, Weikang; Cheng, Kim; Cooney, Gregory J.; Laybutt, D. Ross; So, Trina; Molero, Juan-Carlos; Grey, Shane T.; Andres, Douglas A.

    2012-01-01

    Aims and Hypothesis Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo. Methods Gem-deficient mice were generated and their metabolic phenotype characterised by in vivo testing of glucose tolerance, insulin tolerance and insulin secretion. Calcium flux was measured in isolated islets. Results Gem-deficient mice were glucose intolerant and had impaired glucose stimulated insulin secretion. Furthermore, the islets of Gem-deficient mice exhibited decreased free calcium responses to glucose and the calcium oscillations seen upon glucose stimulation were smaller in amplitude and had a reduced frequency. Conclusions These results suggest that Gem plays an important role in normal beta-cell function by regulation of calcium signalling. PMID:22761801

  7. Effects of fasting and/or oxidizing and reducing agents on absorption of neptunium from the gastrointestinal tract of mice and adult or neonatal rats.

    PubMed

    Sullivan, M F; Ruemmler, P S; Ryan, J L

    1984-12-01

    Neptunium-237(V) nitrate was administered by gavage to groups of fed or fasted adult and 5-day-old rats. Some groups also received the oxidants quinhydrone or ferric iron, and others received the reducing agent ferrous iron. Adult mice received ferric or ferrous iron and 235Np. When the adult rats were killed at 7 days after gavage, measurements showed that, compared with rats that were fed, a 24-hr fast caused a fivefold increase in 237Np absorption and retention. Both quinhydrone and ferric iron caused an even greater increase in absorption in both fed and fasted rats. Ferrous iron, on the other hand, decreased absorption in fasted rats to values lower than those obtained in fed rats. Similar results were obtained in mice treated with 235Np and either ferric or ferrous iron. The highest absorption obtained after gavage of ferric iron to fasted rats and mice was about two orders of magnitude higher than the value obtained in animals that were fed before gavage. The effects of ferric and ferrous iron on neptunium absorption by neonatal rats were similar to their effects on adult animals but of lesser magnitude. These results are consistent with the hypothesis that Np(V), when given in small mass quantities to fed animals, is reduced in the gastrointestinal tract to Np(IV), which is less well absorbed than Np(V).

  8. Experimental Chagas disease in Balb/c mice previously vaccinated with T. rangeli. II. The innate immune response shows immunological memory: reality or fiction?

    PubMed

    Basso, B; Marini, V

    2015-03-01

    Trypanosoma cruzi is a real challenge to the host's immune system, because it requires strong humoral and cellular immune response to remove circulating trypomastigote forms, and to prevent the replication of amastigote forms in tissues, involving many regulator and effector components. This protozoan is responsible for Chagas disease, a major public health problem in Latinamerica. We have developed a model of vaccination with Trypanosoma rangeli, a parasite closely related to T. cruzi, but nonpathogenic to humans, which reduces the infectiousness in three different species of animals, mice, dogs and guinea pigs, against challenge with T. cruzi. In a previous work, we demonstrated that mice vaccinated with T. rangeli showed important soluble mediators that stimulate phagocytic activity versus only infected groups. The aim of this work was to study the innate immune response in mice vaccinated or not with T. rangeli. Different population cells and some soluble mediators (cytokines) in peritoneal fluid and plasma in mice vaccinated-infected and only infected with T. cruzi were studied. In the first hours of challenge vaccinated mice showed an increase of macrophages, NK, granulocytes, and regulation of IL6, IFNγ, TNFα and IL10, with an increase of IL12, with respect to only infected mice. Furthermore an increase was observed of Li T, Li B responsible for adaptative response. Finally the findings showed that the innate immune response plays an important role in vaccinated mice for the early elimination of the parasites, complementary with the adaptative immune response, suggesting that vaccination with T. rangeli modulates the innate response, which develops some kind of immunological memory, recognizing shared antigens with T. cruzi. These results could contribute to the knowledge of new mechanisms which would have an important role in the immune response to Chagas disease.

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

    PubMed

    Jacquelin, C; Strazielle, C; Lalonde, R

    2012-01-01

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

  10. Mice lacking acid-sensing ion channels (ASIC) 1 or 2, but not ASIC3, show increased pain behaviour in the formalin test.

    PubMed

    Staniland, Amelia A; McMahon, Stephen B

    2009-07-01

    Extracellular acidification is a component of the inflammatory process and may be a factor driving the pain accompanying it. Acid-sensing ion channels (ASICs) are neuronal proton sensors and evidence suggests they are involved in signalling inflammatory pain. The aims of this study were to (1) clarify the role of ASICs in nociception and (2) confirm their involvement in inflammatory pain and determine whether this was subunit specific. This was achieved by (1) direct comparison of the sensitivity of ASIC1, ASIC2, ASIC3 and TRPV1 knockout mice versus wildtype littermates to acute thermal and mechanical noxious stimuli and (2) studying the behavioural responses of each transgenic strain to hind paw inflammation with either complete Freund's adjuvant (CFA) or formalin. Naïve ASIC1(-/-) and ASIC2(-/-) mice responded normally to acute noxious stimuli, whereas ASIC3(-/-) mice were hypersensitive to high intensity thermal stimuli. CFA injection decreased mechanical and thermal withdrawal thresholds for up to 8 days. ASIC2(-/-) mice had increased mechanical sensitivity on day 1 post-CFA compared to wildtype controls. TRPV1(-/-) mice had significantly reduced thermal, but not mechanical, hyperalgesia on all days after inflammation. Following formalin injection, ASIC1(-/-) and ASIC2(-/-), but not ASIC3(-/-) or TRPV1(-/-), mice showed enhanced pain behaviour, predominantly in the second phase of the test. These data suggest that whilst ASICs may play a role in mediating inflammatory pain, this role is likely to be modulatory and strongly dependent on channel subtype.

  11. When Age and Culture Interact in an Easy and Yet Cognitively Demanding Task: Older Adults, But Not Younger Adults, Showed the Expected Cultural Differences

    PubMed Central

    Na, Jinkyung; Huang, Chih-Mao; Park, Denise C.

    2017-01-01

    The interaction between age and culture can have various implications for cognition as age represents the effect of biological processes whereas culture represents the effect of sustaining experiences. Nevertheless, their interaction has rarely been examined. Thus, based on the fact that Asians are more intuitive in reasoning than Americans, we examined how this cultural difference might interact with age. Young and old participants from the US and Singapore performed a categorization task (living vs. non-living). To measure their reliance on intuition, we manipulated the typicality of targets (animate vs. inanimate). We showed that (1) RTs for inanimate organisms were slower than RTs for animate organisms (atypicality cost), (2) the cost was particularly large for older adults and (3) an age × culture interaction was observed such that cultural differences in the cost (Singaporeans > Americans) was found only among older participants. Further, we demonstrated that the age effect was associated with cognitive function and the culture effect among older adults was associated with cultural values. Finally, a moderated mediation analysis suggests that cognitive function and cultural values interact with each other in order to jointly influence one’s cognition.

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

    PubMed

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

    2014-01-16

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

  13. Strain dependent effects of conditioned fear in adult C57Bl/6 and Balb/C mice following postnatal exposure to chlorpyrifos: relation to expression of brain acetylcholinesterase mRNA

    PubMed Central

    Oriel, Sarit; Kofman, Ora

    2015-01-01

    Following reports of emotional psychopathology in children and adults exposed to organophosphates, the effects of postnatal chlorpyrifos (CPF) on fear-conditioning and depression-like behaviors were tested in adult mice. Concomitant changes in expression of mRNA for synaptic and soluble splice variants of acetylcholinesterase (AChE) were examined in mouse pups and adults of the Balb/C and C57Bl/6 (B6) strains, which differ in their behavioral and hormonal stress response. Mice were injected subcutaneously with 1 mg/kg CPF on postnatal days 4–10 and tested as adults for conditioned fear, sucrose preference, and forced swim. Acetylcholinesterase activity was assessed in the brains of pups on the first and last day of treatment. Expression of soluble and synaptic AChE mRNA was assessed in brains of treated pups and fear-conditioned adults using real-time PCR. Adult Balb/C mice exposed postnatally to CPF showed exacerbated fear-conditioning and impaired active avoidance. Adult B6 mice exposed postnatally to CPF showed a more specific fear response to tones and less freezing in the inter-tone intervals, in contrast to the vehicle-pretreated mice. Chlorpyrifos also attenuated sweet preference and enhanced climbing in the forced swim test. Chlorpyrifos-treated mice had increased expression of both synaptic and readthrough AChE transcripts in the hippocampus of Balb/C mice and decreased expression in the amygdala following fear-conditioning. In conclusion, postnatal CPF had long-term effects on fear and depression, as well as on expression of AChE mRNA. These changes may be related to alteration in the interaction between hippocampus and amygdala in regulating negative emotions. PMID:25972795

  14. Heterozygous Vangl2(Looptail) mice reveal novel roles for the planar cell polarity pathway in adult lung homeostasis and repair.

    PubMed

    Poobalasingam, Thanushiyan; Yates, Laura L; Walker, Simone A; Pereira, Miguel; Gross, Nina Y; Ali, Akmol; Kolatsi-Joannou, Maria; Jarvelin, Marjo-Riitta; Pekkanen, Juha; Papakrivopoulou, Eugenia; Long, David A; Griffiths, Mark; Wagner, Darcy; Königshoff, Melanie; Hind, Matthew; Minelli, Cosetta; Lloyd, Clare M; Dean, Charlotte H

    2017-02-24

    Lung diseases impose a huge economic and health burden worldwide. A key aspect of several adult lung diseases, such as Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive pulmonary Disease (COPD), including emphysema, is aberrant tissue repair, which leads to an accumulation of damage and impaired respiratory function. Currently, there are few effective treatments available for these diseases and their incidence is rising.The Planar Cell Polarity (PCP) pathway is critical for the embryonic development of many organs, including kidney and lung. We have previously shown that perturbation of the PCP pathway impairs tissue morphogenesis, which disrupts the number and shape of epithelial tubes formed within these organs during embryogenesis. However, very little is known about the role of the PCP pathway beyond birth, partly due to the perinatal lethality of many PCP mouse mutant lines.Here we have investigated heterozygous Looptail (Lp) mice, in which a single copy of the core PCP gene, Vangl2, is disrupted. We show that these mice are viable but display severe airspace enlargement and impaired adult lung function. Underlying these defects, we find that Vangl2(Lp/+) lungs exhibit altered distribution of actin microfilaments and abnormal regulation of the actin modifying protein cofilin. In addition, we show that Vangl2(Lp/+) lungs exhibit many of the hallmarks of tissue damage including an altered macrophage population, abnormal elastin deposition and elevated levels of the elastin-modifying enzyme, Mmp12, all of which are observed in the lung disease, emphysema.In vitro, VANGL2 disruption impairs directed cell migration and reduces the rate of repair following scratch wounding of human alveolar epithelial cells. Moreover, using population data from a birth cohort of young adults, all aged 31, we found evidence of an interactive effect between VANGL2 and smoking (a tissue damaging insult) on lung function. Finally, we show that that PCP genes VANGL2 and

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

    PubMed

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

    2014-01-01

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

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

    PubMed

    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 < 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.

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

    PubMed Central

    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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2013-01-01

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

  20. Seipin knockout in mice impairs stem cell proliferation and progenitor cell differentiation in the adult hippocampal dentate gyrus via reduced levels of PPARγ

    PubMed Central

    Li, Guoxi; Zhou, Libin; Zhu, Ying; Wang, Conghui; Sha, Sha; Xian, Xunde; Ji, Yong; Liu, George; Chen, Ling

    2015-01-01

    ABSTRACT 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. PMID

  1. Endogenous oncornaviral gene expression in adult and fetal mice: quantitative, histologic, and physiologic studies of the major viral glycorprotein, gp70

    PubMed Central

    1976-01-01

    Endogenous expression of the murine leukemia virus (MuLV) genome has been studied in a number of strains of mice. Expression of the major envelope glycoprotein, gp70, is restricted to certain anatomical sites and cell types, prominent among which are lymphoid and epithelial cells. On a quantitative basis, the major site of gp70 expression is the male genital tract. During development, gp70 first appears in the hematopoietic liver of 14-day-old embryos and by day 18, it is already expressed at anatomical sites similar to those of the adult. In toto, these results show that control of expression of the MuLV genome in adult and developing mice is linked to differentiation. PMID:172586

  2. Mice Homozygous for a Deletion in the Glaucoma Susceptibility Locus INK4 Show Increased Vulnerability of Retinal Ganglion Cells to Elevated Intraocular Pressure.

    PubMed

    Gao, Shan; Jakobs, Tatjana C

    2016-04-01

    A genomic region located on chromosome 9p21 is associated with primary open-angle glaucoma and normal tension glaucoma in genome-wide association studies. The genomic region contains the gene for a long noncoding RNA called CDKN2B-AS, two genes that code for cyclin-dependent kinase inhibitors 2A and 2B (CDKN2A/p16(INK4A) and CDKN2B/p15(INK4B)) and an additional protein (p14(ARF)). We used a transgenic mouse model in which 70 kb of murine chromosome 4, syntenic to human chromosome 9p21, are deleted to study whether this deletion leads to a discernible phenotype in ocular structures implicated in glaucoma. Homozygous mice of this strain were previously reported to show persistent hyperplastic primary vitreous. Fundus photography and optical coherence tomography confirmed that finding but showed no abnormalities for heterozygous mice. Optokinetic response, eletroretinogram, and histology indicated that the heterozygous and mutant retinas were normal functionally and morphologically, whereas glial cells were activated in the retina and optic nerve head of mutant eyes. In quantitative PCR, CDKN2B expression was reduced by approximately 50% in the heterozygous mice and by 90% in the homozygous mice, which suggested that the CDKN2B knock down had no deleterious consequences for the retina under normal conditions. However, compared with wild-type and heterozygous animals, the homozygous mice are more vulnerable to retinal ganglion cell loss in response to elevated intraocular pressure.

  3. Microcephalia with mandibular and dental dysplasia in adult Zmpste24-deficient mice

    PubMed Central

    de Carlos, F; Varela, I; Germanà, A; Montalbano, G; Freije, J M P; Vega, J A; López-Otin, C; Cobo, J M

    2008-01-01

    ZMPSTE24 (also called FACE-1) is a zinc-metalloprotease involved in the post-translational processing of prelamin A to mature lamin A, a major component of the nuclear envelope. Mutations in the ZMPSTE24 gene or in that encoding its substrate prelamin A (LMNA) result in a series of human inherited diseases known collectively as laminopathies and showing regional or systemic manifestations (i.e. the Hutchinson–Gilford progeria syndrome). Typically, patients suffering some laminopathies show craniofacial or mandible anomalies, aberrant dentition or facial features characteristic of aged persons. To analyse whether Zmpste24−/– mice reproduce the cranial phenotype observed in humans due to mutations in ZMPSTE24or LMNA, we conducted a craniometric study based on micro-computer tomography (µCT) images. Furthermore, using simple radiology, µCT, µCT-densitometry and scanning electron microscopy, we analysed the mandible and the teeth from Zmpste24−/– mice. Finally, the structure of the lower incisor was investigated using an H&E technique. The results demonstrate that Zmpste24−/– mice are microcephalic and show mandibular and dental dysplasia affecting only the mandible teeth. In all cases, the lower incisor of mice lacking Zmpste24 was smaller than in control animals, showed cylindrical morphology and a transverse fissure at the incisal edge, and the pulpal cavity was severely reduced. Structurally, the dental layers were normally arranged but cellular layers were disorganized. The inferior molars showed a reduced cusp size. Taken together, these data strongly suggest that Zmpste24−/– mice represent a good model to analyse the craniofacial and teeth malformations characteristic of lamin-related pathologies, and might contribute to a better understanding of the molecular events underlying these diseases. PMID:19014358

  4. Microcephalia with mandibular and dental dysplasia in adult Zmpste24-deficient mice.

    PubMed

    de Carlos, F; Varela, I; Germanà, A; Montalbano, G; Freije, J M P; Vega, J A; López-Otin, C; Cobo, J M

    2008-11-01

    ZMPSTE24 (also called FACE-1) is a zinc-metalloprotease involved in the post-translational processing of prelamin A to mature lamin A, a major component of the nuclear envelope. Mutations in the ZMPSTE24 gene or in that encoding its substrate prelamin A (LMNA) result in a series of human inherited diseases known collectively as laminopathies and showing regional or systemic manifestations (i.e. the Hutchinson-Gilford progeria syndrome). Typically, patients suffering some laminopathies show craniofacial or mandible anomalies, aberrant dentition or facial features characteristic of aged persons. To analyse whether Zmpste24(-/-) mice reproduce the cranial phenotype observed in humans due to mutations in ZMPSTE24 or LMNA, we conducted a craniometric study based on micro-computer tomography (microCT) images. Furthermore, using simple radiology, microCT, microCT-densitometry and scanning electron microscopy, we analysed the mandible and the teeth from Zmpste24(-/-) mice. Finally, the structure of the lower incisor was investigated using an H&E technique. The results demonstrate that Zmpste24(-/-) mice are microcephalic and show mandibular and dental dysplasia affecting only the mandible teeth. In all cases, the lower incisor of mice lacking Zmpste24 was smaller than in control animals, showed cylindrical morphology and a transverse fissure at the incisal edge, and the pulpal cavity was severely reduced. Structurally, the dental layers were normally arranged but cellular layers were disorganized. The inferior molars showed a reduced cusp size. Taken together, these data strongly suggest that Zmpste24(-/-) mice represent a good model to analyse the craniofacial and teeth malformations characteristic of lamin-related pathologies, and might contribute to a better understanding of the molecular events underlying these diseases.

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

    Saransaari, P; Oja, S S

    2000-01-01

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

  7. Neuropeptide Y Overexpressing Female and Male Mice Show Divergent Metabolic but Not Gut Microbial Responses to Prenatal Metformin Exposure

    PubMed Central

    Salomäki-Myftari, Henriikka; Vähätalo, Laura H.; Ailanen, Liisa; Pietilä, Sami; Laiho, Asta; Hänninen, Arno; Pursiheimo, Juha-Pekka; Munukka, Eveliina; Rintala, Anniina; Savontaus, Eriika; Pesonen, Ullamari; Koulu, Markku

    2016-01-01

    Background Prenatal metformin exposure has been shown to improve the metabolic outcome in the offspring of high fat diet fed dams. However, if this is evident also in a genetic model of obesity and whether gut microbiota has a role, is not known. Methods The metabolic effects of prenatal metformin exposure were investigated in a genetic model of obesity, mice overexpressing neuropeptide Y in the sympathetic nervous system and in brain noradrenergic neurons (OE-NPYDβH). Metformin was given for 18 days to the mated female mice. Body weight, body composition, glucose tolerance and serum parameters of the offspring were investigated on regular diet from weaning and sequentially on western diet (at the age of 5–7 months). Gut microbiota composition was analysed by 16S rRNA sequencing at 10–11 weeks. Results In the male offspring, metformin exposure inhibited weight gain. Moreover, weight of white fat depots and serum insulin and lipids tended to be lower at 7 months. In contrast, in the female offspring, metformin exposure impaired glucose tolerance at 3 months, and subsequently increased body weight gain, fat mass and serum cholesterol. In the gut microbiota, a decline in Erysipelotrichaceae and Odoribacter was detected in the metformin exposed offspring. Furthermore, the abundance of Sutterella tended to be decreased and Parabacteroides increased. Gut microbiota composition of the metformin exposed male offspring correlated to their metabolic phenotype. Conclusion Prenatal metformin exposure caused divergent metabolic phenotypes in the female and male offspring. Nevertheless, gut microbiota of metformin exposed offspring was similarly modified in both genders. PMID:27681875

  8. The plasma virome of febrile adult Kenyans shows frequent parvovirus B19 infections and a novel arbovirus (Kadipiro virus)

    PubMed Central

    Ngoi, Carolyne N.; Siqueira, Juliana; Li, Linlin; Deng, Xutao; Mugo, Peter; Graham, Susan M.; Price, Matt A.; Sanders, Eduard J.

    2016-01-01

    Viral nucleic acids present in the plasma of 498 Kenyan adults with unexplained fever were characterized by metagenomics analysis of 51 sample pools. The highest to lowest fraction of plasma pools was positive for parvovirus B19 (75 %), pegivirus C (GBV-C) (67 %), alpha anellovirus (59 %), gamma anellovirus (55 %), beta anellovirus (41 %), dengue virus genotype 2 (DENV-2) (16 %), human immunodeficiency virus type 1 (6 %), human herpesvirus 6 (6 %), HBV (4 %), rotavirus (4 %), hepatitis B virus (4 %), rhinovirus C (2 %), Merkel cell polyomavirus (MCPyV; 2 %) and Kadipiro virus (2 %). Ranking by overall percentage of viral reads yielded similar results. Characterization of viral nucleic acids in the plasma of a febrile East African population showed a high frequency of parvovirus B19 and DENV infections and detected a reovirus (Kadipiro virus) previously reported only in Asian Culex mosquitoes, providing a baseline to compare with future virome studies to detect emerging viruses in this region. PMID:27902331

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

    SciTech Connect

    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.

  10. Mandibular coronoid process in parathyroid hormone-related protein-deficient mice shows ectopic cartilage formation accompanied by abnormal bone modeling.

    PubMed

    Shibata, Shunichi; Suda, Naoto; Fukada, Kenji; Ohyama, Kimie; Yamashita, Yasuo; Hammond, Vicki E

    2003-07-01

    Parathyroid hormone-related protein (PTHrP) null mutant mice were analyzed to investigate an additional role for PTHrP in cell differentiation. We found ectopic cartilage formation in the mandibular coronoid process in newborn mice. While many previous studies involving PTHrP gene knockout mouse have shown that the cartilage in various regions becomes smaller, this is the first report showing an "increase" of cartilage volume. Investigations of mandibular growth using normal mice indicated that coronoid secondary cartilage never formed from E 15 to d 4, but small amount of cartilage temporally formed at d 7, and this also applies to PTHrP-wild type mice. Therefore, PTHrP deficiency consequently advanced the secondary cartilage formation, which is a novel role of PTHrP in chondrocyte differentiation. In situ hybridization of matrix proteins showed that this coronoid cartilage had characteristics of the lower hypertrophic cell zone usually present at the site of endochondral bone formation and/or "chondroid bone" occasionally found in distraction osteogenesis. In addition, the coronoid process in the PTHrP-deficient mouse also showed abnormal expansion of bone marrow and an increase in the number of multinucleated osteoclasts, an indication of abnormal bone modeling. These results indicate that PTHrP is involved in bone modeling as well as in chondrocyte differentiation. In situ hybridization of matrix protein mRNAs in the abnormal mandibular condylar cartilage revealed that this cartilage was proportionally smaller, supporting previous immunohistochemical results.

  11. Desensitization and Incomplete Recovery of Hepatic Target Genes After Chronic Thyroid Hormone Treatment and Withdrawal in Male Adult Mice

    PubMed Central

    Ohba, Kenji; Singh, Brijesh Kumar; Sinha, Rohit Anthony; Lesmana, Ronny; Liao, Xiao-Hui; Ghosh, Sujoy; Refetoff, Samuel

    2016-01-01

    Clinical symptoms may vary and not necessarily reflect serum thyroid hormone (TH) levels during acute and chronic hyperthyroidism as well as recovery from hyperthyroidism. We thus examined changes in hepatic gene expression and serum TH/TSH levels in adult male mice treated either with a single T3 (20 μg per 100 g body weight) injection (acute T3) or daily injections for 14 days (chronic T3) followed by 10 days of withdrawal. Gene expression arrays from livers harvested at these time points showed that among positively-regulated target genes, 320 were stimulated acutely and 429 chronically by T3. Surprisingly, only 69 of 680 genes (10.1%) were induced during both periods, suggesting desensitization of the majority of acutely stimulated target genes. About 90% of positively regulated target genes returned to baseline expression levels after 10 days of withdrawal; however, 67 of 680 (9.9%) did not return to baseline despite normalization of serum TH/TSH levels. Similar findings also were observed for negatively regulated target genes. Chromatin immunoprecipitation analysis of representative positively regulated target genes suggested that acetylation of H3K9/K14 was associated with acute stimulation, whereas trimethylation of H3K4 was associated with chronic stimulation. In an in vivo model of chronic intrahepatic hyperthyroidism since birth, adult male monocarboxylate transporter-8 knockout mice also demonstrated desensitization of most acutely stimulated target genes that were examined. In summary, we have identified transcriptional desensitization and incomplete recovery of gene expression during chronic hyperthyroidism and recovery. Our findings may be a potential reason for discordance between clinical symptoms and serum TH levels observed in these conditions. PMID:26866609

  12. Receptor for advanced glycation end products contributes to postnatal pulmonary development and adult lung maintenance program in mice.

    PubMed

    Fineschi, Silvia; De Cunto, Giovanna; Facchinetti, Fabrizio; Civelli, Maurizio; Imbimbo, Bruno P; Carnini, Chiara; Villetti, Gino; Lunghi, Benedetta; Stochino, Stefania; Gibbons, Deena L; Hayday, Adrian; Lungarella, Giuseppe; Cavarra, Eleonora

    2013-02-01

    The role of the receptor for advanced glycation end products (RAGE) in promoting the inflammatory response through activation of NF-κB pathway is well established. Recent findings indicate that RAGE may also have a regulative function in apoptosis, as well as in cellular proliferation, differentiation, and adhesion. Unlike other organs, lung tissue in adulthood and during organ development shows relatively high levels of RAGE expression. Thus a role for the receptor in lung organogenesis and homeostasis may be proposed. To evaluate the role of RAGE in lung development and adult lung homeostasis, we generated hemizygous and homozygous transgenic mice overexpressing human RAGE, and analyzed their lungs from the fourth postnatal day to adulthood. Moderate RAGE hyperexpression during lung development influenced secondary septation, resulting in an impairment of alveolar morphogenesis and leading to significant changes in morphometric parameters such as airspace number and the size of alveolar ducts. An increase in alveolar cell apoptosis and a decrease in cell proliferation were demonstrated by the terminal deoxy-nucleotidyltransferase-mediated dUTP nick end labeling reaction, active caspase-3, and Ki-67 immunohistochemistry. Alterations in elastin organization and deposition and in TGF-β expression were observed. In homozygous mice, the hyperexpression of RAGE resulted in histological changes resembling those changes characterizing human bronchopulmonary dysplasia (BPD). RAGE hyperexpression in the adult lung is associated with an increase of the alveolar destructive index and persistent inflammatory status leading to "destructive" emphysema. These results suggest an important role for RAGE in both alveolar development and lung homeostasis, and open new doors to working hypotheses on the pathogenesis of BPD and chronic obstructive pulmonary disease.

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

    PubMed

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

    2013-01-01

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

  14. A case of adult Langerhans cell histiocytosis showing successfully regenerated osseous tissue of the skull after chemotherapy.

    PubMed

    Suzuki, Takahiro; Izutsu, Koji; Kako, Shinichi; Ohta, Satoshi; Hangaishi, Akira; Kanda, Yoshinobu; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2008-04-01

    Langerhans cell histiocytosis (LCH) is a proliferative disorder of Langerhans cells and extremely rare in adults. Adult LCH is often associated with osteolytic bone lesions, but large bone-defective lesions have been rarely reported. We report an adult case of LCH accompanied by large osteolytic lesions in the skull that successfully responded to chemotherapy. A 47-year-old woman with LCH who had multiple, large osteolytic areas of more than 3 cm in diameter in the skull was admitted to our hospital. She was treated with systemic chemotherapy consisting of prednisolone, vinblastine, and 6-mercaptopurine. Twelve months later, when she completed the treatment, osteolytic areas were covered with hard osseous tissue, and X-ray examination confirmed regeneration of the bone. This case indicates that chemotherapy can be effective even for the treatment of large osteolytic lesions in adult LCH patients.

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

    PubMed

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

    2015-02-02

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

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

    PubMed

    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.

  17. Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas.

    PubMed

    Imgrund, Silke; Hartmann, Dieter; Farwanah, Hany; Eckhardt, Matthias; Sandhoff, Roger; Degen, Joachim; Gieselmann, Volkmar; Sandhoff, Konrad; Willecke, Klaus

    2009-11-27

    (Dihydro)ceramide synthase 2 (cers2, formerly called lass2) is the most abundantly expressed member of the ceramide synthase gene family, which includes six isoforms in mice. CERS2 activity has been reported to be specific toward very long fatty acid residues (C22-C24). In order to study the biological role of CERS2, we have inactivated its coding region in transgenic mice using gene-trapped embryonic stem cells that express lacZ reporter DNA under control of the cers2 promoter. The resulting mice lack ceramide synthase activity toward C24:1 in the brain as well as the liver and show only very low activity toward C18:0-C22:0 in liver and reduced activity toward C22:0 residues in the brain. In addition, these mice exhibit strongly reduced levels of ceramide species with very long fatty acid residues (>or=C22) in the liver, kidney, and brain. From early adulthood on, myelin stainability is progressively lost, biochemically accompanied by about 50% loss of compacted myelin and 80% loss of myelin basic protein. Starting around 9 months, both the medullary tree and the internal granular layer of the cerebellum show significant signs of degeneration associated with the formation of microcysts. Predominantly in the peripheral nervous system, we observed vesiculation and multifocal detachment of the inner myelin lamellae in about 20% of the axons. Beyond 7 months, the CERS2-deficient mice developed hepatocarcinomas with local destruction of tissue architecture and discrete gaps in renal parenchyma. Our results indicate that CERS2 activity supports different biological functions: maintenance of myelin, stabilization of the cerebellar as well as renal histological architecture, and protection against hepatocarcinomas.

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

    PubMed

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

    2017-02-01

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

  19. Neurexin dysfunction in adult neurons results in autistic-like behavior in mice.

    PubMed

    Rabaneda, Luis G; Robles-Lanuza, Estefanía; Nieto-González, José Luis; Scholl, Francisco G

    2014-07-24

    Autism spectrum disorders (ASDs) comprise a group of clinical phenotypes characterized by repetitive behavior and social and communication deficits. Autism is generally viewed as a neurodevelopmental disorder where insults during embryonic or early postnatal periods result in aberrant wiring and function of neuronal circuits. Neurexins are synaptic proteins associated with autism. Here, we generated transgenic βNrx1ΔC mice in which neurexin function is selectively impaired during late postnatal stages. Whole-cell recordings in cortical neurons show an impairment of glutamatergic synaptic transmission in the βNrx1ΔC mice. Importantly, mutant mice exhibit autism-related symptoms, such as increased self-grooming, deficits in social interactions, and altered interaction for nonsocial olfactory cues. The autistic-like phenotype of βNrx1ΔC mice can be reversed after removing the mutant protein in aged animals. The defects resulting from disruption of neurexin function after the completion of embryonic and early postnatal development suggest that functional impairment of mature circuits can trigger autism-related phenotypes.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2007-01-01

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

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

    PubMed

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

    2013-12-21

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

  4. Anxious and Nonanxious Mice Show Similar Hippocampal Sensory Evoked Oscillations under Urethane Anesthesia: Difference in the Effect of Buspirone

    PubMed Central

    Horváth, János; Barkóczi, Balázs; Müller, Géza

    2015-01-01

    Hippocampal oscillations recorded under urethane anesthesia are proposed to be modulated by anxiolytics. All classes of clinically effective anxiolytics were reported to decrease the frequency of urethane theta; however, recent findings raise concerns about the direct correlation of anxiolysis and the frequency of hippocampal theta. Here, we took advantage of our two inbred mouse strains displaying extremes of anxiety (anxious (AX) and nonanxious (nAX)) to compare the properties of hippocampal activity and to test the effect of an anxiolytic drugs. No difference was observed in the peak frequency or in the peak power between AX and nAX strains. Buspirone (Bus) applied in 2.5 mg/kg decreased anxiety of AX but did not have any effect on nAX as was tested by elevated plus maze and open field. Interestingly, Bus treatment increased hippocampal oscillatory frequency in the AX but left it unaltered in nAX mice. Saline injection did not have any effect on the oscillation. Paired-pulse facilitation was enhanced by Bus in the nAX, but not in the AX strain. Collectively, these results do not support the hypothesis that hippocampal activity under urethane may serve as a marker for potential anxiolytic drugs. Moreover, we could not confirm the decrease of frequency after anxiolytic treatment. PMID:25949829

  5. Size does not always matter: Ts65Dn Down syndrome mice show cerebellum-dependent motor learning deficits that cannot be rescued by postnatal SAG treatment.

    PubMed

    Gutierrez-Castellanos, Nicolas; Winkelman, Beerend H J; Tolosa-Rodriguez, Leonardo; Devenney, Benjamin; Reeves, Roger H; De Zeeuw, Chris I

    2013-09-25

    Humans with Down syndrome (DS) and Ts65Dn mice both show a reduced volume of the cerebellum due to a significant reduction in the density of granule neurons. Recently, cerebellar hypoplasia in Ts65Dn mice was rescued by a single treatment with SAG, an agonist of the Sonic hedgehog pathway, administered on the day of birth. In addition to normalizing cerebellar morphology, this treatment restored the ability to learn a spatial navigation task, which is associated with hippocampal function. It is not clear to what extent this improved performance results from restoration of the cerebellar architecture or a yet undefined role of Sonic hedgehog (Shh) in perinatal hippocampal development. The absence of a clearly demonstrated deficit in cerebellar function in trisomic mice exacerbates the problem of discerning how SAG acts to improve learning and memory. Here we show that phase reversal adaptation and consolidation of the vestibulo-ocular reflex is significantly impaired in Ts65Dn mice, providing for the first time a precise characterization of cerebellar functional deficits in this murine model of DS. However, these deficits do not benefit from the normalization of cerebellar morphology following treatment with SAG. Together with the previous observation that the synaptic properties of Purkinje cells are also unchanged by SAG treatment, this lack of improvement in a region-specific behavioral assay supports the possibility that a direct effect of Shh pathway stimulation on the hippocampus might explain the benefits of this potential approach to the improvement of cognition in DS.

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

    ISHIKAWA, CHIE; SENBA, MASACHIKA; MORI, NAOKI

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

    Adriani, Walter; Laviola, Giovanni

    2002-08-01

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

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

    ERIC Educational Resources Information Center

    Schachner, Melitta; Morellini, Fabio; Fellini, Laetitia

    2006-01-01

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

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

    PubMed

    Rajendren, G; Li, X

    2001-11-26

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

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

    EPA Science Inventory

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

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

    EPA Science Inventory

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

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

    EPA Science Inventory

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

  16. Resident microglia from adult mice are refractory to nitric oxide-inducing stimuli due to impaired NOS2 gene expression.

    PubMed

    Brannan, Courtney A; Roberts, Margo R

    2004-11-01

    Microglia are the immunoregulatory cells of the central nervous system (CNS) and share many characteristics with resident macrophages in extracerebral tissues. Nitric oxide (NO) is secreted by macrophages following induction of the NO synthase gene NOS2 by stimuli elicited during a T-cell response and/or by microbial products. NO regulates both innate and adaptive immune responses, such as killing intracellular pathogens and inhibiting T-cell proliferation. Regulation of NO production by microglia, however, is poorly understood. We find that microglia from healthy adult mice produce negligible amounts of NO compared with resident macrophages during restimulation of peptide-specific CD8 T cells, and therefore cannot block T-cell proliferation. The impaired NO response extends to exogenous NOS2-inducing stimuli, including cytokines, CD40 ligation, and lipopolysaccharide. In contrast, microglia produce proinflammatory cytokines in response to these same stimuli, and therefore possess a relatively selective block in NO production. We go on to show that resident microglia fail to produce detectable levels of either the NOS2 enzyme or NOS2 RNA in response to NO-inducing stimuli. We therefore propose that microglia in the healthy adult brain exist in an "NO-incompetent" state in which NO production is blocked at the level of NOS2 RNA. The inability of resident microglia in the healthy CNS to produce NO may allow these immunoregulatory cells to modulate immune processes temporally, and may serve to protect the CNS from irreparable damage at the onset of infection or injury.

  17. A single exposure to bisphenol A alters the levels of important neuroproteins in adult male and female mice.

    PubMed

    Viberg, Henrik; Lee, Iwa

    2012-10-01

    Bisphenol A (BPA) is widely used in polymer products in food and beverage containers, baby bottles, dental sealants and fillings, adhesives, protective coatings, flame retardants, water supply pipes, and compact discs, and is found in the environment and in placental tissue, fetuses and breast milk. We have recently reported that a single neonatal exposure to bisphenol A can induce persistent aberrations in spontaneous behavior, in a dose-dependent manner, and affect the adult response to the cholinergic agent nicotine. Furthermore, other recent reports indicate that pre- and perinatal exposure to bisphenol A can induce neurotoxic effects. The present study indicates that a single neonatal exposure to bisphenol A, on postnatal day 10, during the peak of the brain growth spurt, can alter the adult levels of proteins important for normal brain development (CaMKII and synaptophysin). These alterations are induced in both male and female mice and effects are seen in both hippocampus and cerebral cortex. These results further support our recent study showing that neonatal exposure to bisphenol A can act as a developmental neurotoxicant and the effects are similar to effects seen after a single postnatal exposure to other POPs, such as PBDEs, PCBs and PFCs.

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

    PubMed

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

    1997-01-01

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

  19. Fluorescent Labeling of Newborn Dentate Granule Cells in GAD67-GFP Transgenic Mice: A Genetic Tool for the Study of Adult Neurogenesis

    PubMed Central

    Zhao, Shengli; Zhou, Yang; Gross, Jimmy; Miao, Pei; Qiu, Li; Wang, Dongqing; Chen, Qian; Feng, Guoping

    2010-01-01

    Neurogenesis in the adult hippocampus is an important form of structural plasticity in the brain. Here we report a line of BAC transgenic mice (GAD67-GFP mice) that selectively and transitorily express GFP in newborn dentate granule cells of the adult hippocampus. These GFP+ cells show a high degree of colocalization with BrdU-labeled nuclei one week after BrdU injection and express the newborn neuron marker doublecortin and PSA-NCAM. Compared to mature dentate granule cells, these newborn neurons show immature morphological features: dendritic beading, fewer dendritic branches and spines. These GFP+ newborn neurons also show immature electrophysiological properties: higher input resistance, more depolarized resting membrane potentials, small and non-typical action potentials. The bright labeling of newborn neurons with GFP makes it possible to visualize the details of dendrites, which reach the outer edge of the molecular layer, and their axon (mossy fiber) terminals, which project to the CA3 region where they form synaptic boutons. GFP expression covers the whole developmental stage of newborn neurons, beginning within the first week of cell division and disappearing as newborn neurons mature, about 4 weeks postmitotic. Thus, the GAD67-GFP transgenic mice provide a useful genetic tool for studying the development and regulation of newborn dentate granule cells. PMID:20824075

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2016-11-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2011-01-01

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

  5. FosB Null Mutant Mice Show Enhanced Methamphetamine Neurotoxicity: Potential Involvement of FosB in Intracellular Feedback Signaling and Astroglial Function

    PubMed Central

    Kuroda, Kumi O; Ornthanalai, Veravej G; Kato, Tadafumi; Murphy, Niall P

    2010-01-01

    Previous studies show that (1) two members of fos family transcription factors, c-Fos and FosB, are induced in frontal brain regions by methamphetamine; (2) null mutation of c-Fos exacerbates methamphetamine-induced neurotoxicity; and (3) null mutation of FosB enhances behavioral responses to cocaine. Here we sought a role of FosB in responses to methamphetamine by studying FosB null mutant (−/−) mice. After a 10 mg/kg methamphetamine injection, FosB(−/−) mice were more prone to self-injury. Concomitantly, the intracellular feedback regulators of Sprouty and Rad-Gem-Kir (RGK) family transcripts had lower expression profiles in the frontoparietal cortex and striatum of the FosB(−/−) mice. Three days after administration of four 10 mg/kg methamphetamine injections, the frontoparietal cortex and striatum of FosB(−/−) mice contained more degenerated neurons as determined by Fluoro-Jade B staining. The abundance of the small neutral amino acids, serine, alanine, and glycine, was lower and/or was poorly induced after methamphetamine administration in the frontoparietal cortex and striatum of FosB(−/−) mice. In addition, methamphetamine-treated FosB(−/−) frontoparietal and piriform cortices showed more extravasation of immunoglobulin, which is indicative of blood–brain barrier dysfunction. Methamphetamine-induced hyperthermia, brain dopamine content, and loss of tyrosine hydroxylase immunoreactivity in the striatum, however, were not different between genotypes. These data indicate that FosB is involved in thermoregulation-independent protective functions against methamphetamine neurotoxicity in postsynaptic neurons. Our findings suggest two possible mechanisms of FosB-mediated neuroprotection: one is induction of negative feedback regulation within postsynaptic neurons through Sprouty and RGK. Another is supporting astroglial function such as maintenance of the blood–brain barrier, and metabolism of serine and glycine, which are important

  6. FosB null mutant mice show enhanced methamphetamine neurotoxicity: potential involvement of FosB in intracellular feedback signaling and astroglial function.

    PubMed

    Kuroda, Kumi O; Ornthanalai, Veravej G; Kato, Tadafumi; Murphy, Niall P

    2010-02-01

    Previous studies show that (1) two members of fos family transcription factors, c-Fos and FosB, are induced in frontal brain regions by methamphetamine; (2) null mutation of c-Fos exacerbates methamphetamine-induced neurotoxicity; and (3) null mutation of FosB enhances behavioral responses to cocaine. Here we sought a role of FosB in responses to methamphetamine by studying FosB null mutant (-/-) mice. After a 10 mg/kg methamphetamine injection, FosB(-/-) mice were more prone to self-injury. Concomitantly, the intracellular feedback regulators of Sprouty and Rad-Gem-Kir (RGK) family transcripts had lower expression profiles in the frontoparietal cortex and striatum of the FosB(-/-) mice. Three days after administration of four 10 mg/kg methamphetamine injections, the frontoparietal cortex and striatum of FosB(-/-) mice contained more degenerated neurons as determined by Fluoro-Jade B staining. The abundance of the small neutral amino acids, serine, alanine, and glycine, was lower and/or was poorly induced after methamphetamine administration in the frontoparietal cortex and striatum of FosB(-/-) mice. In addition, methamphetamine-treated FosB(-/-) frontoparietal and piriform cortices showed more extravasation of immunoglobulin, which is indicative of blood-brain barrier dysfunction. Methamphetamine-induced hyperthermia, brain dopamine content, and loss of tyrosine hydroxylase immunoreactivity in the striatum, however, were not different between genotypes. These data indicate that FosB is involved in thermoregulation-independent protective functions against methamphetamine neurotoxicity in postsynaptic neurons. Our findings suggest two possible mechanisms of FosB-mediated neuroprotection: one is induction of negative feedback regulation within postsynaptic neurons through Sprouty and RGK. Another is supporting astroglial function such as maintenance of the blood-brain barrier, and metabolism of serine and glycine, which are important glial modulators of nerve cells.

  7. Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke-Korsakoff syndrome.

    PubMed

    Inaba, Hiroyoshi; Kishimoto, Takuya; Oishi, Satoru; Nagata, Kan; Hasegawa, Shunsuke; Watanabe, Tamae; Kida, Satoshi

    2016-12-01

    Patients with severe Wernicke-Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation.

  8. Vitamin B1-deficient mice show impairment of hippocampus-dependent memory formation and loss of hippocampal neurons and dendritic spines: potential microendophenotypes of Wernicke–Korsakoff syndrome

    PubMed Central

    Inaba, Hiroyoshi; Kishimoto, Takuya; Oishi, Satoru; Nagata, Kan; Hasegawa, Shunsuke; Watanabe, Tamae; Kida, Satoshi

    2016-01-01

    Patients with severe Wernicke–Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation. PMID:27576603

  9. Low intensity, long term exposure to tobacco smoke inhibits hippocampal neurogenesis in adult mice.

    PubMed

    Csabai, Dávid; Csekő, Kata; Szaiff, Lilla; Varga, Zsófia; Miseta, Attila; Helyes, Zsuzsanna; Czéh, Boldizsár

    2016-04-01

    Previous data have shown that high dose of nicotine administration or tobacco smoke exposure can reduce cell formation and the survival rate of adult-born neurons in the dentate gyrus. Here, we subjected adult mice to low intensity cigarette smoke exposure over long time periods. We did a 2×30min/day smoke exposure with two cigarettes per occasion over 1- or 2-months. Subsequently, we carried out a systematic quantitative histopathological analysis to assess the number of newborn neurons in the dentate gyrus. To investigate cell proliferation, the exogenous marker 5-bromo-2'-deoxyuridine (BrdU) was administered on the last experimental day and animals were sacrificed 2h later. To investigate the effect of tobacco smoke on the population of immature neurons, we quantified the number of doublecortin-positive (DCX+) neurons in the same animals. We found that exposing animals to cigarette smoke for 1- or 2-months had no influence on cell proliferation rate, but significantly reduced the number of DCX-positive immature neurons. Our tobacco smoke exposure regimen caused no substantial changes in respiratory functions, but histopathological analysis of the pulmonary tissue revealed a marked perivascular/peribronchial edema formation after 1-month and signs of chronic pulmonary inflammation after 2-months of cigarette smoke exposure. These data demonstrate that even mild exposure to cigarette smoke, without significantly affecting respiratory functions, can have a negative effect on adult-born neurons in the dentate gyrus, when applied over longer time periods. Our data indicate that besides nicotine other factors, such as inflammatory mediators, may also contribute to this effect.

  10. Preschoolers with Down Syndrome Do Not yet Show the Learning and Memory Impairments Seen in Adults with Down Syndrome

    ERIC Educational Resources Information Center

    Roberts, Lynette V.; Richmond, Jenny L.

    2015-01-01

    Individuals with Down syndrome (DS) exhibit a behavioral phenotype of specific strengths and weaknesses, in addition to a generalized cognitive delay. In particular, adults with DS exhibit specific deficits in learning and memory processes that depend on the hippocampus, and there is some suggestion of impairments on executive function tasks that…

  11. Trials in adult critical care that show increased mortality of the new intervention: Inevitable or preventable mishaps?

    PubMed

    Russell, James A; Williams, Mark D

    2016-12-01

    Several promising therapies assessed in the adult critically ill in large, multicenter randomized controlled trials (RCTs) were associated with significantly increased mortality in the intervention arms. Our hypothesis was that there would be wide ranges in sponsorship (industry or not), type(s) of intervention(s), use of DSMBs, presence of interim analyses and early stopping rules, absolute risk increase (ARI), and whether or not adequate prior proof-of-principle Phase II studies were done of RCTs that found increased mortality rates of the intervention compared to control groups. We reviewed RCTs that showed a statistically significant increased mortality rate in the intervention compared to control group(s). We recorded source of sponsorship, sample sizes, types of interventions, mortality rates, ARI (as well as odds ratios, relative risks and number needed to harm), whether there were pre-specified interim analyses and early stopping rules, and whether or not there were prior proof-of-principle (also known as Phase II) RCTs. Ten RCTs (four industry sponsored) of many interventions (high oxygen delivery, diaspirin cross-linked hemoglobin, growth hormone, methylprednisolone, hetastarch, high-frequency oscillation ventilation, intensive insulin, NOS inhibition, and beta-2 adrenergic agonist, TNF-α receptor) included 19,126 patients and were associated with wide ranges of intervention versus control group mortality rates (25.7-59 %, mean 29.9 vs 17-49 %, mean 25 %, respectively) yielding ARIs of 2.6-29 % (mean 5 %). All but two RCTs had pre-specified interim analyses, and seven RCTs were stopped early. All RCTs were preceded by published proof-of-principle RCT(s), two by the same group. Seven interventions (except diaspirin cross-linked hemoglobin and the NOS inhibitor) were available for use clinically at the time of the pivotal RCT. Common, clinically available interventions used in the critically ill were associated with increased mortality in large

  12. Still life with less: North Korean young adult defectors in South Korea show continued poor nutrition and physique.

    PubMed

    Choi, Seul Ki; Park, Sang Min; Joung, Hyojee

    2010-04-01

    North Korean defectors who settle in South Korea have experienced severe food shortage and transition of food environment which could affect their health status. However, little is known about their anthropometric measurements and dietary intake after settlement in South Korea. The purpose of this study is to compare anthropometric measurements and dietary intake between North Korean young adults who defected to South Korea and those of South Koreans. We hypothesized that North Korean young adults' physiques and dietary intake would be poorer than that of South Koreans. We compared anthropometric measurements and dietary intake from 3-day food records in a cross-sectional study of 103 North Korean young adult defectors, aged 12 to 24 and 309 South Korean subjects. North Korean subjects were significantly shorter (4.9 to 10.8 cm) and lighter (6.0 to 12.5 kg) than the control group. Body mass index were significantly different between North and South Korean groups only in men. North Korean young adult defectors had lower mean daily intakes of energy and most nutrients and food groups compared to the control group, while North Korean subjects had higher nutrient density diet than that of South Koreans. The proportion of subjects who had dietary intakes of nutrients of less than the Estimated Average Requirement was higher in North Korean subjects than in controls except for in the cases of vitamin A and vitamin C. In conclusion, we recommend providing nutrition support programs for North Korean young adult defectors to secure adequate nutrient intake.

  13. Prion Protein (PrP) Knock-Out Mice Show Altered Iron Metabolism: A Functional Role for PrP in Iron Uptake and Transport

    PubMed Central

    Singh, Ajay; Kong, Qingzhong; Luo, Xiu; Petersen, Robert B.; Meyerson, Howard; Singh, Neena

    2009-01-01

    Despite overwhelming evidence implicating the prion protein (PrP) in prion disease pathogenesis, the normal function of this cell surface glycoprotein remains unclear. In previous reports we demonstrated that PrP mediates cellular iron uptake and transport, and aggregation of PrP to the disease causing PrP-scrapie (PrPSc) form results in imbalance of iron homeostasis in prion disease affected human and animal brains. Here, we show that selective deletion of PrP in transgenic mice (PrPKO) alters systemic iron homeostasis as reflected in hematological parameters and levels of total iron and iron regulatory proteins in the plasma, liver, spleen, and brain of PrPKO mice relative to matched wild type controls. Introduction of radiolabeled iron (59FeCl3) to Wt and PrPKO mice by gastric gavage reveals inefficient transport of 59Fe from the duodenum to the blood stream, an early abortive spike of erythropoiesis in the long bones and spleen, and eventual decreased 59Fe content in red blood cells and all major organs of PrPKO mice relative to Wt controls. The iron deficient phenotype of PrPKO mice is reversed by expressing Wt PrP in the PrPKO background, demonstrating a functional role for PrP in iron uptake and transport. Since iron is required for essential metabolic processes and is also potentially toxic if mismanaged, these results suggest that loss of normal function of PrP due to aggregation to the PrPSc form induces imbalance of brain iron homeostasis, resulting in disease associated neurotoxicity. PMID:19568430

  14. The cholesterol-lowering agent methyl-β-cyclodextrin promotes glucose uptake via GLUT4 in adult muscle fibers and reduces insulin resistance in obese mice.

    PubMed

    Llanos, Paola; Contreras-Ferrat, Ariel; Georgiev, Tihomir; Osorio-Fuentealba, Cesar; Espinosa, Alejandra; Hidalgo, Jorge; Hidalgo, Cecilia; Jaimovich, Enrique

    2015-02-15

    Insulin stimulates glucose uptake in adult skeletal muscle by promoting the translocation of GLUT4 glucose transporters to the transverse tubule (T-tubule) membranes, which have particularly high cholesterol levels. We investigated whether T-tubule cholesterol content affects insulin-induced glucose transport. Feeding mice a high-fat diet (HFD) for 8 wk increased by 30% the T-tubule cholesterol content of triad-enriched vesicular fractions from muscle tissue compared with triads from control mice. Additionally, isolated muscle fibers (flexor digitorum brevis) from HFD-fed mice showed a 40% decrease in insulin-stimulated glucose uptake rates compared with fibers from control mice. In HFD-fed mice, four subcutaneous injections of MβCD, an agent reported to extract membrane cholesterol, improved their defective glucose tolerance test and normalized their high fasting glucose levels. The preincubation of isolated muscle fibers with relatively low concentrations of MβCD increased both basal and insulin-induced glucose uptake in fibers from controls or HFD-fed mice and decreased Akt phosphorylation without altering AMPK-mediated signaling. In fibers from HFD-fed mice, MβCD improved insulin sensitivity even after Akt or CaMK II inhibition and increased membrane GLUT4 content. Indinavir, a GLUT4 antagonist, prevented the stimulatory effects of MβCD on glucose uptake. Addition of MβCD elicited ryanodine receptor-mediated calcium signals in isolated fibers, which were essential for glucose uptake. Our findings suggest that T-tubule cholesterol content exerts a critical regulatory role on insulin-stimulated GLUT4 translocation and glucose transport and that partial cholesterol removal from muscle fibers may represent a useful strategy to counteract insulin resistance.

  15. Caveolin-1-deficient Mice Show Accelerated Mammary Gland Development During Pregnancy, Premature Lactation, and Hyperactivation of the Jak-2/STAT5a Signaling Cascade

    PubMed Central

    Park, David S.; Lee, Hyangkyu; Frank, Philippe G.; Razani, Babak; Nguyen, Andrew V.; Parlow, Albert F.; Russell, Robert G.; Hulit, James; Pestell, Richard G.; Lisanti, Michael P.

    2002-01-01

    It is well established that mammary gland development and lactation are tightly controlled by prolactin signaling. Binding of prolactin to its cognate receptor (Prl-R) leads to activation of the Jak-2 tyrosine kinase and the recruitment/tyrosine phosphorylation of STAT5a. However, the mechanisms for attenuating the Prl-R/Jak-2/STAT5a signaling cascade are just now being elucidated. Here, we present evidence that caveolin-1 functions as a novel suppressor of cytokine signaling in the mammary gland, akin to the SOCS family of proteins. Specifically, we show that caveolin-1 expression blocks prolactin-induced activation of a STAT5a-responsive luciferase reporter in mammary epithelial cells. Furthermore, caveolin-1 expression inhibited prolactin-induced STAT5a tyrosine phosphorylation and DNA binding activity, suggesting that caveolin-1 may negatively regulate the Jak-2 tyrosine kinase. Because the caveolin-scaffolding domain bears a striking resemblance to the SOCS pseudosubstrate domain, we examined whether Jak-2 associates with caveolin-1. In accordance with this homology, we demonstrate that Jak-2 cofractionates and coimmunoprecipitates with caveolin-1. We next tested the in vivo relevance of these findings using female Cav-1 (−/−) null mice. If caveolin-1 normally functions as a suppressor of cytokine signaling in the mammary gland, then Cav-1 null mice should show premature development of the lobuloalveolar compartment because of hyperactivation of the prolactin signaling cascade via disinhibition of Jak-2. In accordance with this prediction, Cav-1 null mice show accelerated development of the lobuloalveolar compartment, premature milk production, and hyperphosphorylation of STAT5a (pY694) at its Jak-2 phosphorylation site. In addition, the Ras-p42/44 MAPK cascade is hyper-activated. Because a similar premature lactation phenotype is observed in SOCS1 (−/−) null mice, we conclude that caveolin-1 is a novel suppressor of cytokine signaling. PMID:12388746

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

    PubMed

    Kilicaslan, Alper; Belviranli, Muaz; Okudan, Nilsel; Nurullahoglu Atalik, Esra

    2013-12-01

    Volatile anesthetics are known to disturb the spatial memory in aged rodents, but there is insufficient information on their effects on young adult rodents. The aim of this study was to compare the effects of single and repeated exposure to desflurane and sevoflurane on spatial learning and memory functions in young adult mice. Balb/c mice (2 months old) were randomly divided into six equal groups (n = 8). The groups with single inhalation were exposed to 3.3% sevoflurane or 7.8% desflurane or vehicle gas for 4 h, respectively. The groups with repeated inhalation were exposed to 3.3% sevoflurane or 7.8% desflurane or vehicle gas for 2 h a day during 5 consecutive days. Spatial learning and memory were tested in the Morris water maze 24 h after exposure. In the learning phase, the parameters associated with finding the hidden platform and swimming speed, and in the memory phase, time spent in the target quadrant and the adjacent quadrants, were assessed and compared between the groups. In the 4-day learning process, there was no significant difference between the groups in terms of mean latency to platform, mean distance traveled and average speed (P > 0.05). During the memory-test phase, all mice exhibited spatial memory, but there was no significant difference between the groups in terms of time spent in the target quadrant (P > 0.05). Sevoflurane and desflurane anesthesia did not impair acquisition learning and retention memory in young adult mice.

  17. Adolescent mice show anxiety- and aggressive-like behavior and the reduction of long-term potentiation in mossy fiber-CA3 synapses after neonatal maternal separation.

    PubMed

    Shin, S Y; Han, S H; Woo, R-S; Jang, S H; Min, S S

    2016-03-01

    Exposure to maternal separation (MS) during early life is an identified risk factor for emotional disorders such as anxiety and depression later in life. This study investigated the effects of neonatal MS on the behavior and long-term potentiation (LTP) as well as basic synaptic transmission at hippocampal CA3-CA1 and mossy fiber (MF)-CA3 synapses in adolescent mice for 19days. When mice were adolescents, we measured depression, learning, memory, anxious and aggressive behavior using the forced swimming test (FST), Y-maze, Morris water maze (MWM), elevated plus maze (EPM), three consecutive days of the open field test, the social interaction test, the tube-dominance test and the resident-intruder test. The results showed that there was no difference in FST, Y-maze, and MWM performance. However, MS mice showed more anxiety-like behavior in the EPM test and aggressive-like behavior in the tube-dominance and resident-intruder tests. In addition, the magnitude of LTP and release probability in the MF-CA3 synapses was reduced in the MS group but not in the CA3-CA1 synapse. Our results indicate that early life stress due to MS may induce anxiety- and aggressive-like behavior during adolescence, and these effects are associated with synaptic plasticity at the hippocampal MF-CA3 synapses.

  18. The characterization of the first anti-mouse Muc6 antibody shows an increased expression of the mucin in pancreatic tissue of Cftr-knockout mice.

    PubMed

    Gouyer, Valérie; Leir, Shih-Hsing; Tetaert, Daniel; Liu, Yamin; Gottrand, Frédéric; Harris, Ann; Desseyn, Jean-Luc

    2010-05-01

    Gel-forming mucins are large high-molecular weight secreted O-glycoproteins responsible for the gel-properties of the mucus blanket. Five orthologous gel-forming mucins have been cloned in human and mouse. Among them, the mucin MUC6 has been less studied, particularly in rodents and no anti rodent-Muc6 antibody has been reported yet. In order to further study Muc6 in mice, our aims were to obtain a specific Muc6 antibody, to validate it and to test it in Cftr deficient mice. A polyclonal serum named CP4 was isolated from a rabbit immunized by a mouse Muc6 peptide. In Western blot experiments, the antibody detected a high-molecular weight molecule secreted by the gastric tissue. Using immunohistochemistry, we showed that the antibody reacted strongly with deep glands of duodenum and ileum and mucous neck cells of gastric body. CP4 also recognized Muc6 protein secreted at the surface of the stomach and renal collecting tubules. The centroacinar cells of pancreatic tissue also reacted with the antibody. Cftr-/- mice showed a higher expression of Muc6 at both protein and RNA levels compared with their control Cftr+/+ littermates suggesting that as in the human disease, Muc6 may contribute to the formation of materials that block pancreatic acini and ducts in mouse models of cystic fibrosis. The rabbit anti-mouse Muc6 polyclonal antibody seems highly specific to the mouse mucin and will be useful to study pancreatic pathology in cystic fibrosis.

  19. In Utero Exposure to Benzo[a]Pyrene Increases Mutation Burden in the Soma and Sperm of Adult Mice

    PubMed Central

    Meier, Matthew J.; O’Brien, Jason M.; Beal, Marc A.; Allan, Beverly; Yauk, Carole L.; Marchetti, Francesco

    2016-01-01

    Background: Mosaicism, the presence of genetically distinct cell populations within an organism, has emerged as an important contributor to disease. Mutational events occurring during embryonic development can cause mosaicism in any tissue, but the influence of environmental factors on levels of mosaicism is unclear. Objectives: We investigated whether in utero exposure to the widespread environmental mutagen benzo[a]pyrene (BaP) has an impact on the burden and distribution of mutations in adult mice. Methods: We used the Muta™Mouse transgenic rodent model to quantify and characterize mutations in the offspring of pregnant mice exposed to BaP during postconception days 7 through 16, covering the major period of organogenesis in mice. Next-generation DNA sequencing was then used to determine the spectrum of mutations induced in adult mice that were exposed to BaP during fetal development. Results: Mutation frequency was significantly increased in the bone marrow, liver, brain, and sperm of first filial generation (F1) males. Developing embryos accumulated more mutations and exhibited higher proportions of mosaicism than exposed adults, particularly in the brain. Decreased sperm count and motility revealed additional negative impacts on the reproductive function of F1 males. Conclusion: In utero exposure to environmental mutagens contributes to somatic and germline mosaicism, permanently affecting both the genetic health of the F1 and the population gene pool. Citation: Meier MJ, O’Brien JM, Beal MA, Allan B, Yauk CL, Marchetti F. 2017. In utero exposure to benzo[a]pyrene increases mutation burden in the soma and sperm of adult mice. Environ Health Perspect 125:82–88; http://dx.doi.org/10.1289/EHP211 PMID:27448386

  20. Preschoolers with Down syndrome do not yet show the learning and memory impairments seen in adults with Down syndrome.

    PubMed

    Roberts, Lynette V; Richmond, Jenny L

    2015-05-01

    Individuals with Down syndrome (DS) exhibit a behavioral phenotype of specific strengths and weaknesses, in addition to a generalized cognitive delay. In particular, adults with DS exhibit specific deficits in learning and memory processes that depend on the hippocampus, and there is some suggestion of impairments on executive function tasks that depend on the prefrontal cortex. While these functions have been investigated in adults with DS, it is largely unclear how these processes develop in young children with DS. Here we tested preschoolers with DS and typically developing children, age-matched on either receptive language or non-verbal scores as a proxy for mental age (MA), on a battery of eye-tracking and behavioral measures that have been shown to depend on the hippocampus or the prefrontal cortex. Preschoolers with DS performed equivalently to MA-matched controls, suggesting that the disability-specific memory deficits documented in adults with DS, in addition to a cognitive delay, are not yet evident in preschoolers with DS, and likely emerge progressively with age. Our results reinforce the idea that early childhood may be a critical time frame for targeted early intervention. A video abstract of this article can be viewed at https://www.youtube.com/watch?v=r6GUA6my22Q&list=UU3FIcom6UpITHZOIEa8Onnw.

  1. Viable RNaseH1 knockout mice show RNaseH1 is essential for R loop processing, mitochondrial and liver function

    PubMed Central

    Lima, Walt F.; Murray, Heather M.; Damle, Sagar S.; Hart, Christopher E.; Hung, Gene; De Hoyos, Cheryl Li; Liang, Xue-Hai; Crooke, Stanley T.

    2016-01-01

    Viable constitutive and tamoxifen inducible liver-specific RNase H1 knockout mice that expressed no RNase H1 activity in hepatocytes showed increased R-loop levels and reduced mitochondrial encoded DNA and mRNA levels, suggesting impaired mitochondrial R-loop processing, transcription and mitochondrial DNA replication. These changes resulted in mitochondrial dysfunction with marked changes in mitochondrial fusion, fission, morphology and transcriptional changes reflective of mitochondrial damage and stress. Liver degeneration ensued, as indicated by apoptosis, fibrosis and increased transaminase levels. Antisense oligonucleotides (ASOs) designed to serve as substrates for RNase H1 were inactive in the hepatocytes from the RNase H1 knockout mice and in vivo, demonstrating that RNase H1 is necessary for the activity of DNA-like ASOs. During liver regeneration, a clone of hepatocytes that expressed RNase H1 developed and partially restored mitochondrial and liver function. PMID:27131367

  2. Confocal laser scanning microscopic observation on adult Schistosoma japonicum harbored in mice following treatment with single-dose mefloquine.

    PubMed

    Xiao, Shu-Hua; Sun, Jun; Xue, Jian

    2012-06-01

    The aim of the present study is to assess the mefloquine-induced alteration of adult Schistosoma japonicum using confocal laser scanning microscopy (CLSM). Eight out of ten mice infected with 60-80 S. japonicum cercariae for 35 days were treated orally with mefloquine at a single dose of 400 mg/kg. Four groups of two mice were killed at 24 h and 3, 7, and 14 days post-treatment, and schistosomes were collected by perfusion from the liver and mesenteric veins, fixed in 70% alcohol, stained with acid carmine, and examined by CLSM. Worms obtained from untreated mice served as controls. Twenty-four hours post-treatment, focal tegument of adult male and female worms, which composed of fine and short villus-like materials, became thicker and longer, or disorder arrangement, while the musculatures beneath the tegument revealed in focal and irregular swelling with various degrees. In the gut of male and female schistosomes, severe dilatation accompanied by swelling, collapse, and peeling of gut mucosa was universal. In the reproductive organs, no apparent alteration in the testis structure of male worms was seen, while in female worms, slight damage to the ovary included loose arrangement of mature ovary cells accompanied by some of them degenerated and collapsed. As to vitelline glands, severe damage, such as swelling, indistinction, fusion or collapse of vitelline cells, and apparent swelling of parenchymal tissues in vitelline gland lobules, was seen. Meanwhile, abnormal ova emerged in the uterus at this time point. Three to 7 days post-treatment, the damage to the worms aggravated either in extent or in severity along with time. In some focally swollen worm body, the parenchymal tissues revealed in severe swelling. In addition, a large piece of degenerated and necrotic parenchymal tissues emerged closed to the severe destructed oral or ventral sucker. In the gut of male and female worms, the major alterations manifested by focal collapse or peeling of mucosa, and

  3. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water.

    PubMed

    Krishna, Saritha; Dodd, Celia A; Hekmatyar, Shahryar K; Filipov, Nikolay M

    2014-01-01

    Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e., mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) levels, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post-Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure.

  4. Sex and Laterality Differences in Medial Amygdala Neurons and Astrocytes of Adult Mice

    PubMed Central

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

    2016-01-01

    The posterodorsal aspect of the medial amygdala (MePD) in rats is sexually dimorphic, being larger and containing more and larger neurons in males than in females. It is also highly lateralized, with the right MePD larger than the left in both sexes, but with the smaller left MePD actually containing more and larger neurons than the larger right. Astrocytes are also strikingly sexually differentiated, with male-biased numbers and lateralized favoring the right in the rat MePD. However, comparable information is scant for mice where genetic tools offer greater experimental power. Hence, we examined the MePD from adult male and female C57Bl/6J mice. We now report that the MePD is larger in males than in females, with the MePD in males containing more astrocytes and neurons than in females. However, we did not find sex differences in astrocyte complexity or overall glial number nor effects of laterality in either measure. While the mouse MePD is generally less lateralized than in rats, we did find that the sex difference in astrocyte number is only on the right because of a significant lateralization in females, with significantly fewer astrocytes on the right than the left but only in females. A sex difference in neuronal soma size favoring males was also evident, but only on the left. Sex differences in the number of neurons and astrocytes common to both rodent species may represent core morphological features that critically underlie the expression of sex-specific behaviors that depend on the MePD. PMID:26780286

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

    PubMed

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

    2015-10-01

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

  6. Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water

    PubMed Central

    Saritha, Krishna; Celia, Dodd A.; Shahryar, Hekmatyar K.; Nikolay, Filipov M.

    2013-01-01

    Natural leaching processes and/or anthropogenic contamination can result in ground water concentrations of the essential metal manganese (Mn) that far exceed the current regulatory standards. Neurological consequences of Mn drinking water (DW) overexposure to experimental animals, i.e. mice, including its brain deposition/distribution and behavioral effects are understudied. Adult male C57BL/6 mice were exposed to Mn via the DW for 8 weeks. After 5 weeks of Mn exposure, magnetic resonance imaging revealed significant Mn deposition in all examined brain regions; the degree of Mn deposition did not increase further a week later. Behaviorally, early hyperactivity and more time spent in the center of the arenas in an open field test, decreased forelimb grip strength and less time swimming in a forced swim test were observed after 6 weeks of Mn DW exposure. Eight-week Mn DW exposure did not alter striatal dopamine, its metabolites, or the expression of key dopamine homeostatic proteins, but it significantly increased striatal 5-hydroxyindoleacetic acid (a serotonin metabolite) level, without affecting the levels of serotonin itself. Increased expression (mRNA) of glial fibrillary acidic protein (GFAP, an astrocyte activation marker), heme oxygenase-1 and inducible nitric oxide synthase (oxidative and nitrosative stress markers, respectively) were observed 8 weeks post Mn DW exposure in the substantia nigra. Besides mRNA increases, GFAP protein expression was increased in the substantia nigra pars reticulata. In summary, the neurobehavioral deficits, characterized by locomotor and emotional perturbations, and nigral glial activation associated with significant brain Mn deposition are among the early signs of Mn neurotoxicity caused by DW overexposure. PMID:23832297

  7. Mapping of fluorescent protein-expressing neurons and axon pathways in adult and developing Thy1-eYFP-H transgenic mice.

    PubMed

    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.

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

    PubMed

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

    2008-09-01

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

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

    PubMed

    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

  10. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

    PubMed Central

    Ladrón de Guevara-Miranda, David; Millón, Carmelo; Rosell-Valle, Cristina; Pérez-Fernández, Mercedes; Missiroli, Michele; Serrano, Antonia; Pavón, Francisco J.; Rodríguez de Fonseca, Fernando; Martínez-Losa, Magdalena; Álvarez-Dolado, Manuel; Santín, Luis J.

    2017-01-01

    ABSTRACT Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV)+ and neuropeptide Y (NPY)+ interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal. PMID:28138095

  11. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis.

    PubMed

    Ladrón de Guevara-Miranda, David; Millón, Carmelo; Rosell-Valle, Cristina; Pérez-Fernández, Mercedes; Missiroli, Michele; Serrano, Antonia; Pavón, Francisco J; Rodríguez de Fonseca, Fernando; Martínez-Losa, Magdalena; Álvarez-Dolado, Manuel; Santín, Luis J; Castilla-Ortega, Estela

    2017-03-01

    Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA(+), parvalbumin (PV)(+) and neuropeptide Y (NPY)(+) interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA(+) cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV(+) and NPY(+) neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal.

  12. Learning and Memory Deficits in Male Adult Mice Treated with a Benzodiazepine Sleep-Inducing Drug during the Juvenile Period

    PubMed Central

    Furukawa, Yusuke; Tanemura, Kentaro; Igarashi, Katsuhide; Ideta-Otsuka, Maky; Aisaki, Ken-Ichi; Kitajima, Satoshi; Kitagawa, Masanobu; Kanno, Jun

    2016-01-01

    Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian central nervous system, is also known to be important for brain development. Therefore, disturbances of GABA receptor (GABA-R) mediated signaling (GABA-R signal) during brain development may influence normal brain maturation and cause late-onset brain malfunctions. In this study, we examined whether the stimulation of the GABA-R signal during brain development induces late-onset adverse effects on the brain in adult male mice. To stimulate the GABA-R signal, we used either the benzodiazepine sleep-inducing drug triazolam (TZ) or the non-benzodiazepine drug zolpidem (ZP). We detected learning and memory deficits in mice treated with TZ during the juvenile period, as seen in the fear conditioning test. On the other hand, ZP administration during the juvenile period had little effect. In addition, decreased protein expression of GluR1 and GluR4, which are excitatory neurotransmitter receptors, was detected in the hippocampi of mice treated with TZ during the juvenile period. We measured mRNA expression of the immediate early genes (IEGs), which are neuronal activity markers, in the hippocampus shortly after the administration of TZ or ZP to juvenile mice. Decreased IEG expression was detected in mice with juvenile TZ administration, but not in mice with juvenile ZP administration. Our findings demonstrate that TZ administration during the juvenile period can induce irreversible learning and memory deficits in adult mice. It may need to take an extra care for the prescription of benzodiazepine sleep-inducing drugs to juveniles because it might cause learning and memory deficits. PMID:27489535

  13. Transcription levels of sirtuin family in neural stem cells and brain tissues of adult mice.

    PubMed

    Wang, H F; Li, Q; Feng, R L; Wen, T Q

    2012-09-10

    Neural stem cells (NSCs) has been used as a well-known model to investigate apoptosis, differentiation, maintenance of stem cells status, and therapy of neurological disease. The C17.2 NSCs line was produced after v-myc transformation of neural progenitor from mouse cerebellar cortex. Sirtuin family plays important roles involved in neuronal differentiation, genomic stability, lifespan, cell survival. However, little is known about gene expression variation of sirtuin family in C17.2 NSCs, primary NSCs, and different brain tissues in adult mice. Here, we confirmed that the mRNA expression levels of sirt2, 3, 4, 5, and 7 in E14.5 NSCs were significantly higher than in C17.2 NSCs, whereas that sirt 6 displayed an opposing mode. Moreover, a higher mRNA level of sirtuin family was observed in the adult mouse brain compared to C17.2 NSCs. In addition, histone deacetylase (HDAC) inhibitors nicotinamide and Trichostatin A (TSA) were used to explore differential changes at the transcriptional level of sirtuins. Results indicated that the expression of sirt1, sirt5 and sirt6 was significant downregulated by nicotinamide treatment. Whereas, a significant downregulation in sirt1 and sirt3 and a significant upregulation in sirt2, sirt4, sirt6, and sirt7 were observed in the treatment of TSA. Thus our studies indicate different sirtuin mRNA expression profiles between C17.2 NSCs, E14.5 NSCs and brain tissues, suggesting the transcriptional regulation of sirtuin family could be mediated by different histone acetylation.

  14. Culture and adenoviral infection of sinoatrial node myocytes from adult mice

    PubMed Central

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

    2015-01-01

    Pacemaker myocytes in the sinoatrial node of the heart initiate each heartbeat by firing spontaneous action potentials. However, the molecular processes that underlie pacemaking are incompletely understood, in part because of our limited ability to manipulate protein expression within the native cellular context of sinoatrial node myocytes (SAMs). Here we describe a new method for the culture of fully differentiated SAMs from adult mice, and we demonstrate that robust expression of introduced proteins can be achieved within 24–48 h in vitro via adenoviral gene transfer. Comparison of morphological and electrophysiological characteristics of 48 h-cultured versus acutely isolated SAMs revealed only minor changes in vitro. Specifically, we found that cells tended to flatten in culture but retained an overall normal morphology, with no significant changes in cellular dimensions or membrane capacitance. Cultured cells beat spontaneously and, in patch-clamp recordings, the spontaneous action potential firing rate did not differ between cultured and acutely isolated cells, despite modest changes in a subset of action potential waveform parameters. The biophysical properties of two membrane currents that are critical for pacemaker activity in SAMs, the “funny current” (If) and voltage-gated Ca2+ currents (ICa), were also indistinguishable between cultured and acutely isolated cells. This new method for culture and adenoviral infection of fully-differentiated SAMs from the adult mouse heart expands the range of experimental techniques that can be applied to study the molecular physiology of cardiac pacemaking because it will enable studies in which protein expression levels can be modified or genetically encoded reporter molecules expressed within SAMs. PMID:26001410

  15. Rotavirus Infection Activates Dendritic Cells from Peyer's Patches in Adult Mice ▿ †

    PubMed Central

    Lopez-Guerrero, Delia V.; Meza-Perez, Selene; Ramirez-Pliego, Oscar; Santana-Calderon, Maria A.; Espino-Solis, Pavel; Gutierrez-Xicotencatl, Lourdes; Flores-Romo, Leopoldo; Esquivel-Guadarrama, Fernando R.

    2010-01-01

    This study used an in vivo mouse model to analyze the response of dendritic cells (DCs) in Peyer's patches (PPs) within the first 48 h of infection with the wild-type murine rotavirus EDIM (EDIMwt). After the infection, the absolute number of DCs was increased by 2-fold in the PPs without a modification of their relative percentage of the total cell number. Also, the DCs from PPs of infected mice showed a time-dependent migration to the subepithelial dome (SED) and an increase of the surface activation markers CD40, CD80, and CD86. This response was more evident at 48 h postinfection (p.i.) and depended on viral replication, since DCs from PPs of mice inoculated with UV-treated virus did not show this phenotype. As a result of the activation, the DCs showed an increase in the expression of mRNA for the proinflammatory cytokines interleukin-12/23p40 (IL-12/23p40), tumor necrosis factor alpha (TNF-α), and beta interferon (IFN-β), as well as for the regulatory cytokine IL-10. These results suggest that, a short time after rotavirus infection, the DCs from PPs play a critical role in controlling the infection and, at the same time, avoiding an excessive inflammatory immune response. PMID:20007263

  16. YAC128 Huntington's disease transgenic mice show enhanced short-term hippocampal synaptic plasticity early in the course of the disease.

    PubMed

    Ghilan, Mohamed; Bostrom, Crystal A; Hryciw, Brett N; Simpson, Jessica M; Christie, Brian R; Gil-Mohapel, Joana

    2014-09-18

    Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the protein huntingtin. The disease progresses over decades, but often patients develop cognitive impairments that precede the onset of the classical motor symptoms. Similar to the disease progression in humans, the yeast artificial chromosome (YAC) 128 HD mouse model also exhibits cognitive dysfunction that precedes the onset of the neuropathological and motor impairments characteristic of HD. Thus, the purpose of this study was to evaluate whether short- and long-term synaptic plasticity in the hippocampus, two related biological models of learning and memory processes, were altered in YAC128 mice in early stages of disease progression. We show that the YAC128 hippocampal dentate gyrus (DG) displays marked reductions in paired-pulse depression both at 3 and 6 months of age. In addition, significantly enhanced post-tetanic and short-term potentiation are apparent in YAC128 mice after high-frequency stimulation at this time. Early and late forms of long-term plasticity were not altered at this stage. Together these findings indicate that there may be elevated neurotransmitter release in response to synaptic stimulation in YAC128 mice during the initial phase of disease progression. These abnormalities in short-term plasticity detected at this stage in YAC128 HD transgenic mice indicate that aberrant information processing at the level of the synapses may contribute, at least in part, to the early onset of cognitive deficits that are characteristic of this devastating neurodegenerative disorder.

  17. Embryonic exposure to dimethoate and/or deltamethrin impairs sexual development and programs reproductive success in adult male offspring mice.

    PubMed

    Ben Slima, A; Ben Abdallah, F; Keskes-Ammar, L; Mallek, Z; El Feki, A; Gdoura, R

    2012-05-01

    Pesticides can be toxic to desirable plants and animals, including humans. The aim of this study was to investigate the reproductive effects of low doses of pesticides on male offspring of exposed pregnant mice. Three groups of five female mice were treated daily by oral gavage with dimethoate (5 mg kg(-1) per day), deltamethrin (5 mg kg(-1) per day) and their mixture at 5 mg kg(-1) per day from day 3 to day 21 of pregnancy. Fertility, sexual behaviour and a number of reproductive endpoints, such as organ weights, sperm evaluations and testicular histology, were examined on four adult male offspring of exposed pregnant mice. When compared with control, a dose of deltamethrin 5 mg kg j(-1) causes a decrease in the absolute and relative weight of the testes of exposed mice and it affects their fertility by reducing the density, mobility and vitality of sperm and increasing the number of abnormal forms of these cells (P ≤ 0.01). The same results were obtained in mice exposed to a dose of 5 mg kg j(-1) combination of dimethoate and deltamethrin. This study demonstrated that deltamethrin and combination of dimethoate and deltamethrin caused a decrease in the absolute and relative weight of the testes, which affected the sperm parameters of male offspring of exposed mice to a low dose of these pesticides during pregnancy.

  18. Botulism in metronidazole- treated conventional adult mice challenged orogastrically with spores of Clostridium botulinum type A or B.

    PubMed Central

    Wang, Y; Sugiyama, H

    1984-01-01

    Conventional adult mice were pretreated with metronidazole to make their intestinal tracts receptive to colonization by Clostridium botulinum. These mice, in groups of 10, were fed 0 (controls), 10(2), 10(3), 10(4), or 10(5) C. botulinum type B spores and were placed for observation in filter-lid cages whose screen floors minimized the amounts of feces available for coprophagy. The opportunity to eat feces was made equal for all mouse groups by placing one mouse of every group in each of 10 cages. Mice given a spore inoculum began to develop botulism after incubation periods of slightly less than 2.75 days. Morbidity rates, which reached maxima within 5 days of challenge, were related to inocula levels. Mortality rates were also dose related. Mice given 10(5) spores and then type B antitoxin intraperitoneally, a treatment not affecting intraintestinal toxin production, remained healthy. Morbidity among control mice was seldom more than 10% and could be ascribed to toxin ingested with feces. A C. botulinum type A spore suspension gave similar results, although morbidity and mortality rates were generally lower than after challenge with a comparable number of type B spores. Mice challenged with 10(2) or 10(5) spores had similar toxin levels in their large intestines 48 h later. Morbidity rates correlated better with toxin levels in the small intestines. PMID:6389360

  19. Individual Diet Modeling Shows How to Balance the Diet of French Adults with or without Excessive Free Sugar Intakes

    PubMed Central

    Lluch, Anne; Maillot, Matthieu; Gazan, Rozenn; Vieux, Florent; Delaere, Fabien; Vaudaine, Sarah; Darmon, Nicole

    2017-01-01

    Dietary changes needed to achieve nutritional adequacy for 33 nutrients were determined for 1719 adults from a representative French national dietary survey. For each individual, an iso-energy nutritionally adequate diet was generated using diet modeling, staying as close as possible to the observed diet. The French food composition table was completed with free sugar (FS) content. Results were analyzed separately for individuals with FS intakes in their observed diets ≤10% or >10% of their energy intake (named below FS-ACCEPTABLE and FS-EXCESS, respectively). The FS-EXCESS group represented 41% of the total population (average energy intake of 14.2% from FS). Compared with FS-ACCEPTABLE individuals, FS-EXCESS individuals had diets of lower nutritional quality and consumed more energy (2192 vs. 2123 kcal/day), particularly during snacking occasions (258 vs. 131 kcal/day) (all p-values < 0.01). In order to meet nutritional targets, for both FS-ACCEPTABLE and FS-EXCESS individuals, the main dietary changes in optimized diets were significant increases in fresh fruits, starchy foods, water, hot beverages and plain yogurts; and significant decreases in mixed dishes/sandwiches, meat/eggs/fish and cheese. For FS-EXCESS individuals only, the optimization process significantly increased vegetables and significantly decreased sugar-sweetened beverages, sweet products and fruit juices. The diets of French adults with excessive intakes of FS are of lower nutritional quality, but can be optimized via specific dietary changes. PMID:28230722

  20. Influence of Botulinumtoxin A on the Expression of Adult MyHC Isoforms in the Masticatory Muscles in Dystrophin-Deficient Mice (Mdx-Mice)

    PubMed Central

    Todorov, Teodor

    2016-01-01

    The most widespread animal model to investigate Duchenne muscular dystrophy is the mdx-mouse. In contrast to humans, phases of muscle degeneration are replaced by regeneration processes; hence there is only a restricted time slot for research. The aim of the study was to investigate if an intramuscular injection of BTX-A is able to break down muscle regeneration and has direct implications on the gene expression of myosin heavy chains in the corresponding treated and untreated muscles. Therefore, paralysis of the right masseter muscle was induced in adult healthy and dystrophic mice by a specific intramuscular injection of BTX-A. After 21 days the mRNA expression and protein content of MyHC isoforms of the right and left masseter, temporal, and the tongue muscle were determined using quantitative RT-PCR and Western blot technique. MyHC-IIa and MyHC-I-mRNA expression significantly increased in the paralyzed masseter muscle of control-mice, whereas MyHC-IIb and MyHC-IIx/d-mRNA were decreased. In dystrophic muscles no effect of BTX-A could be detected at the level of MyHC. This study suggests that BTX-A injection is a suitable method to simulate DMD-pathogenesis in healthy mice but further investigations are necessary to fully analyse the BTX-A effect and to generate sustained muscular atrophy in mdx-mice. PMID:27689088

  1. The Protein Kinase KIS Impacts Gene Expression during Development and Fear Conditioning in Adult Mice

    PubMed Central

    Manceau, Valérie; Kremmer, Elisabeth; Nabel, Elizabeth G.; Maucuer, Alexandre

    2012-01-01

    The brain-enriched protein kinase KIS (product of the gene UHMK1) has been shown to phosphorylate the human splicing factor SF1 in vitro. This phosphorylation in turn favors the formation of a U2AF65-SF1-RNA complex which occurs at the 3′ end of introns at an early stage of spliceosome assembly. Here, we analyzed the effects of KIS knockout on mouse SF1 phosphorylation, physiology, adult behavior, and gene expression in the neonate brain. We found SF1 isoforms are differently expressed in KIS-ko mouse brains and fibroblasts. Re-expression of KIS in fibroblasts restores a wild type distribution of SF1 isoforms, confirming the link between KIS and SF1. Microarray analysis of transcripts in the neonate brain revealed a subtle down-regulation of brain specific genes including cys-loop ligand-gated ion channels and metabolic enzymes. Q-PCR analyses confirmed these defects and point to an increase of pre-mRNA over mRNA ratios, likely due to changes in splicing efficiency. While performing similarly in prepulse inhibition and most other behavioral tests, KIS-ko mice differ in spontaneous activity and contextual fear conditioning. This difference suggests that disregulation of gene expression due to KIS inactivation affects specific brain functions. PMID:22937132

  2. Nicotine-Cadmium Interaction Alters Exploratory Motor Function and Increased Anxiety in Adult Male Mice

    PubMed Central

    Chris Ajonijebu, Duyilemi; Adeyemi Adeniyi, Philip; Oloruntoba Adekeye, Adeshina; Peter Olatunji, Babawale; Olakunle Ishola, Azeez; Michael Ogundele, Olalekan

    2014-01-01

    In this study we evaluated the time dependence in cadmium-nicotine interaction and its effect on motor function, anxiety linked behavioural changes, serum electrolytes, and weight after acute and chronic treatment in adult male mice. Animals were separated randomly into four groups of n = 6 animals each. Treatment was done with nicotine, cadmium, or nicotine-cadmium for 21 days. A fourth group received normal saline for the same duration (control). Average weight was determined at 7-day interval for the acute (D1-D7) and chronic (D7-D21) treatment phases. Similarly, the behavioural tests for exploratory motor function (open field test) and anxiety were evaluated. Serum electrolytes were measured after the chronic phase. Nicotine, cadmium, and nicotine-cadmium treatments caused no significant change in body weight after the acute phase while cadmium-nicotine and cadmium caused a decline in weight after the chronic phase. This suggests the role of cadmium in the weight loss observed in tobacco smoke users. Both nicotine and cadmium raised serum Ca2+ concentration and had no significant effect on K+ ion when compared with the control. In addition, nicotine-cadmium treatment increased bioaccumulation of Cd2+ in the serum which corresponded to a decrease in body weight, motor function, and an increase in anxiety. PMID:26317007

  3. Toll-like receptor 2 mediates ischemia-reperfusion injury of the small intestine in adult mice.

    PubMed

    Watanabe, Toshio; Tanigawa, Tetsuya; Kobata, Atsushi; Takeda, Shogo; Nadatani, Yuji; Otani, Koji; Yamagami, Hirokazu; Shiba, Masatsugu; Tominaga, Kazunari; Fujiwara, Yasuhiro; Arakawa, Tetsuo

    2014-01-01

    Toll-like receptor 2 (TLR2) recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R) injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO), a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory mediators

  4. Maneb disturbs expression of superoxide dismutase and glutathione peroxidase, increases reactive oxygen species production, and induces genotoxicity in liver of adult mice.

    PubMed

    Ben Amara, Ibtissem; Ben Saad, Hajer; Hamdaoui, Latifa; Karray, Aida; Boudawara, Tahia; Ben Ali, Yassine; Zeghal, Najiba

    2015-08-01

    Maneb (MB), a fungicide largely used in agriculture throughout the world including Tunisia, protects many vegetables, fruits and field crops against a wide spectrum of fungal diseases. However there is a lack of informations regarding the risks arising from MB exposure on non target organisms, especially mammals. The aim of this study was to investigate the morphological, biochemical and molecular aspects of liver injury after exposure of mice to MB. Four doses of MB corresponding to 1/8 (group D1), 1/6 (group D2), 1/4 (group D3), and 1/2 (group D4) of lethal dose (DL50 = 1500 mg/kg body weight) were administered to adult mice. Oxidative stress parameters were also objectified by molecular and histological endpoints in the liver. Maneb caused hepatotoxicity as characterized by the significant increase in the levels of malondialdehyde and protein oxidation marker, advanced oxidation protein products (AOPP). The activities of catalase, glutathione peroxidase, superoxide dismutase and the levels of glutathione decreased significantly in all treated mice, while vitamin C levels decreased only in group D4. We also noted a significant decrease in gene expression of superoxide dismutase and glutathione peroxidase enzymes. Maneb caused nucleic acids degradation testifying its genotoxicity. Yet, biochemical markers in plasma showed a decrease in total protein and an increase in aspartate, alanine amino transferases and bilirubin levels in all treatment groups. Moreover, plasma levels of cholesterol, triglycerides and low density lipoprotein-cholesterol significantly increased, while those of high density lipoprotein-cholesterol decreased. These biochemical alterations were correlated with significantly histological changes. Our data showed, for the first time, that intraperitoneal injection of very high non environmentally relevant MB concentrations to adult mice resulted in oxidative stress leading to hepatotoxicity and the impairment of defense systems, confirming the

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

    PubMed

    Soumiya, Hitomi; Godai, Ayumi; Araiso, Hiromi; Mori, Shingo; Furukawa, Shoei; Fukumitsu, Hidefumi

    2016-01-01

    Abnormalities in tactile perception, such as sensory defensiveness, are common features in autism spectrum disorder (ASD). While not a diagnostic criterion for ASD, deficits in tactile perception contribute to the observed lack of social communication skills. However, the influence of tactile perception deficits on the development of social behaviors remains uncertain, as do the effects on neuronal circuits related to the emotional regulation of social interactions. In neonatal rodents, whiskers are the most important tactile apparatus, so bilateral whisker trimming is used as a model of early tactile deprivation. To address the influence of tactile deprivation on adult behavior, we performed bilateral whisker trimming in mice for 10 days after birth (BWT10 mice) and examined social behaviors, tactile discrimination, and c-Fos expression, a marker of neural activation, in adults after full whisker regrowth. Adult BWT10 mice exhibited significantly shorter crossable distances in the gap-crossing test than age-matched controls, indicating persistent deficits in whisker-dependent tactile perception. In contrast to controls, BWT10 mice exhibited no preference for the social compartment containing a conspecific in the three-chamber test. Furthermore, the development of amygdala circuitry was severely affected in BWT10 mice. Based on the c-Fos expression pattern, hyperactivity was found in BWT10 amygdala circuits for processing fear/anxiety-related responses to height stress but not in circuits for processing reward stimuli during whisker-dependent cued learning. These results demonstrate that neonatal whisker trimming and concomitant whisker-dependent tactile discrimination impairment severely disturbs the development of amygdala-dependent emotional regulation.

  6. Early postnatal GFAP-expressing cells produce multilineage progeny in cerebrum and astrocytes in cerebellum of adult mice.

    PubMed

    Guo, Zhibao; Wang, Xijuan; Xiao, Jun; Wang, Yihui; Lu, Hong; Teng, Junfang; Wang, Wei

    2013-09-26

    Early postnatal GFAP-expressing cells are thought to be immature astrocytes. However, it is not clear if they possess multilineage capacity and if they can generate different lineages (astrocytes, neurons and oligodendrocytes) in the brain of adult mice. In order to identify the fate of astroglial cells in the postnatal brain, hGFAP-Cre-ER(T2) transgenic mice were crossed with the R26R Cre reporter mouse strains which exhibit constitutive expression of β-galactosidase (β-gal). Mice carrying the hGFAP-Cre-ER(T2)/R26R transgene were treated with Tamoxifen to induce Cre recombination in astroglial cells at postnatal (P) day 6 and Cre recombinase-expressing cells were identified by X-gal staining. Immunohistochemical staining was used to identify the type(s) of these reporter-tagged cells. Sixty days after recombination, X-gal-positive cells in different cerebral regions of the adult mice expressed the astroglial markers Blbp and GFAP, the neuronal marker NeuN, the oligodendrocyte precursor cell marker NG2 and the mature oligodendrocyte marker CC1. X-gal-positive cells in the cerebellum coexpressed the astroglial marker Blbp, but not the granule cell marker NeuN, Purkinje cell marker Calbindin or oligodendrocyte precursor cell marker NG2. Our genetic fate mapping data demonstrated that early postnatal GFAP-positive cells possessed multilineage potential and eventually differentiated into neurons, astrocytes, and oligodendrocyte precursor cells in the cerebrum and into astrocytes (including Bergmann glia) in the cerebellum of adult mice.

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

    PubMed Central

    Soumiya, Hitomi; Godai, Ayumi; Araiso, Hiromi; Mori, Shingo; Furukawa, Shoei; Fukumitsu, Hidefumi

    2016-01-01

    Abnormalities in tactile perception, such as sensory defensiveness, are common features in autism spectrum disorder (ASD). While not a diagnostic criterion for ASD, deficits in tactile perception contribute to the observed lack of social communication skills. However, the influence of tactile perception deficits on the development of social behaviors remains uncertain, as do the effects on neuronal circuits related to the emotional regulation of social interactions. In neonatal rodents, whiskers are the most important tactile apparatus, so bilateral whisker trimming is used as a model of early tactile deprivation. To address the influence of tactile deprivation on adult behavior, we performed bilateral whisker trimming in mice for 10 days after birth (BWT10 mice) and examined social behaviors, tactile discrimination, and c-Fos expression, a marker of neural activation, in adults after full whisker regrowth. Adult BWT10 mice exhibited significantly shorter crossable distances in the gap-crossing test than age-matched controls, indicating persistent deficits in whisker-dependent tactile perception. In contrast to controls, BWT10 mice exhibited no preference for the social compartment containing a conspecific in the three-chamber test. Furthermore, the development of amygdala circuitry was severely affected in BWT10 mice. Based on the c-Fos expression pattern, hyperactivity was found in BWT10 amygdala circuits for processing fear/anxiety-related responses to height stress but not in circuits for processing reward stimuli during whisker-dependent cued learning. These results demonstrate that neonatal whisker trimming and concomitant whisker-dependent tactile discrimination impairment severely disturbs the development of amygdala-dependent emotional regulation. PMID:27362655

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

    PubMed

    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

  9. Two weeks of predatory stress induces anxiety-like behavior with co-morbid depressive-like behavior in adult male mice.

    PubMed

    Burgado, Jillybeth; Harrell, Constance S; Eacret, Darrell; Reddy, Renuka; Barnum, Christopher J; Tansey, Malú G; Miller, Andrew H; Wang, Huichen; Neigh, Gretchen N

    2014-12-15

    Psychological stress can have devastating and lasting effects on a variety of behaviors, especially those associated with mental illnesses such as anxiety and depression. Animal models of chronic stress are frequently used to elucidate the mechanisms underlying the relationship between stress and mental health disorders and to develop improved treatment options. The current study expands upon a novel chronic stress paradigm for mice: predatory stress. The predatory stress model incorporates the natural predator-prey relationship that exists among rats and mice and allows for greater interaction between the animals, in turn increasing the extent of the stressful experience. In this study, we evaluated the behavioral effects of exposure to 15 days of predatory stress on an array of behavioral indices. Up to 2 weeks after the end of stress, adult male mice showed an increase of anxiety-like behaviors as measured by the open field and social interaction tests. Animals also expressed an increase in depressive-like behavior in the sucrose preference test. Notably, performance on the novel object recognition task, a memory test, improved after predatory stress. Taken as a whole, our results indicate that 15 exposures to this innovative predatory stress paradigm are sufficient to elicit robust anxiety-like behaviors with evidence of co-morbid depressive-like behavior, as well as changes in cognitive behavior in male mice.

  10. Exposure to music in the perinatal period enhances learning performance and alters BDNF/TrkB signaling in mice as adults.

    PubMed

    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.

  11. Neonatal exposure to polybrominated diphenyl ether (PBDE 153) disrupts spontaneous behaviour, impairs learning and memory, and decreases hippocampal cholinergic receptors in adult mice.

    PubMed

    Viberg, Henrik; Fredriksson, Anders; Eriksson, Per

    2003-10-15

    Neonatal exposure to polybrominated diphenyl ether (PBDE 153) disrupts spontaneous behaviour, impairs learning and memory, and decreases hippocampal cholinergic receptors in adult mice. Flame retardants are used to suppress or inhibit combustion processes in an effort to reduce the risk of fire. One class of flame retardants, polybrominated diphenyl ethers (PBDEs), are present and increasing in the environment and in human milk. The present study shows that neonatal exposure to 2,2',4,4',5,5'-hexaBDE (PBDE 153), a PBDE persistent both in environment and in human milk, can induce developmental neurotoxic effects, such as changes in spontaneous behaviour (hyperactivity), impairments in learning and memory, and reduced amounts of nicotinic receptors, effects that get worse with age. Neonatal NMRI male mice were orally exposed on day 10 to 0.45, 0.9, or 9.0 mg of PBDE 153/kg of body weight. Spontaneous behaviour (locomotion, rearing, and total activity) was observed in 2-, 4-, and 6-month-old mice, Morris water maze at an age of 6 months. The behaviour tests showed that the effects were dose-response and time-response related. Animals showing defects in learning and memory also showed significantly reduced amounts of nicotinic receptors in hippocampus, using alpha-bungarotoxin binding assay. The observed developmental neurotoxic effects seen for PBDE 153 are similar to those seen for PBDE 99 and for certain PCBs. Furthermore, PBDEs appear to as potent as the PCBs.

  12. 55P0110, a Novel Synthetic Compound Developed from a Plant Derived Backbone Structure, Shows Promising Anti-Hyperglycaemic Activity in Mice.

    PubMed

    Brunmair, Barbara; Lehner, Zsuzsanna; Stadlbauer, Karin; Adorjan, Immanuel; Frobel, Klaus; Scherer, Thomas; Luger, Anton; Bauer, Leonhardt; Fürnsinn, Clemens

    2015-01-01

    Starting off with a structure derived from the natural compound multiflorine, a derivatisation program aimed at the discovery and initial characterisation of novel compounds with antidiabetic potential. Design and discovery of the structures was guided by oral bioactivities obtained in oral glucose tolerance tests in mice. 55P0110, one among several new compounds with distinct anti-hyperglycaemic activity, was further examined to characterise its pharmacology and mode of action. Whereas a single oral dose of 55P0110 did not affect basal glycaemia, it markedly improved the glucose tolerance of healthy and diabetic mice (peak blood glucose in glucose tolerance test, mmol/l: healthy mice with 90 mg/kg 55P0110, 17.0 ± 1.2 vs. 10.1 ± 1.1; diabetic mice with 180 mg/kg 55P0110, 23.1 ± 0.9 vs. 11.1 ± 1.4; p<0.001 each). Closer examination argued against retarded glucose resorption from the gut, increased glucose excretion in urine, acute insulin-like or insulin sensitising properties, and direct inhibition of dipeptidyl peptidase-4 as the cause of glucose lowering. Hence, 55P0110 seems to act via a target not exploited by any drug presently approved for the treatment of diabetes mellitus. Whereas the insulinotropic sulfonylurea gliclazide (16 mg/kg) distinctly increased the circulating insulin-per-glucose ratio under basal conditions, 55P0110 (90 mg/kg) lacked such an effect (30 min. after dosing, nmol/mol: vehicle, 2.49 ± 0.27; 55P0110, 2.99 ± 0.35; gliclazide, 8.97 ± 0.49; p<0.001 each vs. gliclazide). Under an exogenous glucose challenge, however, 55P0110 increased this ratio to the same extent as gliclazide (20 min. after glucose feeding: vehicle, 2.53 ± 0.41; 55P0110, 3.80 ± 0.46; gliclazide, 3.99 ± 0.26; p<0.05 each vs. vehicle). By augmenting the glucose stimulated increase in plasma insulin, 55P0110 thus shows distinct anti-hyperglycaemic action in combination with low risk for fasting hypoglycaemia in mice. In summary, we have discovered a novel class of

  13. Characteristics of Multi-Organ Lymphangiectasia Resulting from Temporal Deletion of Calcitonin Receptor-Like Receptor in Adult Mice

    PubMed Central

    Hoopes, Samantha L.; Willcockson, Helen H.; Caron, Kathleen M.

    2012-01-01

    Adrenomedullin (AM) and its receptor complexes, calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2/3, are highly expressed in lymphatic endothelial cells and are required for embryonic lymphatic development. To determine the role of Calcrl in adulthood, we used an inducible Cre-loxP system to temporally and ubiquitously delete Calcrl in adult mice. Following tamoxifen injection, Calcrlfl/fl/CAGGCre-ER™ mice rapidly developed corneal edema and inflammation that was preceded by and persistently associated with dilated corneoscleral lymphatics. Lacteals and submucosal lymphatic capillaries of the intestine were also dilated, while mesenteric collecting lymphatics failed to properly transport chyle after an acute Western Diet, culminating in chronic failure of Calcrlfl/fl/CAGGCre-ER™ mice to gain weight. Dermal lymphatic capillaries were also dilated and chronic edema challenge confirmed significant and prolonged dermal lymphatic insufficiency. In vivo and in vitro imaging of lymphatics with either genetic or pharmacologic inhibition of AM signaling revealed markedly disorganized lymphatic junctional proteins ZO-1 and VE-cadherin. The maintenance of AM signaling during adulthood is required for preserving normal lymphatic permeability and function. Collectively, these studies reveal a spectrum of lymphatic defects in adult Calcrlfl/fl/CAGGCre-ER™ mice that closely recapitulate the clinical symptoms of patients with corneal, intestinal and peripheral lymphangiectasia. PMID:23028890

  14. The anaesthetic combination of ketamine/midazolam does not alter the acquisition of spatial and motor tasks in adult mice.

    PubMed

    Valentim, A M; Olsson, I A S; Antunes, L M

    2013-01-01

    The ketamine/midazolam association of a dissociative with a sedative agent is used for the induction and maintenance of anaesthesia in laboratory animals. Anaesthesia may interfere with research results through side-effects on the nervous system, such as memory impairment. It is known that ketamine and midazolam affect cognition; however, their effects have not been clarified when used in a context of balanced anaesthesia. Thus, this study evaluated the effects of ketamine/midazolam on the acquisition of motor and of a spatial memory task in adult mice. Twenty-eight C57BL/6 adult male mice were divided into three groups: untreated control, treated with ketamine/midazolam (75 mg/kg / 10 mg/kg) and treated with midazolam (10 mg/kg) groups. Respiratory rate, heart rate and systolic pressure were measured every 5 min in the animals treated with ketamine/midazolam, as this was the only group that exhibited loss of the righting reflex. One day after treatment, animals were tested in the open field, rotarod and radial arm maze. There were no differences between treatments regarding open-field activity, rotarod performance or number of working and reference memory errors in the radial arm maze task. In conclusion, the learning process of spatial and motor tasks was not disrupted by the anaesthetic combination of ketamine/midazolam. These results suggest its safe use in adult mice in projects where acquisition of a spatial and motor task is necessary.

  15. Developmental dioxin exposure of either parent is associated with an increased risk of preterm birth in adult mice.

    PubMed

    Ding, Tianbing; McConaha, Melinda; Boyd, Kelli L; Osteen, Kevin G; Bruner-Tran, Kaylon L

    2011-04-01

    We have previously described diminished uterine progesterone response and increased uterine sensitivity to inflammation in adult female mice with a history of developmental exposure to TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin). Since parturition in mammals is an inflammatory process mediated in part by a decline in progesterone action, toxicant-mediated disruption of progesterone receptor (PR) expression at the maternal-fetal interface would likely impact the timing of birth. Therefore, in the current study, we examined pregnancy outcomes in adult female mice with a similar in utero exposure to TCDD. We also examined the impact of in utero TCDD exposure of male mice on pregnancy outcomes in unexposed females since the placenta, a largely paternally derived organ, plays a major role in the timing of normal parturition via inflammatory signaling. Our studies indicate that developmental exposure of either parent to TCDD is associated with preterm birth in a subsequent adult pregnancy due to altered PR expression and placental inflammation.

  16. Postnatal Proteasome Inhibition Induces Neurodegeneration and Cognitive Deficiencies in Adult Mice: A New Model of Neurodevelopment Syndrome

    PubMed Central

    Romero-Granados, Rocío; Fontán-Lozano, Ángela; Aguilar-Montilla, Francisco Javier; Carrión, Ángel Manuel

    2011-01-01

    Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering proteasome inhibitors daily during the first 10 days of life, affects the behaviour of adult mice. We found that this regime of exposure to the proteasome inhibitors MG132 or lactacystin did not produce significant behavioural or morphological changes in the first 15 days of life. However, towards the end of the treatment with proteasome inhibitors, there was a loss of mitochondrial markers and activity, and an increase in DNA oxidation. On reaching adulthood, the memory of mice that were injected with proteasome inhibitors postnatally was impaired in hippocampal and amygdala-dependent tasks, and they suffered motor dysfunction and imbalance. These behavioural deficiencies were correlated with neuronal loss in the hippocampus, amygdala and brainstem, and with diminished adult neurogenesis. Accordingly, impairing proteasome activity at early postnatal ages appears to cause morphological and behavioural alterations in adult mice that resemble those associated with certain neurodegenerative diseases and/or syndromes of mental retardation. PMID:22174927

  17. Conjugated Linoleic Acid Supplementation under a High-Fat Diet Modulates Stomach Protein Expression and Intestinal Microbiota in Adult Mice.

    PubMed

    Chaplin, Alice; Parra, Pilar; Serra, Francisca; Palou, Andreu

    2015-01-01

    The gastrointestinal tract constitutes a physiological interface integrating nutrient and microbiota-host metabolism. Conjugated linoleic acids (CLA) have been reported to contribute to decreased body weight and fat accretion. The modulation by dietary CLA of stomach proteins related to energy homeostasis or microbiota may be involved, although this has not been previously analysed. This is examined in the present study, which aims to underline the potential mechanisms of CLA which contribute to body weight regulation. Adult mice were fed either a normal fat (NF, 12% kJ content as fat) or a high-fat (HF, 43% kJ content as fat) diet. In the latter case, half of the animals received daily oral supplementation of CLA. Expression and content of stomach proteins and specific bacterial populations from caecum were analysed. CLA supplementation was associated with an increase in stomach protein expression, and exerted a prebiotic action on both Bacteroidetes/Prevotella and Akkermansia muciniphila. However, CLA supplementation was not able to override the negative effects of HF diet on Bifidobacterium spp., which was decreased in both HF and HF+CLA groups. Our data show that CLA are able to modulate stomach protein expression and exert a prebiotic effect on specific gut bacterial species.

  18. Prolonged high-fat diet induces gradual and fat depot-specific DNA methylation changes in adult mice

    PubMed Central

    Zwamborn, Ramona A. J.; Slieker, Roderick C.; Mulder, Petra C. A.; Zoetemelk, Inge; Verschuren, Lars; Suchiman, H. Eka D.; Toet, Karin H.; Droog, Simone; Slagboom, P. Eline; Kooistra, Teake; Kleemann, Robert; Heijmans, Bastiaan T.

    2017-01-01

    High-fat diets (HFD) are thought to contribute to the development of metabolism-related diseases. The long-term impact of HFD may be mediated by epigenetic mechanisms, and indeed, HFD has been reported to induce DNA methylation changes in white adipose tissue (WAT) near metabolism related genes. However, previous studies were limited to a single WAT depot, a single time-point and primarily examined the pre-pubertal period. To define dynamic DNA methylation patterns specific for WAT depots, we investigated DNA methylation of Pparg2 and Leptin in gonadal adipose tissue (GAT) and subcutaneous adipose tissue (SAT), at baseline and after 6, 12 and 24 weeks of HFD exposure in adult mice. HFD induced hypermethylation of both the Leptin promoter (max. 19.6% at week 24, P = 2.6·10−3) and the Pparg2 promoter in GAT (max. 10.5% at week 12, P = 0.001). The differential methylation was independent of immune cell infiltration upon HFD exposure. In contrast, no differential methylation in the Pparg2 and Leptin promoter was observed in SAT. Leptin and Pparg2 DNA methylation were correlated with gene expression in GAT. Our study shows that prolonged exposure to HFD in adulthood is associated with a gradually increasing DNA methylation level at the Leptin and Pparg2 promoters in a depot-specific manner. PMID:28256596

  19. Brain-derived neurotrophic factor signaling does not stimulate subventricular zone neurogenesis in adult mice and rats.

    PubMed

    Galvão, Rui P; Garcia-Verdugo, José Manuel; Alvarez-Buylla, Arturo

    2008-12-10

    In rodents, the adult subventricular zone (SVZ) generates neuroblasts which migrate to the olfactory bulb (OB) and differentiate into interneurons. Recent work suggests that the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) can enhance adult SVZ neurogenesis, but the mechanism by which it acts is unknown. Here, we analyzed the role of BDNF and its receptor TrkB in adult SVZ neurogenesis. We found that TrkB is the most prominent neurotrophin receptor in the mouse SVZ, but only the truncated, kinase-negative isoform (TrkB-TR) was detected. TrkB-TR is expressed in SVZ astrocytes and ependymal cells, but not in neuroblasts. TrkB mutants have reduced SVZ proliferation and survival and fewer new OB neurons. To test whether this effect is cell-autonomous, we grafted SVZ cells from TrkB knock-out mice (TrkB-KO) into the SVZ of wild-type mice (WT). Grafted progenitors generated neuroblasts that migrated to the OB in the absence of TrkB. The survival and differentiation of granular interneurons and Calbindin(+) periglomerular interneurons seemed unaffected by the loss of TrkB, whereas dopaminergic periglomerular neurons were reduced. Intra-ventricular infusion of BDNF yielded different results depending on the animal species, having no effect on neuron production from mouse SVZ, while decreasing it in rats. Interestingly, mice and rats also differ in their expression of the neurotrophin receptor p75. Our results indicate that TrkB is not essential for adult SVZ neurogenesis and do not support the current view that delivering BDNF to the SVZ can enhance adult neurogenesis.

  20. Increased sensitivity to alcohol induced changes in ERK Map kinase phosphorylation and memory disruption in adolescent as compared to adult C57BL/6J mice.

    PubMed

    Spanos, Marina; Besheer, Joyce; Hodge, Clyde W

    2012-04-21

    Adolescence is a critical period of brain development that is accompanied by increased probability of risky behavior, such as alcohol use. Emerging research indicates that adolescents are differentially sensitive to the behavioral effects of acute ethanol as compared to adults but the neurobiological mechanisms of this effect remain to be fully elucidated. This study was designed to evaluate effects of acute ethanol on extracellular signal-regulated kinase phosphorylation (p-ERK1/2) in mesocorticolimbic brain regions. We also sought to determine if age-specific effects of ethanol on p-ERK1/2 are associated with ethanol-induced behavioral deficits on acquisition of the hippocampal-dependent novel object recognition (NOR) test. Adolescent and adult C57BL/6J mice were administered acute ethanol (0 0.5, 1, or 3g/kg, i.p.). Brains were removed 30-min post injection and processed for analysis of p-ERK1/2 immunoreactivity (IR). Additional groups of mice were administered ethanol (0 or 1g/kg) prior to the NOR test. Analysis of p-ERK1/2 IR showed that untreated adolescent mice had significantly higher levels of p-ERK1/2 IR in the nucleus accumbens shell, basolateral amygdala (BLA), central amygdala (CeA), and medial prefrontal cortex (mPFC) as compared to adults. Ethanol (1g/kg) selectively reduced p-ERK1/2 IR in the dentate gyrus and increased p-ERK1/2 IR in the BLA only in adolescent mice. Ethanol (3g/kg) produced the same effects on p-ERK1/2 IR in both age groups with increases in CeA and mPFC, but a decrease in the dentate gyrus, as compared to age-matched saline controls. Pretreatment with ethanol (1g/kg) disrupted performance on the NOR test specifically in adolescents, which corresponds with the ethanol-induced inhibition of p-ERK1/2 IR in the hippocampus. These data show that adolescent mice have differential expression of basal p-ERK1/2 IR in mesocorticolimbic brain regions. Acute ethanol produces a unique set of changes in ERK1/2 phosphorylation in the adolescent

  1. Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon.

    PubMed

    Macrì, Simone; Ceci, Chiara; Onori, Martina Proietti; Invernizzi, Roberto William; Bartolini, Erika; Altabella, Luisa; Canese, Rossella; Imperi, Monica; Orefici, Graziella; Creti, Roberta; Margarit, Immaculada; Magliozzi, Roberta; Laviola, Giovanni

    2015-08-25

    Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities.

  2. Mice repeatedly exposed to Group-A β-Haemolytic Streptococcus show perseverative behaviors, impaired sensorimotor gating, and immune activation in rostral diencephalon

    PubMed Central

    Macrì, Simone; Ceci, Chiara; Onori, Martina Proietti; Invernizzi, Roberto William; Bartolini, Erika; Altabella, Luisa; Canese, Rossella; Imperi, Monica; Orefici, Graziella; Creti, Roberta; Margarit, Immaculada; Magliozzi, Roberta; Laviola, Giovanni

    2015-01-01

    Repeated exposure to Group-A β-Haemolytic Streptococcus (GAS) may constitute a vulnerability factor in the onset and course of pediatric motor disturbances. GAS infections/colonization can stimulate the production of antibodies, which may cross the blood brain barrier, target selected brain areas (e.g. basal ganglia), and exacerbate motor alterations. Here, we exposed developing SJL male mice to four injections with a GAS homogenate and evaluated the following domains: motor coordination; general locomotion; repetitive behaviors; perseverative responses; and sensorimotor gating (pre-pulse inhibition, PPI). To demonstrate that behavioral changes were associated with immune-mediated brain alterations, we analyzed, in selected brain areas, the presence of infiltrates and microglial activation (immunohistochemistry), monoamines (HPLC), and brain metabolites (in vivo Magnetic Resonance Spectroscopy). GAS-exposed mice showed increased repetitive and perseverative behaviors, impaired PPI, and reduced concentrations of serotonin in prefrontal cortex, a brain area linked to the behavioral domains investigated, wherein they also showed remarkable elevations in lactate. Active inflammatory processes were substantiated by the observation of infiltrates and microglial activation in the white matter of the anterior diencephalon. These data support the hypothesis that repeated GAS exposure may elicit inflammatory responses in brain areas involved in motor control and perseverative behavior, and result in phenotypic abnormalities. PMID:26304458

  3. Adult mice voluntarily progress to nicotine dependence in an oral self-selection assay.

    PubMed

    Locklear, Laura L; McDonald, Craig G; Smith, Robert F; Fryxell, Karl J

    2012-09-01

    Nicotine has both rewarding and aversive properties in rodents, as shown by intravenous self-administration, intracranial self-stimulation, and conditioned place preference experiments. However, high throughput models of nicotine reward have not been developed in mice. In previous two-bottle studies, mice often chose to drink less from the nicotine bottle than from the water bottle, which raises the question whether these paradigms provide a model of the reinforcing properties of oral nicotine. We hypothesized that previous two-bottle choice paradigms included factors (such as the brief duration of trials, the addition of flavorings to both bottles, water bottles located relatively close to each other, etc.) that may have obstructed the formation of a learned association between the taste of nicotine and its delayed pharmacological effects. Here we show that a paradigm designed to simplify the acquisition of a learned association resulted in nicotine consumption by various strains and sexes that diverged progressively over a period of seven weeks. The strain and sex with the highest nicotine consumption (C57BL/6J females) showed steady and statistically significant increases in nicotine consumption throughout this period. C57BL/6J females were clearly responding to the reinforcing properties of nicotine because they chose to drink over 70% of their fluids from the nicotine bottle. Moreover, they became nicotine dependent, as shown by highly significant nicotine withdrawal symptoms after the nicotine bottle was removed. The strain and sex with the lowest consumption (A/J males) showed a significant decrease in nicotine consumption, and by the end of the experiment were drinking only 24% of their fluids from the nicotine bottle.

  4. Neonatal respiratory syncytial virus infection has an effect on lung inflammation and the CD4(+) CD25(+) T cell subpopulation during ovalbumin sensitization in adult mice.

    PubMed

    Comas-García, A; López-Pacheco, C P; García-Zepeda, E A; Soldevila, G; Ramos-Martínez, P; Ramos-Castañeda, J

    2016-08-01

    In BALB/c adult mice, respiratory syncytial virus (RSV) infection enhances the degree of lung inflammation before and/or after ovalbumin (OVA) respiratory sensitization. However, it is unclear whether RSV infection in newborn mice has an effect on the immune response to OVA respiratory sensitization in adult mice. The aim of this study was to determine if RSV neonatal infection alters T CD4(+) population and lung inflammation during OVA respiratory sensitization in adult mice. BALB/c mice were infected with RSV on the fourth day of life and challenged by OVA 4 weeks later. We found that in adult mice, RSV neonatal infection prior to OVA sensitization reduces the CD4(+) CD25(+) and CD4(+) CD25(+) forkhead protein 3 (FoxP3)(+) cell populations in the lungs and bronchoalveolar lavage. Furthermore, it also attenuates the inflammatory infiltrate and cytokine/chemokine expression levels in the mouse airways. In conclusion, the magnitude of the immune response to a non-viral respiratory perturbation in adult mice is not enhanced by a neonatal RSV infection.

  5. Feeding Pregnant and Lactating Mice Rhodiola kirilowii Extracts helps to Preserve Thymus Function of their Adult Progeny.

    PubMed

    Bień, K; Lewicki, S; Zdanowski, R; Skopinska-Różewska, E; Krzyżowska, M

    2016-09-01

    Plants belonging to Rhodiola kirilowii species, members of Rhodiola genus and Crassulaceae family, grow wildly in Tibet, Mongolia and China mountains and are traditionally used as adaptogens, antidepressants and anti-inflammatory remedies. Nowadays, R. kirilowii is cultivated in some countries, also in Poland. In our previous papers we reported immuno- and angio-modulatory effects of aqueous and hydro-alcoholic extracts of radix and rhizome of this plant in non-pregnant and pregnant mice. The aim of the present study was to evaluate the effect of feeding pregnant and further lactating mice these extracts on selected thymus function parameters in adult progeny. The counts of M-30+ apoptotic cells, in the thymuses obtained from progeny of mice fed during pregnancy and lactation water or 50% water-alcoholic extract of Rhodiola kirilowii, were significantly lower (p<0.05) than apoptotic cells counts observed in the control mice. No significant differences in the counts of IL-7-positive cells in the thymuses obtained from progeny of the control mice and mothers treated with water or hydro-alcohol extracts of Rhodiola kirilowii were observed.

  6. [Effect of amantadine or 3-cyclopentyl adamantanamine on the immobility of adult or aged mice, in the forced swim test].

    PubMed

    Vamvakidès, A

    2000-12-01

    Amantadine (AMA), an antiparkinsonian drug, (20 mg/Kg, ip) or 3-cyclopentyl adamantanamine (AdCP), an AMA derivative synthesized recently, (20 mg/Kg, ip) induced an anti-immobility effect-comparable to those of imipramine (IMI), an antidepressive drug, (30 mg/Kg, ip) - in the forced swim test (FST), on adult (4 months) Balb-C mice. In contrast, on aged (10 months) Balb-C mice, only AdCP (20 or 40 mg/Kg, ip) was active in the FST. It is suggested that the inactivity of AMA or IMI on the aged Balb-C mice could be the consequence of their NMDA (i.e., N-methyl-D-aspartic acid sensitive) receptors failure. This NMDA receptors dysfunction could render non significant the antagonism of the mice immobility in the FST, induced by AMA or IMI, which could result (in part for IMI) from the anti-NMDA effect of these drugs. In contrast AdCP, which may principally act by glycinergic A (strychnine sensitive) effect, inhibiting the release of the brain monoamines and glutamate, conserved its activity in the FST on aged mice. In conclusion, it seems that the neurochemical profile of the drugs studied in the FST, could be useful for understanding their anti-immobility effect and for a rational approach of their possible clinical use as antidepressant.

  7. PENTACHLOROPHENOL POTENTIATES BENZO[A]PYRENE DNA ADDUCT FORMATION IN ADULT BUT NOT INFANT B6C3F1 MALE MICE

    EPA Science Inventory

    Abstract

    The objective of this study is to determine whether pentachlorophenol (PCP) alters benzo[a]pyrene (B[a]P) induced DNA adduct formation in infant and adult B6C3Fl mice. Mice were exposed to 55 ug B[a]P/g body weight (BW) alone and in combination with several dose...

  8. Islets of Langerhans from prohormone convertase-2 knockout mice show α-cell hyperplasia and tumorigenesis with elevated α-cell neogenesis.

    PubMed

    Jones, Huw B; Reens, Jaimini; Brocklehurst, Simon R; Betts, Catherine J; Bickerton, Sue; Bigley, Alison L; Jenkins, Richard P; Whalley, Nicky M; Morgan, Derrick; Smith, David M

    2014-02-01

    Antagonism of the effects of glucagon as an adjunct therapy with other glucose-lowering drugs in the chronic treatment of diabetes has been suggested to aggressively control blood glucose levels. Antagonism of glucagon effects, by targeting glucagon secretion or disabling the glucagon receptor, is associated with α-cell hyperplasia. We evaluated the influence of total glucagon withdrawal on islets of Langerhans using prohormone convertase-2 knockout mice (PC2-ko), in which α-cell hyperplasia is present from a young age and persists throughout life, in order to understand whether or not sustained glucagon deficit would lead to islet tumorigenesis. PC2-ko and wild-type (WT) mice were maintained drug-free, and cohorts of these groups sampled at 3, 12 and 18 months for plasma biochemical and morphological (histological, immunohistochemical, electron microscopical and image analytical) assessments. WT mice showed no islet tumours up to termination of the study, but PC2-ko animals displayed marked changes in islet morphology from α-cell hypertrophy/hyperplasia/atypical hyperplasia, to adenomas and carcinomas, these latter being first encountered at 6-8 months. Islet hyperplasias and tumours primarily consisted of α-cells associated to varying degrees with other islet endocrine cell types. In addition to substantial increases in islet neoplasia, increased α-cell neogenesis associated primarily with pancreatic duct(ule)s was present. We conclude that absolute blockade of the glucagon signal results in tumorigenesis and that the PC2-ko mouse represents a valuable model for investigation of islet tumours and pancreatic ductal neogenesis.

  9. Evaluation of antioxidant effects of crocin on sperm quality in cyclophosphamide treated adult mice

    PubMed Central

    Bakhtiary, Zahra; Shahrooz, Rasoul; Ahmadi, Abbas; Zarei, Leila

    2014-01-01

    Cyclophosphamide (CP) is one of the anti-neoplastic drugs. Despite its numerous clinical applications, it has devastating effects on the testicles and declines the sperm quality in treated patients. This study was aimed to investigate the protective effect of crocin in improving the toxicity induced by CP in reproductive system. In this study, 24 male adult mice (6 to 8 weeks) were randomly divided into three groups, control group received normal saline (0.1 mL, IP, daily), the CP group received CP (15 mg kg-1, IP, weekly) and the CP + crocin group received CP along with crocin (200 mg kg-1, IP, daily). After 35 days of treatment, animals were sacrificed. The samples of epididymis in human tubal fluid medium incubated for 30 min in 5% CO2 for flotation of sperm. Sperm were obtained from caudal epididymis using dissecting method. Then, the parameters of sperm quality including sperm count, motility, viability, DNA damage, nuclear maturation, and sperm morphology were evaluated. In CP group, the sperm count, motility, viability, nuclear maturation and sperm morphology were significantly decreased compared to control group (p < 0.05) and in the CP + crocin group all of these parameters significantly increased compared to CP group (p < 0.05). The percentage of sperm with DNA damage in the CP group significantly increased compared to other groups (p < 0.05). The results of this study indicated that the crocin was able to suppress free radicals and enhance the quality of sperm in CP treated animals. PMID:25568721

  10. Tetrahydrohyperforin increases adult hippocampal neurogenesis in wild-type and APPswe/PS1ΔE9 mice.

    PubMed

    Abbott, Ana C; Calderon Toledo, Carla; Aranguiz, Florencia C; Inestrosa, Nibaldo C; Varela-Nallar, Lorena

    2013-01-01

    Tetrahydrohyperforin (IDN5706), a semi-synthetic derivative of hyperforin, has shown neuroprotective properties preventing the impairment of synaptic plasticity and cognitive decline in an in vivo model of Alzheimer's disease (AD). Considering the reported role of adult neurogenesis in the plasticity of the hippocampal network, we investigated whether IDN5706 affects adult neurogenesis and hippocampal function. In hippocampal progenitors cultured from adult rats, IDN5706 increased proliferation. Moreover, treatment with IDN5706 for 4 weeks increased cell proliferation in the subgranular zone (SGZ) of the hippocampus in 2 month-old wild-type mice in vivo. As determined by double labeling with BrdU and neuronal markers, IDN5706 treatment increased the number of immature neurons and newborn mature neurons in the adult dentate gyrus. In addition, IDN5706 treatment improved long-term memory in a hippocampal-dependent spatial memory task. Finally, IDN5706 treatment increased cell proliferation and neural commitment in the SGZ of the double transgenic APPswe/PS1ΔE9 mouse model of AD. These results indicate that IDN5706 increases adult hippocampal neurogenesis and may have therapeutic value in neurological disorders in which adult neurogenesis is impaired.

  11. In Utero Environmental Tobacco Smoke Exposure Alters Gene Expression in Lungs of Adult BALB/c Mice

    PubMed Central

    Rouse, Rodney L.; Boudreaux, Marc J.; Penn, Arthur L.

    2007-01-01

    Background In utero environmental tobacco smoke (ETS) exposure exacerbates initial lung responses of adult mice to ovalbumin (OVA), a common allergen in rodent models of allergic asthma. Objective We tested the hypothesis that in utero ETS exposure alters expression of genes (including asthma-related and inflammatory genes) in the lungs of adult mice and that this differential expression is reflected in differential respiratory and immune responses to nontobacco allergens. Methods Using Affymetrix Mouse Genome 430 2.0 arrays, we examined gene expression changes in lungs of BALB/c mice exposed to ETS in utero, OVA, or saline aerosol at weeks 7–8, and OVA sensitization and challenge at weeks 11–15. Data sets were filtered by transcript p-value (≤ 0.05), false discovery rate (≤ 0.05), and fold change (≥ 1.5). Differential expression of selected genes was confirmed by polymerase chain reaction (PCR). Results Genes differentially expressed as a result of in utero ETS exposure are involved in regulation of biological processes (immune response, cell proliferation, apoptosis, cell metabolism) through altered cytoskeleton, adhesion, transcription, and enzyme molecules. A number of genes prominent in lung inflammation were differentially expressed on PCR but did not pass selection criteria for microarray, including arginase (Arg1), chitinases (Chia, Chi3l3, Chi3l4), eotaxins (Ccl11, Ccl24), small proline-rich protein 2a (Sprr2a), and cytokines (Il4, Il6, Il10, Il13, Tnfa) . Conclusion The differential lung gene expression reported here is consistent with previously reported functional changes in lungs of mice exposed in utero to ETS and as adults to the nontobacco allergen OVA. PMID:18087596

  12. Long-term, low-level adolescent nicotine exposure produces dose-dependent changes in cocaine sensitivity and reward in adult mice.

    PubMed

    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

  13. Presynaptic size of associational/commissural CA3 synapses is controlled by fibroblast growth factor 22 in adult mice.

    PubMed

    Pasaoglu, Taliha; Schikorski, Thomas

    2016-02-01

    Associational/commissural CA3-CA3 synapses define the recurrent CA3 network that generates the input to CA1 pyramidal neurons. We quantified the fine structure of excitatory synapses in the stratum radiatum of the CA3d area in adult wild type (WT) and fibroblast growth factor 22 knock-out (FGF22KO) mice by using serial 3D electron microscopy. WT excitatory CA3 synapses are rather small yet range 10 fold in size. Spine size, however, was small and uniform and did not correlate with the size of the synaptic junction. To reveal mechanisms that regulate presynaptic structure, we investigated the role of FGF22, a target-derived signal specific for the distal part of area CA3 (CA3d). In adult FGF22KO mice, postsynaptic properties of associational CA3 synapses were unaltered. Presynaptically, the number of synaptic vesicles (SVs), the bouton volume, and the number of vesicles in axonal regions (the super pool) were reduced. This concurrent decrease suggests concerted control by FGF22 of presynaptic size. This hypothesis is supported by the finding that WT presynapses in the proximal part of area CA3 (CA3p) that do not receive FGF22 signaling in WT mice were smaller than presynapses in CA3d in WT but of comparable size in CA3d of FGF22KO mice. Docked SV density was decreased in CA1, CA3d, and CA3p in FGF22KO mice. Because CA1 and CA3p are not directly affected by the loss of FGF22, the smaller docked SV density may be an adaptation to activity changes in the CA3 network. Thus, docked SV density potentially is a long-term regulator for the synaptic release probability and/or the strength of short-term depression in vivo.

  14. Peripubertal Vitamin D3 Deficiency Delays Puberty and Disrupts the Estrous Cycle in Adult Female Mice1

    PubMed Central

    Dicken, Cary L.; Israel, Davelene D.; Davis, Joe B.; Sun, Yan; Shu, Jun; Hardin, John; Neal-Perry, Genevieve

    2012-01-01

    ABSTRACT The mechanism(s) by which vitamin D3 regulates female reproduction is minimally understood. We tested the hypothesis that peripubertal vitamin D3 deficiency disrupts hypothalamic-pituitary-ovarian physiology. To test this hypothesis, we used wild-type mice and Cyp27b1 (the rate-limiting enzyme in the synthesis of 1,25-dihydroxyvitamin D3) null mice to study the effect of vitamin D3 deficiency on puberty and reproductive physiology. At the time of weaning, mice were randomized to a vitamin D3-replete or -deficient diet supplemented with calcium. We assessed the age of vaginal opening and first estrus (puberty markers), gonadotropin levels, ovarian histology, ovarian responsiveness to exogenous gonadotropins, and estrous cyclicity. Peripubertal vitamin D3 deficiency significantly delayed vaginal opening without affecting the number of GnRH-immunopositive neurons or estradiol-negative feedback on gonadotropin levels during diestrus. Young adult females maintained on a vitamin D3-deficient diet after puberty had arrested follicular development and prolonged estrous cycles characterized by extended periods of diestrus. Ovaries of vitamin D3-deficient Cyp27b1 null mice responded to exogenous gonadotropins and deposited significantly more oocytes into the oviducts than mice maintained on a vitamin D3-replete diet. Estrous cycles were restored when vitamin D3-deficient Cyp27b1 null young adult females were transferred to a vitamin D3-replete diet. This study is the first to demonstrate that peripubertal vitamin D3 sufficiency is important for an appropriately timed pubertal transition and maintenance of normal female reproductive physiology. These data suggest vitamin D3 is a key regulator of neuroendocrine and ovarian physiology. PMID:22572998

  15. Comprehensive Behavioral Analysis of Male Ox1r (-/-) Mice Showed Implication of Orexin Receptor-1 in Mood, Anxiety, and Social Behavior.

    PubMed

    Abbas, Md G; Shoji, Hirotaka; Soya, Shingo; Hondo, Mari; Miyakawa, Tsuyoshi; Sakurai, Takeshi

    2015-01-01

    Neuropeptides orexin A and orexin B, which are exclusively produced by neurons in the lateral hypothalamic area, play an important role in the regulation of a wide range of behaviors and homeostatic processes, including regulation of sleep/wakefulness states and energy homeostasis. The orexin system has close anatomical and functional relationships with systems that regulate the autonomic nervous system, emotion, mood, the reward system, and sleep/wakefulness states. Recent pharmacological studies using selective antagonists have suggested that orexin receptor-1 (OX1R) is involved in physiological processes that regulate emotion, the reward system, and autonomic nervous system. Here, we examined Ox1r (-/-) mice with a comprehensive behavioral test battery to screen additional OX1R functions. Ox1r (-/-) mice showed increased anxiety-like behavior, altered depression-like behavior, slightly decreased spontaneous locomotor activity, reduced social interaction, increased startle response, and decreased prepulse inhibition. These results suggest that OX1R plays roles in social behavior and sensory motor gating in addition to roles in mood and anxiety.

  16. Cannabinoid receptor 1 antagonist treatment induces glucagon release and shows an additive therapeutic effect with GLP-1 agonist in diet-induced obese mice.

    PubMed

    Patel, Kartikkumar Navinchandra; Joharapurkar, Amit Arvind; Patel, Vishal; Kshirsagar, Samadhan Govind; Bahekar, Rajesh; Srivastava, Brijesh Kumar; Jain, Mukul R

    2014-12-01

    Cannabinoid 1 (CB1) receptor antagonists reduce body weight and improve insulin sensitivity. Preclinical data indicates that an acute dose of CB1 antagonist rimonabant causes an increase in blood glucose. A stable analog of glucagon-like peptide 1 (GLP-1), exendin-4 improves glucose-stimulated insulin secretion in pancreas, and reduces appetite through activation of GLP-1 receptors in the central nervous system and liver. We hypothesized that the insulin secretagogue effect of GLP-1 agonist exendin-4 may synergize with the insulin-sensitizing action of rimonabant. Intraperitoneal as well as intracerebroventricular administration of rimonabant increased serum glucose upon glucose challenge in overnight fasted, diet-induced obese C57 mice, with concomitant rise in serum glucagon levels. Exendin-4 reversed the acute hyperglycemia induced by rimonabant. The combination of exendin-4 and rimonabant showed an additive effect in the food intake, and sustained body weight reduction upon repeated dosing. The acute efficacy of both the compounds was additive for inducing nausea-like symptoms in conditioned aversion test in mice, whereas exendin-4 treatment antagonized the effect of rimonabant on forced swim test upon chronic dosing. Thus, the addition of exendin-4 to rimonabant produces greater reduction in food intake owing to increased aversion, but reduces the other central nervous system side effects of rimonabant. The hyperglucagonemia induced by rimonabant is partially responsible for enhancing the antiobesity effect of exendin-4.

  17. Artificial sweetener neohesperidin dihydrochalcone showed antioxidative, anti-inflammatory and anti-apoptosis effects against paraquat-induced liver injury in mice.

    PubMed

    Shi, Qiong; Song, Xiufang; Fu, Juanli; Su, Chuanyang; Xia, Xiaomin; Song, Erqun; Song, Yang

    2015-12-01

    The present study evaluated the protective effect of artificial sweetener neohesperidin dihydrochalcone (NHDC) against paraquat (PQ)-induced acute liver injury in mice. A single dose of PQ (75mg/kg body weight, i.p.) induced acute liver toxicity with the evidences of increased liver damage biomarkers, aspartate transaminase (AST) and alanine transaminase (ALT) activities in serum. Consistently, PQ decreased the antioxidant capacity by reducing glutathione peroxidase (GP-X), glutathione-S-transferase (GST) and catalase (CAT) activities, glutathione (GSH) level and total antioxidant capacity (T-AOC), as well as increasing reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) levels. Histopathological examination revealed that PQ induced numerous changes in the liver tissues. Immunochemical staining assay indicated the upregulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions. However, NHDC ameliorates PQ-induced hepatic toxicity in mice by reversing these parameters. Additionally, NHDC significantly inhibited PQ-induced nuclear factor-kappa B (NF-κB) expression and mitochondrial-driven apoptotic signaling. TUNEL assay confirmed that PQ-induced apoptosis was relieved by NHDC. In conclusion, these findings suggested that NHDC showed potent antioxidant, anti-inflammatory and anti-apoptotic effects against PQ-induced acute liver damage.

  18. T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants

    PubMed Central

    Gangarossa, Giuseppe; Laffray, Sophie; Bourinet, Emmanuel; Valjent, Emmanuel

    2014-01-01

    The fine-tuning of neuronal excitability relies on a tight control of Ca2+ homeostasis. The low voltage-activated (LVA) T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms) play a critical role in regulating these processes. Despite their wide expression throughout the central nervous system, the implication of T-type Cav3.2 isoform in brain functions is still poorly characterized. Here, we investigate the effect of genetic ablation of this isoform in affective disorders, including anxiety, cognitive functions as well as sensitivity to drugs of abuse. Using a wide range of behavioral assays we show that genetic ablation of the cacna1h gene results in an anxiety-like phenotype, whereas novelty-induced locomotor activity is unaffected. Deletion of the T-type channel Cav3.2 also triggers impairment of hippocampus-dependent recognition memories. Acute and sensitized hyperlocomotion induced by d-amphetamine and cocaine are dramatically reduced in T-type Cav3.2 deficient mice. In addition, the administration of the T-type blocker TTA-A2 prevented the expression of locomotor sensitization observed in wildtype mice. In conclusion, our data reveal that physiological activity of this specific Ca2+ channel is required for affective and cognitive behaviors. Moreover, our work highlights the interest of T-type channel blockers as therapeutic strategies to reverse drug-associated alterations. PMID:24672455

  19. Octaphlorethol A: a potent α-glucosidase inhibitor isolated from Ishige foliacea shows an anti-hyperglycemic effect in mice with streptozotocin-induced diabetes.

    PubMed

    Lee, Seung-Hong; Kang, Sung-Myung; Ko, Seok-Chun; Moon, Sang-Ho; Jeon, Byong-Tae; Lee, Dae Ho; Jeon, You-Jin

    2014-10-01

    α-Glucosidase inhibitors are important agents for decreasing postprandial hyperglycemia. The current study examined the inhibitory effects of octaphlorethol A (OPA) isolated from Ishige foliacea, a brown alga, on α-glucosidase, and analyzed the inhibitor's binding modes using the crystal structure of α-glucosidase. The effects of OPA on postprandial blood glucose levels after meals were also investigated. The IC50 value of OPA against α-glucosidase was 0.11 mM, which is higher than that of the commercial inhibitor acarbose. For further insights, we predicted the 3D structure of α-glucosidase and used a docking algorithm to simulate binding between α-glucosidase and OPA. These molecular modeling studies were successful, and indicated that OPA interacts with Phe575, His600, Arg526, Met444, Asp542, Tyr605, Ser448, Asp203, Lys480, and Phe450. Furthermore, increases in postprandial blood glucose levels were significantly suppressed in the OPA-treated group compared with those in the streptozotocin-induced diabetic or normal mice. Additionally, the area under the curve was significantly reduced following OPA administration (907 versus 1034 mg h dL(-1)) in the diabetic mice, along with a delay in the absorption of dietary carbohydrates. Collectively, these results indicated that OPA is a potent inhibitor of α-glucosidase, and shows potential to be used as an anti-diabetic agent.

  20. Mice deficient for the type II topoisomerase-like DNA transesterase Spo11 show normal immunoglobulin somatic hypermutation and class switching.

    PubMed

    Klein, Ulf; Esposito, Gloria; Baudat, Frédéric; Keeney, Scott; Jasin, Maria

    2002-02-01

    Somatic hypermutation in B cells undergoing T cell dependent immune responses generates high affinity antibodies that provide protective immunity. B cells also switch from the expression of immunoglobulin (Ig) M and IgD to that of other Ig classes through somatic DNA recombination. Recent work has implicated DNA strand breaks, possibly DNA double strand breaks (DSB), as the initiating lesions in both class switch recombination and hypermutation, although the etiology of these lesions is not understood. Spo11, a protein structurally related to archaeal type II topoisomerases, generates DSB that initiate meiotic recombination. This characteristic, together with its expression pattern, marks this enzyme as a potential candidate for the initiation of hypermutation, and perhaps also for Ig class switching. To investigate whether Spo11 is involved in these processes, we studied the T cell dependent immune response of Spo11-deficient (Spo11(-/-)) mice against the hapten nitrophenyl (NP). We found that V186.2-bearing IgG1 transcripts had normal levels and patterns of somatic hypermutation. Furthermore, Spo11(-/-) mice showed normal serum levels of all Ig isotypes. These results indicate that Spo11 is not required for Ig hypermutation or class switch recombination.

  1. Induced Wnt5a expression perturbs embryonic outgrowth and intestinal elongation, but is well-tolerated in adult mice.

    PubMed

    Bakker, Elvira R M; Raghoebir, Lalini; Franken, Patrick F; Helvensteijn, Werner; van Gurp, Léon; Meijlink, Frits; van der Valk, Martin A; Rottier, Robbert J; Kuipers, Ernst J; van Veelen, Wendy; Smits, Ron

    2012-09-01

    Wnt5a is essential during embryonic development, as indicated by mouse Wnt5a knockout embryos displaying outgrowth defects of multiple structures including the gut. The dynamics of Wnt5a involvement in these processes is unclear, and perinatal lethality of Wnt5a knockout embryos has hampered investigation of Wnt5a during postnatal stages in vivo. Although in vitro studies have suggested a relevant role for Wnt5a postnatally, solid evidence for a significant impact of Wnt5a within the complexity of an adult organism is lacking. We generated a tightly-regulated inducible Wnt5a transgenic mouse model and investigated the effects of Wnt5a induction during different time-frames of embryonic development and in adult mice, focusing on the gastrointestinal tract. When induced in embryos from 10.5 dpc onwards, Wnt5a expression led to severe outgrowth defects affecting the gastrointestinal tracts, limbs, facial structures and tails, closely resembling the defects observed in Wnt5a knockout mice. However, Wnt5a induction from 13.5 dpc onwards did not cause this phenotype, indicating that the most critical period for Wnt5a in embryonic development is prior to 13.5 dpc. In adult mice, induced Wnt5a expression did not reveal abnormalities, providing the first in vivo evidence that Wnt5a has no major impact on mouse intestinal homeostasis postnatally. Protein expression of Wnt5a receptor Ror2 was strongly reduced in adult intestine compared to embryonic stages. Moreover, we uncovered a regulatory process where induction of Wnt5a causes downregulation of its receptor Ror2. Taken together, our results indicate a role for Wnt5a during a restricted time-frame of embryonic development, but suggest no impact during homeostatic postnatal stages.

  2. Residual sarcoplasmic reticulum Ca2+ concentration after Ca2+ release in skeletal myofibers from young adult and old mice.

    PubMed

    Wang, Zhong-Min; Tang, Shen; Messi, María Laura; Yang, Jenny J; Delbono, Osvaldo

    2012-04-01

    Contrasting information suggests either almost complete depletion of sarcoplasmic reticulum (SR) Ca(2+) or significant residual Ca(2+) concentration after prolonged depolarization of the skeletal muscle fiber. The primary obstacle to resolving this controversy is the lack of genetically encoded Ca(2+) indicators targeted to the SR that exhibit low-Ca(2+) affinity, a fast biosensor: Ca(2+) off-rate reaction, and can be expressed in myofibers from adult and older adult mammalian species. This work used the recently designed low-affinity Ca(2+) sensor (Kd = 1.66 mM in the myofiber) CatchER (calcium sensor for detecting high concentrations in the ER) targeted to the SR, to investigate whether prolonged skeletal muscle fiber depolarization significantly alters residual SR Ca(2+) with aging. We found CatchER a proper tool to investigate SR Ca(2+) depletion in young adult and older adult mice, consistently tracking SR luminal Ca(2+) release in response to brief and repetitive stimulation. We evoked SR Ca(2+) release in whole-cell voltage-clamped flexor digitorum brevis muscle fibers from young and old FVB mice and tested the maximal SR Ca(2+) release by directly activating the ryanodine receptor (RyR1) with 4-chloro-m-cresol in the same myofibers. Here, we report for the first time that the Ca(2+) remaining in the SR after prolonged depolarization (2 s) in myofibers from aging (~220 μM) was larger than young (~132 μM) mice. These experiments indicate that SR Ca(2+) is far from fully depleted under physiological conditions throughout life, and support the concept of excitation-contraction uncoupling in functional senescent myofibers.

  3. Selective rather than inductive mechanisms favour specific replacement of Purkinje cells by embryonic cerebellar cells transplanted to the cerebellum of adult Purkinje cell degeneration (pcd) mutant mice.

    PubMed

    Carletti, Barbara; Rossi, Ferdinando

    2005-09-01

    Cell replacement after neuronal degeneration in the adult CNS depends on the availability of specific cues to direct specification, differentiation and integration of newly born neurons into mature circuits. Following recent reports indicating that neurogenic signals may be reactivated in the adult injured CNS, here we asked whether such signals are expressed in the cerebellum after Purkinje cell degeneration. Thus, we compared the fate of embryonic cerebellar cells transplanted to the cerebella of adult wild-type and Purkinje cell degeneration (pcd) mutant mice. Donor cells were dissected from beta-actin-enhanced green fluorescent protein (EGFP) transgenic mice and transplanted as a single cell suspension. In both hosts, grafted cells generated all major cerebellar phenotypes, with a precise localization in the recipient cortex or white matter. Nevertheless, the phenotypic distributions showed striking quantitative differences. Most notably, in the pcd cerebellum there was a higher amount of Purkinje cells, while other phenotypes were less frequent. Analysis of cell proliferation by 5-bromo-2'-deoxyuridine (BrDU) incorporation revealed that in both hosts mitotic activity was strongly reduced shortly after transplantation, and virtually all donor Purkinje cells were actually generated before grafting. Together, these results indicate that some compensatory mechanisms operate in the pcd environment. However, the very low mitotic rate of transplanted cells suggests that the adult cerebellum, either wild-type or mutant, does not provide instructive neurogenic cues to direct the specification of uncommitted progenitors. Rather, specific replacement in mutant hosts is achieved through selective mechanisms that favour the survival and integration of donor Purkinje cells at the expense of other phenotypes.

  4. Immunization of Newborn Mice Accelerates the Architectural Maturation of Lymph Nodes, But AID-Dependent IgG Responses Are Still Delayed Compared to the Adult

    PubMed Central

    Munguía-Fuentes, Rosario; Yam-Puc, Juan Carlos; Silva-Sánchez, Aarón; Marcial-Juárez, Edith; Gallegos-Hernández, Isis Amara; Calderón-Amador, Juana; Randall, Troy D.; Flores-Romo, Leopoldo

    2017-01-01

    Lymph nodes (LNs) have evolved to maximize antigen (Ag) collection and presentation as well as lymphocyte proliferation and differentiation—processes that are spatially regulated by stromal cell subsets, including fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs). Here, we showed that naïve neonatal mice have poorly organized LNs with few B and T cells and undetectable FDCs, whereas adult LNs have numerous B cells and large FDC networks. Interestingly, immunization on the day of birth accelerated B cell accumulation and T cell recruitment into follicles as well as FDC maturation and FRC organization in neonatal LNs. However, compared to adults, the formation of germinal centers was both delayed and reduced following immunization of neonatal mice. Although immunized neonates poorly expressed activation-induced cytidine deaminase (AID), they were able to produce Ag-specific IgGs, but with lower titers than adults. Interestingly, the Ag-specific IgM response in neonates was similar to that in adults. These results suggest that despite an accelerated structural maturation of LNs in neonates following vaccination, the B cell response is still delayed and reduced in its ability to isotype switch most likely due to poor AID expression. Of note, naïve pups born to Ag-immunized mothers had high titers of Ag-specific IgGs from day 0 (at birth). These transferred antibodies confirm a mother-derived coverage to neonates for Ags to which mothers (and most likely neonates) are exposed, thus protecting the neonates while they produce their own antibodies. Finally, the type of Ag used in this study and the results obtained also indicate that T cell help would be operating at this stage of life. Thus, neonatal immune system might not be intrinsically immature but rather evolutionary adapted to cope with Ags at birth. PMID:28154564

  5. The environmental chemical tributyltin chloride (TBT) shows both estrogenic and adipogenic activities in mice which might depend on the exposure dose

    SciTech Connect

    Penza, M.; Jeremic, M.; Marrazzo, E.; Maggi, A.; Ciana, P.; Rando, G.; Grigolato, P.G.; Di Lorenzo, D.

    2011-08-15

    Exposure during early development to chemicals with hormonal action may be associated with weight gain during adulthood because of altered body homeostasis. It is known that organotins affect adipose mass when exposure occurs during fetal development, although no knowledge of effects are available for exposures after birth. Here we show that the environmental organotin tributyltin chloride (TBT) exerts adipogenic action when peripubertal and sexually mature mice are exposed to the chemical. The duration and extent of these effects depend on the sex and on the dose of the compound, and the effects are relevant at doses close to the estimated human intake (0.5 {mu}g/kg). At higher doses (50-500 {mu}g/kg), TBT also activated estrogen receptors (ERs) in adipose cells in vitro and in vivo, based on results from acute and longitudinal studies in ERE/luciferase reporter mice. In 3T3-L1 cells (which have no ERs), transiently transfected with the ERE-dependent reporter plus or minus ER{alpha} or ER{beta}, TBT (in a dose range of 1-100 nM) directly targets each ER subtype in a receptor-specific manner through a direct mechanism mediated by ER{alpha} in undifferentiated preadipocytic cells and by ER{beta} in differentiating adipocytes. The ER antagonist ICI-182,780 inhibits this effect. In summary, the results of this work suggest that TBT is adipogenic at all ages and in both sexes and that it might be an ER activator in fat cells. These findings might help to resolve the apparent paradox of an adipogenic chemical being also an estrogen receptor activator by showing that the two apparently opposite actions are separated by the different doses to which the organism is exposed. - Research Highlights: > The environmental organotin tributyltin chloride shows dose-dependent estrogenic and adipogenic activities in mice. > The duration and extent of these effects depend on the sex and the dose of the compound. > The estrogenic and adipogenic effects of TBT occur at doses closed to

  6. Adenosine A2A receptors are necessary and sufficient to trigger memory impairment in adult mice

    PubMed Central

    Pagnussat, N; Almeida, A S; Marques, D M; Nunes, F; Chenet, G C; Botton, P H S; Mioranzza, S; Loss, C M; Cunha, R A; Porciúncula, L O

    2015-01-01

    Background and Purpose Caffeine (a non-selective adenosine receptor antagonist) prevents memory deficits in aging and Alzheimer’s disease, an effect mimicked by adenosine A2A receptor, but not A1 receptor, antagonists. Hence, we investigated the effects of adenosine receptor agonists and antagonists on memory performance and scopolamine-induced memory impairment in mice. Experimental Approach We determined whether A2A receptors are necessary for the emergence of memory impairments induced by scopolamine and whether A2A receptor activation triggers memory deficits in naïve mice, using three tests to assess short-term memory, namely the object recognition task, inhibitory avoidance and modified Y-maze. Key Results Scopolamine (1.0 mg·kg−1, i.p.) impaired short-term memory performance in all three tests and this scopolamine-induced amnesia was prevented by the A2A receptor antagonist (SCH 58261, 0.1–1.0 mg·kg−1, i.p.) and by the A1 receptor antagonist (DPCPX, 0.2–5.0 mg·kg−1, i.p.), except in the modified Y-maze where only SCH58261 was effective. Both antagonists were devoid of effects on memory or locomotion in naïve rats. Notably, the activation of A2A receptors with CGS 21680 (0.1–0.5 mg·kg−1, i.p.) before the training session was sufficient to trigger memory impairment in the three tests in naïve mice, and this effect was prevented by SCH 58261 (1.0 mg·kg−1, i.p.). Furthermore, i.c.v. administration of CGS 21680 (50 nmol) also impaired recognition memory in the object recognition task. Conclusions and Implications These results show that A2A receptors are necessary and sufficient to trigger memory impairment and further suggest that A1 receptors might also be selectively engaged to control the cholinergic-driven memory impairment. PMID:25939452

  7. Socially induced morphine pseudosensitization in adolescent mice.

    PubMed

    Hodgson, Stephen R; Hofford, Rebecca S; Roberts, Kris W; Wellman, Paul J; Eitan, Shoshana

    2010-03-01

    Given that social influences are among the strongest predictors of adolescents' drug use, this study examined the effect of social interaction on morphine-induced hyperlocomotion in both adolescent and adult mice. Three experimental groups of adolescent and adult male mice were examined (i) morphine-treated mice (twice daily, 10-40 mg/kg, subcutaneous), (ii) saline-injected mice housed together with the morphine-treated mice ('saline cage-mates'), and (iii) saline-injected mice housed physically and visually separated from the morphine-treated mice ('saline alone'). After the treatment period, mice were tested individually for their locomotor response to 10 mg/kg morphine (subcutaneous). Adolescent saline cage-mates, though administered morphine for the very first time, exhibited an enhanced hyperlocomotion response similar to the locomotor sensitization response exhibited by the morphine-treated mice. This was not observed in adults. In adults, there were no significant differences in morphine-induced hyperlocomotion between saline alone and saline cage-mates. As expected, morphine-treated adults and adolescents both exhibited locomotor sensitization. These results show a vulnerability to social influences in adolescent mice, which does not exist in adult mice.

  8. Analysis of large new South African dataset using two host-specificity indices shows generalism in both adult and larval ticks of mammals.

    PubMed

    Espinaze, Marcela P A; Hellard, Eléonore; Horak, Ivan G; Cumming, Graeme S

    2016-03-01

    Ticks and tick-borne pathogens can have considerable impacts on the health of livestock, wildlife and people. Knowledge of tick-host preferences is necessary for both tick and pathogen control. Ticks were historically considered as specialist parasites, but the range of sampled host species has been limited, infestation intensity has not been included in prior analyses, and phylogenetic distances between hosts have not been previously considered. We used a large dataset of 35 604 individual collections and two host-specificity indices to assess the specificity of 61 South African tick species, as well as distinctions between adult and juvenile ticks, for 95 mammalian hosts. When accounting for host phylogeny, most adult and juvenile ticks behaved as generalists, with juveniles being significantly more generalist than adults. When we included the intensity of tick infestation, ticks exhibited a wider diversity of specificity in all life stages. Our results show that ticks of mammals in South Africa tend to behave largely as generalists and that adult ticks are more host-specific. More generally, our analysis shows that the incorporation of life-stage differences, infestation intensity and phylogenetic distances between hosts, as well as the use of more than one specificity index, can all contribute to a deeper understanding of host-parasite interactions.

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

    PubMed Central

    Yang, Junhua; Qi, Fangfang; Yao, Zhibin

    2016-01-01

    The Bacillus Calmette-Guérin (BCG) vaccine is routinely administered to human neonates worldwide. BCG has recently been identified as a neuroprotective immune mediator in several neuropathological conditions, exerting neuroprotection in a mouse model of Parkinson's disease and slowing the progression of clinically isolated syndrome in patients with multiple sclerosis. The immune system is significantly involved in brain development, and several types of neonatal immune activations exert influences on the brain and behavior following a secondary immune challenge in adulthood. However, whether the neonatal BCG vaccination affects the brain in adulthood remains to be elucidated. In the present study, newborn C57BL/6 mice were injected subcutaneously with BCG (105 colony forming units) or phosphate-buffered saline (PBS). A total of 12 weeks later, the mice were injected intraperitoneally with 330 µg/kg lipopolysaccharide (LPS) o