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  1. 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

  2. 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.

  3. Examining Young Recreational Male Soccer Players' Experience in Adult- and Peer-Led Structures

    ERIC Educational Resources Information Center

    Imtiaz, Faizan; Hancock, David J.; Côté, Jean

    2016-01-01

    Purpose: Youth sport has the potential to be one of the healthiest and most beneficial activities in which children can partake. Participation in a combination of adult-led and peer-led sport structures appears to lead to favorable outcomes such as enhanced physical fitness, as well as social and emotional development. The purpose of the present…

  4. Evaluation of a Peer-Led, Low-Intensity Physical Activity Program for Older Adults

    ERIC Educational Resources Information Center

    Werner, Danilea; Teufel, James; Brown, Stephen L.

    2014-01-01

    Background: Physical inactivity is a primary contributor to decreasing functional physical fitness and increasing chronic disease in older adults. Purpose: This study assessed the health-related benefits of ExerStart for Lay Leaders, a 20-week, community based, peer-led, low-impact exercise program for older adults. ExerStart focuses on aerobic…

  5. 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

  6. High-throughput imaging of adult fluorescent zebrafish with an LED fluorescence macroscope

    PubMed Central

    Blackburn, Jessica S; Liu, Sali; Raimondi, Aubrey R; Ignatius, Myron S; Salthouse, Christopher D; Langenau, David M

    2011-01-01

    Zebrafish are a useful vertebrate model for the study of development, behavior, disease and cancer. A major advantage of zebrafish is that large numbers of animals can be economically used for experimentation; however, high-throughput methods for imaging live adult zebrafish had not been developed. Here, we describe protocols for building a light-emitting diode (LED) fluorescence macroscope and for using it to simultaneously image up to 30 adult animals that transgenically express a fluorescent protein, are transplanted with fluorescently labeled tumor cells or are tagged with fluorescent elastomers. These protocols show that the LED fluorescence macroscope is capable of distinguishing five fluorescent proteins and can image unanesthetized swimming adult zebrafish in multiple fluorescent channels simultaneously. The macroscope can be built and used for imaging within 1 day, whereas creating fluorescently labeled adult zebrafish requires 1 hour to several months, depending on the method chosen. The LED fluorescence macroscope provides a low-cost, high-throughput method to rapidly screen adult fluorescent zebrafish and it will be useful for imaging transgenic animals, screening for tumor engraftment, and tagging individual fish for long-term analysis. PMID:21293462

  7. 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.

  8. Eliminating Medicaid adult dental coverage in California led to increased dental emergency visits and associated costs.

    PubMed

    Singhal, Astha; Caplan, Daniel J; Jones, Michael P; Momany, Elizabeth T; Kuthy, Raymond A; Buresh, Christopher T; Isman, Robert; Damiano, Peter C

    2015-05-01

    Dental coverage for adults is an elective benefit under Medicaid. As a result of budget constraints, California Medicaid eliminated its comprehensive adult dental coverage in July 2009. We examined the impact of this policy change on emergency department (ED) visits by Medicaid-enrolled adults for dental problems in the period 2006-11. We found that the policy change led to a significant and immediate increase in dental ED use, amounting to more than 1,800 additional dental ED visits per year. Young adults, members of racial/ethnic minority groups, and urban residents were disproportionately affected by the policy change. Average yearly costs associated with dental ED visits increased by 68 percent. The California experience provides evidence that eliminating Medicaid adult dental benefits shifts dental care to costly EDs that do not provide definitive dental care. The population affected by the Medicaid adult dental coverage policy is increasing as many states expand their Medicaid programs under the ACA. Hence, such evidence is critical to inform decisions regarding adult dental coverage for existing Medicaid enrollees and expansion populations.

  9. 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

  10. 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.

  11. 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

  12. 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

  13. In vivo laboratory practicals in research-led teaching: an example using glucose tolerance tests in lean and obese mice.

    PubMed

    King, Aileen J F; Bowe, James E; Sprake, Juliet A; Kinchin, Ian M

    2011-01-01

    The use of animal models is an essential part of medical research and drug development. The essential skills required to be able to do such research includes experimental design, statistical analysis and the actual handling and treating of the animals (in vivo skills). The number of students in the U.K. receiving training in handling and experimenting on animals has declined rapidly in the last few decades which has led to initiatives to increase numbers of students with these skills to meet demand. Within the Department of Pharmacology and Therapeutics at King's College London, we run a course for 2nd year undergraduates entitled "Animal models of disease and injury". This course not only covers the theoretical and ethical aspects of using animals in research, but also contains practical laboratory classes in which students get hands-on experience using animals. One of the laboratory classes we run is a glucose tolerance test in obese and lean mice. This is an example of research-led teaching which aims to develop research skills through engaging students in research like activities. In this paper, we outline the methodology of the glucose tolerance practical and highlight some of the skills we and the students think they gain by research-led teaching such as this.

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. The effect of pharmacist-led interventions in optimising prescribing in older adults in primary care: A systematic review

    PubMed Central

    Riordan, David O; Walsh, Kieran A; Galvin, Rose; Sinnott, Carol; Kearney, Patricia M; Byrne, Stephen

    2016-01-01

    Objective: To evaluate studies of pharmacist-led interventions on potentially inappropriate prescribing among community-dwelling older adults receiving primary care to identify the components of a successful intervention. Data sources: An electronic search of the literature was conducted using the following databases from inception to December 2015: PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, MEDLINE (through Ovid), Trip, Centre for Reviews and Dissemination databases, Cochrane Database of Systematic Reviews, ISI Web of Science, ScienceDirect, ClinicalTrials.gov, metaRegister of Controlled Trials, ProQuest Dissertations & Theses Database (Theses in Great Britain, Ireland and North America). Review methods: Studies were included if they were randomised controlled trials or quasi-randomised studies involving a pharmacist-led intervention compared to usual/routine care which aimed to reduce potentially inappropriate prescribing in older adults in primary care. Methodological quality of the included studies was independently assessed. Results: A comprehensive literature search was conducted which identified 2193 studies following removal of duplicates. Five studies met the inclusion criteria. Four studies involved a pharmacist conducting a medication review and providing feedback to patients or their family physician. One randomised controlled trial evaluated the effect of a computerised tool that alerted pharmacists when elderly patients were newly prescribed potentially inappropriate medications. Four studies were associated with an improvement in prescribing appropriateness. Conclusion: Overall, this review demonstrates that pharmacist-led interventions may improve prescribing appropriateness in community-dwelling older adults. However, the quality of evidence is low. The role of a pharmacist working as part of a multidisciplinary primary care team requires further investigation to optimise prescribing in this group of patients. PMID

  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. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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. ...

  8. 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.

  9. Alzheimer's disease and methanol toxicity (part 1): chronic methanol feeding led to memory impairments and tau hyperphosphorylation in mice.

    PubMed

    Yang, Meifeng; Lu, Jing; Miao, Junye; Rizak, Joshua; Yang, Jianzhen; Zhai, Rongwei; Zhou, Jun; Qu, Jiagui; Wang, Jianhong; Yang, Shangchuan; Ma, Yuanye; Hu, Xintian; He, Rongqiao

    2014-01-01

    Although methanol toxicity is well known for acute neurological sequelae leading to blindness or death, there is a new impetus to investigate the chronic effects of methanol exposure. These include a recently established link between formaldehyde, a methanol metabolite, and Alzheimer's disease (AD) pathology. In the present study, mice were fed with methanol to revisit the chronic effects of methanol toxicity, especially as it pertains to AD progression. Three groups of mice (n = 9) were given either water as a control or a methanol solution (concentrations of 2% or 3.8%) over a 6-week period. The methanol-fed mice were found to have impaired spatial recognition and olfactory memory in Y-maze and olfactory memory paradigms. Immunohistochemical analysis of the mouse brains found increased neuronal tau phosphorylation in the hippocampus and an increased cellular apoptotic marker in hippocampal CA1 neurons (~10% of neurons displayed chromatin condensation) in the methanol-fed groups. Two additional in vitro experiments in mouse embryonic cerebral cortex neurons and mouse neuroblastoma N2a cells found that formaldehyde, but not methanol or the methanol end product formic acid, induced microtubule disintegration and tau protein hyperphosphorylation. The findings of the behavioral tests and immunohistochemical analysis suggested that the methanol-fed mice presented with partial AD-like symptoms. The in vitro experiments suggested that formaldehyde was most likely the detrimental component of methanol toxicity related to hippocampal tau phosphorylation and the subsequent impaired memory in the mice. These findings add to a growing body of evidence that links formaldehyde to AD pathology.

  10. 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…

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Meeting the needs? Perceived support of a nurse-led lifestyle programme for young adults with mental illness in a primary health-care setting.

    PubMed

    Rönngren, Ylva; Björk, Annette; Kristiansen, Lisbeth; Haage, David; Enmarker, Ingela; Audulv, Åsa

    2017-04-04

    Being a young adult with mental illness challenges all aspects of health, including an increased risk for developing lifestyle-related diseases. There is a lack of lifestyle programmes in primary health care that target physical, mental, and social needs for young adults with mental illness. The aim of the present study was to describe the experiences of young adults with mental illness receiving support from a nurse-led lifestyle programme, and how this support was related to their life context, including challenges and coping strategies. Two focus groups and six individual interviews were performed with 13 young adults (16-25 years), and analysed using a qualitative content analysis. The findings showed that the young adults experienced challenges in their daily lives, including psychiatric symptoms, lack of social understanding, and loneliness. The study indicated that the programme could support lifestyle habits with its components of supportive interpersonal relationships, awareness of coping strategies, understanding of health and illness, and cognitive support (e.g. schedules and reminders). However, the programme could not meet everyone's needs for new social relationships or more comprehensive support. Even so, this nurse-led programme provides health information-management strategies that could easily be integrated in a primary health-care setting.

  17. The effect of cerebellar transplantation and enforced physical activity on motor skills and spatial learning in adult Lurcher mutant mice.

    PubMed

    Cendelín, Jan; Korelusová, Ivana; Vozeh, Frantisek

    2009-03-01

    Lurcher mutant mice represent a model of olivocerebellar degeneration. They are used to investigate cerebellar functions, consequences of cerebellar degeneration and methods of therapy influencing them. The aim of the work was to assess the effect of foetal cerebellar graft transplantation, repeated enforced physical activity and the combination of both these types of treatment on motor skills, spontaneous motor activity and spatial learning ability in adult B6CBA Lurcher mice. Foetal cerebellar grafts were applied into the cerebellum of Lurchers in the form of solid tissue pieces. Enforced motor activity was realised through rotarod training. Motor functions were examined using bar, ladder and rotarod tests. Spatial learning was tested in the Morris water maze. Spontaneous motor activity in the open field was observed. The presence of the graft was examined histologically. Enforced physical activity led to moderate improvement of some motor skills and to a significant amelioration of spatial learning ability in Lurchers. The transplantation of cerebellar tissue did not influence motor functions significantly but led to an improvement of spatial learning ability. Mutual advancement of the effects of both types of treatment was not observed. Spontaneous motor activity was influenced neither by physical activity nor by the transplantation. Physical activity did not influence the graft survival and development. Because nerve sprouting and cell migration from the graft to the host cerebellum was poor, the functional effects of the graft should be explained with regard to its trophic influence rather than with any involvement of the grafted cells into neural circuitries.

  18. 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

  19. 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.

  20. 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.

  1. Targeted Disruption of the Lama3 Gene in Adult Mice Is Sufficient to Induce Skin Inflammation and Fibrosis.

    PubMed

    Pesch, Monika; König, Sabrina; Aumailley, Monique

    2017-02-01

    Genetic, clinical, and biochemical studies have shown that integrity of the dermal-epidermal junction requires a particular subset of laminins, that is, those containing the α3 chain encoded by the Lama3 gene. Inherited mutations in the human gene or introduction of constitutive mutations in the mouse gene prevent expression of these laminins, causing junctional epidermolysis bullosa, a very severe, often lethal disorder characterized by detachment of the epidermis from the dermis. This has precluded in vivo functional analysis of α3 chain-containing laminins, and it is still unknown whether and how they contribute to adult skin homeostasis. To address this question, we have disrupted the Lama3 gene in basal keratinocytes of adult mice. This led to the gradual disappearance of α3 chain-containing laminins along the dermal-epidermal junction and formation of subepidermal blisters like in congenital junctional epidermis bullosa. The mice lose their nails and have bullae and erosions on the footpads. Because the blistering is restricted to the interfollicular epidermis, the animals do not lose the epidermis and are viable. There is abundant and scattered deposition of collagen VII on the dermal side of the blisters, inflammation, and development of skin fibrosis with extensive accumulation of interstitial and microfibrillar collagens.

  2. 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.

  3. 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.

  4. 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

  5. Promoting Exercise as Part of a Physiotherapy-Led Falls Pathway Service for Adults with Intellectual Disabilities: A Service Evaluation

    ERIC Educational Resources Information Center

    Crockett, Jennifer; Finlayson, Janet; Skelton, Dawn A.; Miller, Gillian

    2015-01-01

    Background: People with intellectual disabilities experience high rates of falls. Balance and gait problems are common in people with intellectual disabilities, increasing the likelihood of falls; thus, tailored exercise interventions to improve gait and balance are recommended. The present authors set up a physiotherapy-led falls pathway service…

  6. EVALUATION OF PERFLUOROOCTANOIC ACID IMMUNOTOXICITY IN ADULT MICE.

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) is used in the manufacture of fluoropolymers and may be formed by metabolism or degradation of other perfluoroalkyl acids. Safety concerns led the U.S. EPA to conduct a risk assessment of PFOA and related compounds due to their environmental persist...

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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...

  16. 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.

  17. Dependent coverage provision led to uneven insurance gains and unchanged mortality rates in young adult trauma patients.

    PubMed

    Scott, John W; Sommers, Benjamin D; Tsai, Thomas C; Scott, Kirstin W; Schwartz, Aaron L; Song, Zirui

    2015-01-01

    Insurance coverage has increased among young adults as a result of the Affordable Care Act (ACA) provision that allows young adults to remain covered under their parents' plans until age twenty-six. However, little is known about the provision's effects on the clinical outcomes and insurance coverage of patients with trauma--the most frequent cause of death and physical disability among young adults. Using 2007-12 data from the National Trauma Data Bank, we conducted a difference-in-differences analysis of coverage rates among trauma patients ages 19-25 (compared to patients ages 26-34, who served as the control group), and we examined trauma-relevant outcomes by patient, injury, and hospital characteristics. We found a 3.4-percentage-point decrease in uninsurance status among younger trauma patients following the policy change. The decrease was concentrated among men, non-Hispanic whites, those with relatively less severe injuries, and those who presented to nonteaching hospitals. We did not detect significant changes in the use of intensive care or in overall mortality. The heterogeneous coverage impact of the ACA dependent coverage provision on high- versus low-risk trauma patients has implications for future efforts to expand coverage.

  18. 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

  19. 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.

  20. The Joanna Briggs Institute Best Practice Information Sheet: Nurse-led interventions to reduce cardiac risk factors in adults.

    PubMed

    2010-09-01

    This Best Practice Information Sheet updates and supersedes an earlier publication of the Joanna Briggs Institute in 2005. The information that is contained in this publication is based upon a systematic review of six randomized clinical trials. Additional information has been derived from a second systematic review; thus, in total, the information is derived from 22 randomized controlled trials. The original references can be sourced from the systematic reviews. Coronary heart disease (CHD) is the major cause of illness in Western society and it is becoming increasingly important to establish effective strategies in order to reduce the incidence of CHD. Nurse-led clinics are becoming more prominent in community settings and the importance of nurse interventions in the management of CHD and risk factor reduction is recognized in terms of improved health outcomes for patients. However, the variation in outcome measures and inconsistent findings between some studies make it difficult to draw firm conclusions.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. LED Update

    SciTech Connect

    Johnson, Mark L.; Gordon, Kelly L.

    2006-09-01

    This article, which will appear in RESIDENTIAL LIGHTING MAGAZINE, interviews PNNL's Kelly Gordon and presents the interview in question and answer format. The topic is a light emitting diode (LED) lighting also known as solid state lighting. Solid state lighting will be a new category in an energy efficient lighting fixture design competition called Lighting for Tomorrow sponsored by the US Department of Energy Emerging Technologies Office, the American Institute for Lighting, and the Consortium for Energy Efficiency. LED technology has been around since the ’60s, but it has been used mostly for indicator lights on electronics equipment. The big breakthrough was the development in the 1990s of blue LEDs which can be combined with the red and green LEDs that already existed to make white light. LEDs produce 25 to 40 lumens of light per watt of energy used, almost as much as a CFL (50 lumens per watt) and much more efficient than incandescent sources, which are around 15 lumens per watt. They are much longer lived and practical in harsh environments unsuitable for incandescent lighting. They are ready for niche applications now, like under-counter lighting and may be practical for additional applications as technological challenges are worked out and the technology is advancing in leaps and bounds.

  11. LED lamp

    SciTech Connect

    Galvez, Miguel; Grossman, Kenneth; Betts, David

    2013-11-12

    There is herein described a lamp for providing white light comprising a plurality of light sources positioned on a substrate. Each of said light sources comprises a blue light emitting diode (LED) and a dome that substantially covers said LED. A first portion of said blue light from said LEDs is transmitted through said domes and a second portion of said blue light is converted into a red light by a first phosphor contained in said domes. A cover is disposed over all of said light sources that transmits at least a portion of said red and blue light emitted by said light sources. The cover contains a second phosphor that emits a yellow light in response to said blue light. The red, blue and yellow light combining to form the white light and the white light having a color rendering index (CRI) of at least about 80.

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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...

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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

  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. 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.

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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

  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. 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

  9. 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.

  10. 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

  11. 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

  12. 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

  13. Scavenger Receptor Class B Type 1 Deletion Led to Coronary Atherosclerosis and Ischemic Heart Disease in Low-density Lipoprotein Receptor Knockout Mice on Modified Western-type Diet

    PubMed Central

    Liao, Jiawei; Guo, Xin; Wang, Mengyu; Dong, Chengyan; Gao, Mingming; Wang, Huan; Kayoumu, Abudurexiti; Shen, Qiang; Wang, Yuhui; Wang, Fan; Liu, George

    2017-01-01

    Aim: Atherosclerosis-prone apolipoprotein E (apoE) or low-density lipoprotein receptor (LDL-R) knockout (KO) mice are generally resistant to developing coronary atherosclerosis (CA) and ischemic heart disease (IHD). However, studies have demonstrated the occurrence of spontaneous CA and IHD in scavenger receptor class B type 1 (SR-BI)/apoE double KO (dKO) mice, which suggests that SR-BI could be a potential target for the prevention and therapy of CA and IHD. This possibility was later investigated in SR-BI/LDL-R dKO mice, but no signs of CA or IHD was identified when mice were fed a normal western-type diet. Here we explored whether SR-BI deletion could result in CA and IHD in LDL-R KO mice when fed a modified western-type diet containing higher (0.5%) cholesterol. Methods: Cardiac functions were detected by electrocardiography, single photon emission computed tomography (SPECT), echocardiography (Echo) and 2,3,5-triphenyltetrazolium chloride staining. CA was visualized by hematoxylin-eosin staining. Results: After 12 weeks on the modified diet, SR-BI/LDL-R dKO mice developed cardiac ischemia/infarction, together with systolic dysfunction and left ventricular dilatation. CA was most severe at the aortic sinus level to an extent that no dKO mice survived to 20 weeks on the modified diet. None of control mice, however, developed CA or IHD. Conclusions: SR-BI deletion led to CA and IHD in LDL-R KO mice when fed the modified western-type diet. We established SR-BI/LDL-R dKO mice as a diet-induced murine model of human IHD and developed detection methods, using a combination of SPECT and Echo, for effective in vivo evaluation of cardiac functions. PMID:27373983

  14. 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

  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. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  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. 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.

  3. 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

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. Can a Free Wearable Activity Tracker Change Behavior? The Impact of Trackers on Adults in a Physician-Led Wellness Group

    PubMed Central

    Rosenbluth, Sandra; Phillips, Jeffrey

    2016-01-01

    Background Wearable activity trackers (trackers) are increasingly popular devices used to track step count and other health indicators. Trackers have the potential to benefit those in need of increased physical activity, such as adults who are older and face significant health challenges. These populations are least likely to purchase trackers and most likely to face challenges in using them, yet may derive educational, motivational, and health benefits from their use once these barriers are removed. Objective The aim of this pilot research is to investigate the use of trackers by adults with chronic medical conditions who have never used trackers previously. Specifically, we aim to determine (1) if participants would accept and use trackers to increase their physical activity; (2) if there were barriers to use besides cost and training; (3) if trackers would educate participants on their baseline and ongoing activity levels and support behavior change; and (4) if clinical outcomes would show improvements in participants’ health. Methods This study was conducted with patients (N=10) in a 12-week physician-led wellness group offered by Family Doctors, LLC. Patients were given trackers in the second week of The Wellness Group and were interviewed 2 to 4 weeks after it ended. The study investigators analyzed the interview notes to extract themes about the participants’ attitudes and behavior changes and collected and analyzed participants’ clinical data, including weight and low-density lipoprotein (LDL) cholesterol over the course of the study. Results Over the 12 to 14 weeks of tracker use, improvements were seen in clinical outcomes, attitudes towards the trackers, and physical activity behaviors. Participants lost an average of 0.5 lbs per week (SD 0.4), with a mean total weight loss of 5.97 lbs (P=.004). Other short-term clinical outcomes included a 9.2% decrease in LDL levels (P=.038). All participants reported an increase in well-being and confidence in

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. Effects of a major androgen-dependent urinary protein,. alpha. 2u-globulin on the pituitary-gonadal axis and hypothalamic monoamines in adult male mice

    SciTech Connect

    Ghosh, P.K.; Chandrashekar, V.; Steger, R. Bartke, A. )

    1990-01-01

    The purpose of the present study was to evaluate the effects of alpha-2u-globulin, a sex-dependent male rat urinary protein on pituitary-gonadal functions and hypothalamic monamine contents in male mice. Adult male mice, maintained under standardized laboratory conditions were injected subcutaneously with alpha-2u-globulin or with vehicle daily for 14 days and killed 16 h after the last injection. Plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T) and testicular levels of T were measured by radioimmunoassays. The concentrations of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) in medial basal hypothalamus (MBH) and anterior hypothalamus (AH) were measured by high performance liquid chromatography. Administration of alpha-2u-globulin led to a significant increase in plasma FSH and LH levels. In the MBH of alpha-2u-globulin treated mice, there were significant elevations of NE, DA and 5-HT contents. In the AH, both DA and 5-HT contents were decreased while NE content remained unaltered.

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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.'.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. In vitro characterisation of cell-level neurophysiological diversity in the rostral nucleus reuniens of adult mice.

    PubMed

    Walsh, D A; Brown, J T; Randall, A D

    2017-03-11

    The nucleus reuniens (Re) is the largest of the midline thalamic nuclei. We have performed a detailed neurophysiological characterization of neurons in the rostral Re of brain slices prepared from adult male mice. At resting potential (-63.7 ± 0.6 mV), circa 90% of Re neurons fired action potentials, typically continuously at ∼8 Hz. Although Re neurons experience a significant spontaneous barrage of fast, amino-acid-mediate synaptic transmission, this was not predominantly responsible for spontaneous spiking as firing persisted in the presence of glutamate and GABA receptor antagonists. With resting potential preset to -80 mV -20 pA current injections revealed a mean input resistance of 615 MΩ and mean time constant of 38 ms. Following cessation of this stimulus a significant rebound potential was seen that was sometimes large enough to trigger a short burst of very high frequency (100-300 Hz) firing. In most cells short (2 ms), strong (2 nA) current injections elicited a single spike followed by a large afterdepolarizing potential (ADP) which, when suprathreshold, generated high frequency spiking. Similarly, in the majority of cells preset at -80 mV, 500 ms depolarizing current injections to cells led to a brief initial burst of very high frequency firing, although this was lost when cells were preset at -72 mV. Biophysical and pharmacological experiments indicate a prominent role for T-type Ca(2+) channels in the high-frequency bursting of Re neurons. Finally, we describe a novel form of activity-dependent intrinsic plasticity that persistently eliminates the burst firing potential of Re neurons. This article is protected by copyright. All rights reserved.

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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)…

  4. 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.

  5. 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...

  6. 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...

  7. 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...

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. Low intensity, long term exposure to tobacco smoke inhibits hippocampal neurogenesis in adult mice.

    PubMed

    Csabai, Dávid; Csekő, Kata; Szaiff, Lilla; Varga, Zsófia; Miseta, Attila; Helyes, Zsuzsanna; Czéh, Boldizsár

    2016-04-01

    Previous data have shown that high dose of nicotine administration or tobacco smoke exposure can reduce cell formation and the survival rate of adult-born neurons in the dentate gyrus. Here, we subjected adult mice to low intensity cigarette smoke exposure over long time periods. We did a 2×30min/day smoke exposure with two cigarettes per occasion over 1- or 2-months. Subsequently, we carried out a systematic quantitative histopathological analysis to assess the number of newborn neurons in the dentate gyrus. To investigate cell proliferation, the exogenous marker 5-bromo-2'-deoxyuridine (BrdU) was administered on the last experimental day and animals were sacrificed 2h later. To investigate the effect of tobacco smoke on the population of immature neurons, we quantified the number of doublecortin-positive (DCX+) neurons in the same animals. We found that exposing animals to cigarette smoke for 1- or 2-months had no influence on cell proliferation rate, but significantly reduced the number of DCX-positive immature neurons. Our tobacco smoke exposure regimen caused no substantial changes in respiratory functions, but histopathological analysis of the pulmonary tissue revealed a marked perivascular/peribronchial edema formation after 1-month and signs of chronic pulmonary inflammation after 2-months of cigarette smoke exposure. These data demonstrate that even mild exposure to cigarette smoke, without significantly affecting respiratory functions, can have a negative effect on adult-born neurons in the dentate gyrus, when applied over longer time periods. Our data indicate that besides nicotine other factors, such as inflammatory mediators, may also contribute to this effect.

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

    PubMed Central

    2011-01-01

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

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

    SciTech Connect

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

    2011-11-15

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

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

    PubMed

    Rammal, Hassan; Bouayed, Jaouad; Soulimani, Rachid

    2010-02-10

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

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

    PubMed

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

    2013-02-01

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

  1. Acceptability and Preliminary Outcomes of a Peer-Led Depression Prevention Intervention for African American Adolescents and Young Adults in Employment Training Programs

    ERIC Educational Resources Information Center

    Tandon, Darius; Mendelson, Tamar; Mance, GiShawn

    2011-01-01

    This study examines the acceptability and preliminary outcomes from an open trial of a depression prevention intervention for low-income African American adolescents and young adults in employment training programs. The sample (N=42) consisted of predominately African American adolescents and young adults (mean age=19.1) exhibiting subclinical…

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

    PubMed

    Kilicaslan, Alper; Belviranli, Muaz; Okudan, Nilsel; Nurullahoglu Atalik, Esra

    2013-12-01

    Volatile anesthetics are known to disturb the spatial memory in aged rodents, but there is insufficient information on their effects on young adult rodents. The aim of this study was to compare the effects of single and repeated exposure to desflurane and sevoflurane on spatial learning and memory functions in young adult mice. Balb/c mice (2 months old) were randomly divided into six equal groups (n = 8). The groups with single inhalation were exposed to 3.3% sevoflurane or 7.8% desflurane or vehicle gas for 4 h, respectively. The groups with repeated inhalation were exposed to 3.3% sevoflurane or 7.8% desflurane or vehicle gas for 2 h a day during 5 consecutive days. Spatial learning and memory were tested in the Morris water maze 24 h after exposure. In the learning phase, the parameters associated with finding the hidden platform and swimming speed, and in the memory phase, time spent in the target quadrant and the adjacent quadrants, were assessed and compared between the groups. In the 4-day learning process, there was no significant difference between the groups in terms of mean latency to platform, mean distance traveled and average speed (P > 0.05). During the memory-test phase, all mice exhibited spatial memory, but there was no significant difference between the groups in terms of time spent in the target quadrant (P > 0.05). Sevoflurane and desflurane anesthesia did not impair acquisition learning and retention memory in young adult mice.

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

    PubMed

    Ivannikov, Maxim V; Van Remmen, Holly

    2015-07-01

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

  4. Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice

    PubMed Central

    Melariri, Paula; Kalombo, Lonji; Nkuna, Patric; Dube, Admire; Hayeshi, Rose; Ogutu, Benhards; Gibhard, Liezl; deKock, Carmen; Smith, Peter; Wiesner, Lubbe; Swai, Hulda

    2015-01-01

    Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes <20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min·μmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity. PMID:25759576

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. LEDs for Efficient Energy

    ERIC Educational Resources Information Center

    Guerin, David A.

    1978-01-01

    Light-emitting diodes (LEDs) are described and three classroom experiments are given, one to prove the, low power requirements and efficiency of LEDs, an LED on-off detector circuit, and the third an LED photoelectric smoke detector. (BB)

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. The investigation of neonatal MK-801 administration and physical environmental enrichment on emotional and cognitive functions in adult Balb/c mice.

    PubMed

    Akillioglu, Kubra; Babar Melik, Emine; Melik, Enver; Kocahan, Sayad

    2012-09-01

    N-methyl-D-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. It is known that growing up in an enriched environment has effects on emotional and cognitive performance. In our study, we evaluated the effects of physically enriched environment on the emotional and cognitive functions of the adult brain in the setting of previous NMDA receptor hypoactivity during the critical developmental period of the nervous system. In this study, NMDA receptor blockade was induced 5-10 days postnatally (PD5-10) using MK-801 in mice Balb/c (twice a day 0.25 mg/kg, for 5 days, intraperitoneal). MK-801 was given to developing mice living in a standard (SE) and an enrichment environment (EE) and once the animals reached adulthood, emotional behaviors were evaluated using an open field test (OF) and an elevated plus maze (EPM) test whereas cognitive processes were evaluated using the Morris water-maze (MWM). The EE group showed decreased locomotor activity (p<0.05) in the OF and increased exploratory behaviour (p<0.01) and decreased fear of heights/anxiety-like behaviour (p<0.05) in the EPM test. The EE had positive effects on spatial learning in the MWM (p<0.05). Blockade of the NMDA receptor increased the fear of height (p<0.05), decreased exploratory behaviour and locomotor activity (p<0.001). Also, it led to decreased spatial learning (p<0.05). The decreases in spatial learning and exploratory behaviours and the increase in fear of heights/anxiety-like behaviour with NMDA receptor blockade was not reversed by EE. NMDA receptor blockade during the critical period of development led to deterioration in the emotional and cognitive processes during adulthood. An enriched environmental did not reverse the deleterious effects of the NMDA receptor blockade on emotional and cognitive functions.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. Estrous cycle staging before mating led to increased efficiency in the production of pseudopregnant recipients without negatively affecting embryo transfer in mice.

    PubMed

    Heykants, Malte; Mahabir, Esther

    2016-03-15

    The goal was to increase pseudopregnant mice production by estrous cycle staging by visual examination before pairing and to determine the effect of such pseudopregnant recipients on embryo transfer. To compare methods of estrous cycle staging over 14 days, groups consisted of 10 females in proestrus-estrus and 10 vasectomized males; group 1: only daily visual observation; group 2: daily visual observation and cytological examination on day 1; group 3: daily visual observation and daily cytological examination. The average time to first vaginal plug was 1.8 days in group 1, 2.7 days in group 2, and 3.2 days in group 3, whereas the average time between consecutive vaginal plugs was 9.2 days (group 1), 10 days (group 2), and 9.25 days (group 3). The average time between consecutive estrous cycles was 9.7 days (group 1), 11.8 days (group 2), and 9.4 days (group 3). The congruence between visual and cytological examination in determining proestrus-estrus in group 2 was 100% and that for the four stages in group 3 was 79% with a range of 44% to 100%. From 162 plug-positive females originally selected in proestrus-estrus, 49%, 30%, 19%, and 2% were plug-positive on Day 1, Day 2, Day 3, and Day 4, respectively, showing that pseudopregnant mice production was significantly increased on the first 2 days. From 192 plug-positive females originally selected randomly, these values were 31%, 21%, 35%, 10%, and 3% on d1, d2, d3, d4, and d5, respectively. No significant differences were observed between groups with respect to embryo transfers with fresh or cryopreserved embryos although the number of pups born per litter was higher in group A with fresh (7.57 vs. 6.39) and cryopreserved-thawed embryos (5.0 vs. 4.38). Furthermore, the sex ratio and the genotype of the pups were not significantly affected.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  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. 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.

  5. Longitudinal comparison of a physiotherapist-led, home-based and group-based program for increasing physical activity in community-dwelling middle-aged adults.

    PubMed

    Freene, Nicole; Waddington, Gordon; Davey, Rachel; Cochrane, Tom

    2015-01-01

    Few studies have compared the longer-term effects of physical activity interventions. Here we compare a 6-month physiotherapist-led, home-based physical activity program to a community group exercise program over 2 years. Healthy, sedentary community-dwelling 50-65 year olds were recruited to a non-randomised community group exercise program (G, n = 93) or a physiotherapist-led, home-based physical activity program (HB, n = 65). Outcomes included 'sufficient' physical activity (Active Australia Survey), minutes of moderate-vigorous physical activity (ActiGraph GT1M), aerobic capacity (2-min step-test), quality of life (SF-12v2), blood pressure, waist circumference, waist-to-hip ratio and body mass index. Outcome measures were collected at baseline, 6, 12, 18 and 24 months. Using intention-to-treat analysis, both interventions resulted in significant and sustainable increases in the number of participants achieving 'sufficient' physical activity (HB 22 v. 41%, G 22 v. 47%, P ≤ 0.001) and decreases in waist circumference (HB 90 v. 89 cm, G 93 v. 91 cm, P < 0.001) over 2 years. The home-based program was less costly (HB A$47 v. G $84 per participant) but less effective in achieving the benefits at 2 years. The physiotherapist-led, home-based physical activity program may be a low-cost alternative to increase physical activity levels for those not interested in, or unable to attend, a group exercise program.

  6. The In-Service Training of Adult Literacy, Numeracy and English for Speakers of Other Languages Teachers in England; the Challenges of a "Standards-Led Model"

    ERIC Educational Resources Information Center

    Lucas, Norman

    2007-01-01

    Drawing upon two research projects, this paper analyses changes affecting the in-service training of adult literacy, numeracy and teachers of English for Speakers of Other Languages in England. There are many issues raised in this paper, particularly how in-service teacher education programmes in England can meet the diversity of learner need, how…

  7. 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.

  8. 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.

  9. 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.

  10. [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.

  11. 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...

  12. 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

  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. 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.

  15. 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

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

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

    PubMed Central

    Yang, Junhua; Qi, Fangfang; Yao, Zhibin

    2016-01-01

    The Bacillus Calmette-Guérin (BCG) vaccine is routinely administered to human neonates worldwide. BCG has recently been identified as a neuroprotective immune mediator in several neuropathological conditions, exerting neuroprotection in a mouse model of Parkinson's disease and slowing the progression of clinically isolated syndrome in patients with multiple sclerosis. The immune system is significantly involved in brain development, and several types of neonatal immune activations exert influences on the brain and behavior following a secondary immune challenge in adulthood. However, whether the neonatal BCG vaccination affects the brain in adulthood remains to be elucidated. In the present study, newborn C57BL/6 mice were injected subcutaneously with BCG (105 colony forming units) or phosphate-buffered saline (PBS). A total of 12 weeks later, the mice were injected intraperitoneally with 330 µg/kg lipopolysaccharide (LPS) or PBS. The present study reported that the neonatal BCG vaccination alleviated sickness, anxiety and depression-like behavior, lessened the impairments in hippocampal cell proliferation and downregulated the proinflammatory responses in the serum and brain that were induced by the adult LPS challenge. However, BCG vaccination alone had no evident influence on the brain and behavior in adulthood. In conclusion, the neonatal BCG vaccination alleviated the neurobehavioral impairments and neuroinflammation induced by LPS exposure in adult mice, suggesting a potential neuroprotective role of the neonatal BCG vaccination in adulthood. PMID:27357155

  3. Changes in caregiving satisfaction and information needs among relatives of adults with mental illness: results of a randomized evaluation of a family-led education intervention.

    PubMed

    Pickett-Schenk, Susan A; Bennett, Cynthia; Cook, Judith A; Steigman, Pamela; Lippincott, Richard; Villagracia, Ian; Grey, Dennis

    2006-10-01

    The authors examined changes in caregiving satisfaction and information needs among 462 relatives of individuals with mental illness who participated in a study of a family-led education course, the Journey of Hope (JOH). Participants were randomly assigned to receive JOH or to a control group waiting list and followed for 9 months. General linear model repeated measures analysis of variance found that, compared with the control group, the intervention group showed significant improvement in caregiving satisfaction and information needs following course completion and maintained these gains for another 6 months. Education and support from other family members in the form of a structured course is effective in meeting the caregiving needs of relatives of persons with mental illness.

  4. Adult Gli2+/–;Gli3Δ699/+ Male and Female Mice Display a Spectrum of Genital Malformation

    PubMed Central

    He, Fei; Akbari, Pedram; Mo, Rong; Zhang, Jennifer J.; Hui, Chi-Chung; Kim, Peter C.; Farhat, Walid A.

    2016-01-01

    Disorders of sexual development (DSD) encompass a broad spectrum of urogenital malformations and are amongst the most common congenital birth defects. Although key genetic factors such as the hedgehog (Hh) family have been identified, a unifying postnatally viable model displaying the spectrum of male and female urogenital malformations has not yet been reported. Since human cases are diagnosed and treated at various stages postnatally, equivalent mouse models enabling analysis at similar stages are of significant interest. Additionally, all non-Hh based genetic models investigating DSD display normal females, leaving female urogenital development largely unknown. Here, we generated compound mutant mice, Gli2+/–;Gli3Δ699/+, which exhibit a spectrum of urogenital malformations in both males and females upon birth, and also carried them well into adulthood. Analysis of embryonic day (E)18.5 and adult mice revealed shortened anogenital distance (AGD), open ventral urethral groove, incomplete fusion of scrotal sac, abnormal penile size and structure, and incomplete testicular descent with hypoplasia in male mice, whereas female mutant mice displayed reduced AGD, urinary incontinence, and a number of uterine anomalies such as vaginal duplication. Male and female fertility was also investigated via breeding cages, and it was identified that male mice were infertile while females were unable to deliver despite becoming impregnated. We propose that Gli2+/–;Gli3Δ699/+ mice can serve as a genetic mouse model for common DSD such as cryptorchidism, hypospadias, and incomplete fusion of the scrotal sac in males, and a spectrum of uterine and vaginal abnormalities along with urinary incontinence in females, which could prove essential in revealing new insights into their equivalent diseases in humans. PMID:27814383

  5. Increased nitric oxide bioavailability in adult GRK2 hemizygous mice protects against angiotensin II-induced hypertension.

    PubMed

    Avendaño, María S; Lucas, Elisa; Jurado-Pueyo, María; Martínez-Revelles, Sonia; Vila-Bedmar, Rocío; Mayor, Federico; Salaices, Mercedes; Briones, Ana M; Murga, Cristina

    2014-02-01

    G protein-coupled receptor kinase 2 (GRK2) is a ubiquitous serine/threonine protein kinase able to phosphorylate and desensitize the active form of several G protein-coupled receptors. Given the lack of selective inhibitors for GRK2, we investigated the effects elicited by GRK2 inhibition in vascular responses using global adult hemizygous mice (GRK2(+/-)). The vasodilator responses to acetylcholine or isoproterenol were increased in aortas and mesenteric resistance arteries from GRK2(+/-) mice compared with wild-type (WT) littermates. After angiotensin II (AngII) infusion, GRK2(+/-) mice were partially protected against hypertension, vascular remodeling, and mechanical alterations, even when resting basal blood pressures were not significantly different. AngII infusion also (1) increased GRK2 levels in WT but not in GRK2(+/-) vessels; (2) increased vasoconstrictor responses to phenylephrine in WT but not in GRK2(+/-) mice; and (3) decreased vasodilator responses to acetylcholine and vascular pAkt and eNOS levels more in WT than in GRK2(+/-) animals. Vascular NO production and the modulation of vasoconstrictor responses by endothelial-derived NO remained enhanced in GRK2(+/-) mice infused with AngII. Thus, GRK2(+/-) mice are resistant to the development of vascular remodeling and mechanical alterations, endothelial dysfunction, increased vasoconstrictor responses, and hypertension induced by AngII at least partially through the preservation of NO bioavailability. In conclusion, our results describe an important role for GRK2 in systemic hypertension and further establish that an inhibition of GRK2 could be a beneficial treatment for this condition.

  6. 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.

  7. Perinatal exposure of mice to the pesticide DDT impairs energy expenditure and metabolism in adult female offspring.

    PubMed

    La Merrill, Michele; Karey, Emma; Moshier, Erin; Lindtner, Claudia; La Frano, Michael R; Newman, John W; Buettner, Christoph

    2014-01-01

    Dichlorodiphenyltrichloroethane (DDT) has been used extensively to control malaria, typhus, body lice and bubonic plague worldwide, until countries began restricting its use in the 1970s. Its use in malaria control continues in some countries according to recommendation by the World Health Organization. Individuals exposed to elevated levels of DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) have an increased prevalence of diabetes and insulin resistance. Here we hypothesize that perinatal exposure to DDT disrupts metabolic programming leading to impaired metabolism in adult offspring. To test this, we administered DDT to C57BL/6J mice from gestational day 11.5 to postnatal day 5 and studied their metabolic phenotype at several ages up to nine months. Perinatal DDT exposure reduced core body temperature, impaired cold tolerance, decreased energy expenditure, and produced a transient early-life increase in body fat in female offspring. When challenged with a high fat diet for 12 weeks in adulthood, female offspring perinatally exposed to DDT developed glucose intolerance, hyperinsulinemia, dyslipidemia, and altered bile acid metabolism. Perinatal DDT exposure combined with high fat feeding in adulthood further impaired thermogenesis as evidenced by reductions in core temperature and in the expression of numerous RNA that promote thermogenesis and substrate utilization in the brown adipose tissue of adult female mice. These observations suggest that perinatal DDT exposure impairs thermogenesis and the metabolism of carbohydrates and lipids which may increase susceptibility to the metabolic syndrome in adult female offspring.

  8. Developmental Exposure of Mice to TCDD Elicits a Similar Uterine Phenotype in Adult Animals as Observed in Women with Endometriosis

    PubMed Central

    Nayyar, Tultul; Bruner-Tran, Kaylon L.; Piestrzeniewicz-Ulanska, Dagmara; Osteen, Kevin G.

    2007-01-01

    Whether environmental toxicants impact an individual woman’s risk for developing endometriosis remains uncertain. Although the growth of endometrial glands and stroma at extra-uterine sites is associated with retrograde menstruation, our studies suggest that reduced responsiveness to progesterone may increase the invasive capacity of endometrial tissue in women with endometriosis. Interestingly, our recent studies using isolated human endometrial cells in short-term culture suggest that experimental exposure to the environmental contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) can alter the expression of progesterone receptor isotypes. Compared to adult exposure, toxicant exposure during development can exert a significantly greater biological impact, potentially affecting the incidence of endometriosis in adults. To address this possibility, we exposed mice to TCDD at critical developmental time points and subsequently examined uterine progesterone receptor expression and steroid responsive transforming growth factor-β2 expression in adult animals. We find that the uterine phenotype of toxicant-exposed mice is markedly similarly to the endometrial phenotype of women with endometriosis. PMID:17056225

  9. 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.

  10. 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.

  11. Conditional Deletion of Fgfr3 in Chondrocytes leads to Osteoarthritis-like Defects in Temporomandibular Joint of Adult Mice

    PubMed Central

    Zhou, Siru; Xie, Yangli; Li, Wei; Huang, Junlan; Wang, Zuqiang; Tang, Junzhou; Xu, Wei; Sun, Xianding; Tan, Qiaoyan; Huang, Shuo; Luo, Fengtao; Xu, Meng; Wang, Jun; Wu, Tingting; chen, Liang; Chen, Hangang; Su, Nan; Du, Xiaolan; Shen, Yue; Chen, Lin

    2016-01-01

    Osteoarthritis (OA) in the temporomandibular joint (TMJ) is a common degenerative disease in adult, which is characterized by progressive destruction of the articular cartilage. To investigate the role of FGFR3 in the homeostasis of TMJ cartilage during adult stage, we generated Fgfr3f/f; Col2a1-CreERT2 (Fgfr3 cKO) mice, in which Fgfr3 was deleted in chondrocytes at 2 months of age. OA-like defects were observed in Fgfr3 cKO TMJ cartilage. Immunohistochemical staining and quantitative real-time PCR analyses revealed a significant increase in expressions of COL10, MMP13 and AMAMTS5. In addition, there was a sharp increase in chondrocyte apoptosis at the Fgfr3 cKO articular surface, which was accompanied by a down-regulation of lubricin expression. Importantly, the expressions of RUNX2 and Indian hedgehog (IHH) were up-regulated in Fgfr3 cKO TMJ. Primary Fgfr3 cKO chondrocytes were treated with IHH signaling inhibitor, which significantly reduced expressions of Runx2, Col10, Mmp13 and Adamts5. Furthermore, the IHH signaling inhibitor partially alleviated OA-like defects in the TMJ of Fgfr3 cKO mice, including restoration of lubricin expression and improvement of the integrity of the articular surface. In conclusion, our study proposes that FGFR3/IHH signaling pathway plays a critical role in maintaining the homeostasis of TMJ articular cartilage during adult stage. PMID:27041063

  12. Transient Treg-cell depletion in adult mice results in persistent self-reactive CD4(+) T-cell responses.

    PubMed

    Nyström, Sofia N; Bourges, Dorothée; Garry, Sarah; Ross, Ellen M; van Driel, Ian R; Gleeson, Paul A

    2014-12-01

    Depletion of Foxp3(+) CD4(+) regulatory T cells (Treg) in adults results in chronic inflammation and autoimmune disease. However, the impact of transient Treg-cell depletion on self-reactive responses is poorly defined. Here, we studied the effect of transient depletion of Treg cells on CD4(+) T-cell responses to endogenous self-antigens. Short-term ablation of Treg cells in mice resulted in rapid activation of CD4(+) T cells, increased percentage of IFN-γ(+) and Th17 cells in lymphoid organs, and development of autoimmune gastritis. To track self-reactive responses, we analyzed the activation of naïve gastric-specific CD4(+) T cells. There was a dramatic increase in proliferation and acquisition of effector function of gastric-specific T cells in the stomach draining LNs of Treg-cell-depleted mice, compared with untreated mice, either during Treg-cell depletion or after Treg-cell reconstitution. Moreover, the hyperproliferation of gastric-specific T cells in the Treg-cell-ablated mice was predominantly antigen-dependent. Transient depletion of Treg cells resulted in a shift in the ratio of peripheral:thymic Treg cells in the reemerged Treg-cell population, indicating an altered composition of Treg cells. These findings indicate that transient Treg-cell depletion results in ongoing antigen-driven self-reactive T-cell responses and emphasize the continual requirement for an intact Treg-cell population.

  13. Chronic social defeat stress increases dopamine D2 receptor dimerization in the prefrontal cortex of adult mice.

    PubMed

    Bagalkot, T R; Jin, H-M; Prabhu, V V; Muna, S S; Cui, Y; Yadav, B K; Chae, H-J; Chung, Y-C

    2015-12-17

    The present study aimed to examine the effects of chronic social defeat stress on the dopamine receptors and proteins involved in post-endocytic trafficking pathways. Adult mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. Western blot analysis was used to measure the protein expression levels of dopamine D2 receptors (D2Rs), a short (D2S) and a long form (D2L) and, D2R monomers and dimers, dopamine D1 receptors (D1Rs), neuronal calcium sensor-1 (NCS-1) and G protein-coupled receptor-associated sorting protein-1 (GASP-1), and reverse transcription-polymerase chain reaction (RT-PCR) was used to measure the mRNA expression levels of D2S, D2L, D2R monomers and dimers, and D1Rs in different brain areas. We observed increased expression of D2S, D2L and D2Rs dimers in the prefrontal cortex (PFC) of susceptible and/or unsusceptible mice compared with controls. The only significant findings with regard to mRNA expression levels were lower expression of D2S mRNA in the amygdala (AMYG) of susceptible and unsusceptible mice compared with controls. The present study demonstrated that chronic social defeat stress induced increased expression of D2S, D2L, and D2R dimers in the PFC of susceptible and/or unsusceptible mice.

  14. Properties of Taurine Release in Glucose-Free Media in Hippocampal Slices from Developing and Adult Mice

    PubMed Central

    Oja, Simo S.; Saransaari, Pirjo

    2015-01-01

    The release of preloaded [3H]taurine from hippocampal slices from developing 7-day-old and young adult 3-month-old mice was studied in a superfusion system in the absence of glucose. These hypoglycemic conditions enhanced the release at both ages, the effect being markedly greater in developing mice. A depolarizing K+ concentration accentuated the release, which indicates that it was partially mediated by exocytosis. The anion channel blockers were inhibitory, witnessing the contribution of ion channels. NO-generating agents fomented the release as a sign of the participation of excitatory amino acid receptors. The other second messenger systems were apparently less efficient. The much greater taurine release could be a reason for the well-known greater tolerance of developing nervous tissue to lack of glucose. PMID:26347028

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

    PubMed

    Trinchero, Mariela F; Koehl, Muriel; Bechakra, Malik; Delage, Pauline; Charrier, Vanessa; Grosjean, Noelle; Ladeveze, Elodie; Schinder, Alejandro F; Abrous, D Nora

    2015-11-01

    New dentate granule cells (GCs) are generated in the hippocampus throughout life. These adult-born neurons are required for spatial learning in the Morris water maze (MWM). In rats, spatial learning shapes the network by regulating their number and dendritic development. Here, we explored whether such modulatory effects exist in mice. New GCs were tagged using thymidine analogs or a GFP-expressing retrovirus. Animals were exposed to a reference memory protocol for 10-14 days (spaced training) at different times after newborn cells labeling. Cell proliferation, cell survival, cell death, neuronal phenotype, and dendritic and spine development were examined using immunohistochemistry. Surprisingly, spatial learning did not modify any of the parameters under scrutiny including cell number and dendritic morphology. These results suggest that although new GCs are required in mice for spatial learning in the MWM, they are, at least for the developmental intervals analyzed here, refractory to behavioral stimuli generated in the course of learning in the MWM.

  16. Effects of neuron-specific estrogen receptor (ER) α and ERβ deletion on the acute estrogen negative feedback mechanism in adult female mice.

    PubMed

    Cheong, Rachel Y; Porteous, Robert; Chambon, Pierre; Abrahám, István; Herbison, Allan E

    2014-04-01

    The negative feedback mechanism through which 17β-estradiol (E2) acts to suppress the activity of the GnRH neurons remains unclear. Using inducible and cell-specific genetic mouse models, we examined the estrogen receptor (ER) isoforms expressed by neurons that mediate acute estrogen negative feedback. Adult female mutant mice in which ERα was deleted from all neurons in the neonatal period failed to exhibit estrous cycles or negative feedback. Adult mutant female mice with neonatal neuronal ERβ deletion exhibited normal estrous cycles, but a failure of E2 to suppress LH secretion was seen in ovariectomized mice. Mutant mice with a GnRH neuron-selective deletion of ERβ exhibited normal cycles and negative feedback, suggesting no critical role for ERβ in GnRH neurons in acute negative feedback. To examine the adult roles of neurons expressing ERα, an inducible tamoxifen-based Cre-LoxP approach was used to ablate ERα from neurons that express calmodulin kinase IIα in adults. This resulted in mice with no estrous cycles, a normal increase in LH after ovariectomy, but an inability of E2 to suppress LH secretion. Finally, acute administration of ERα- and ERβ-selective agonists to adult ovariectomized wild-type mice revealed that activation of ERα suppressed LH secretion, whereas ERβ agonists had no effect. This study highlights the differences in adult reproductive phenotypes that result from neonatal vs adult ablation of ERα in the brain. Together, these experiments expand previous global knockout studies by demonstrating that neurons expressing ERα are essential and probably sufficient for the acute estrogen negative feedback mechanism in female mice.

  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. 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

  19. 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.

  20. Comparison of the deleterious effects of binge drinking-like alcohol exposure in adolescent and adult mice.

    PubMed

    Lacaille, Hélène; Duterte-Boucher, Dominique; Liot, Donovan; Vaudry, Hubert; Naassila, Mickael; Vaudry, David

    2015-03-01

    A major cause of alcohol toxicity is the production of reactive oxygen species generated during ethanol metabolism. The aim of this study was to compare the effect of binge drinking-like alcohol exposure on a panel of genes implicated in oxidative mechanisms in adolescent and adult mice. In adolescent animals, alcohol decreased the expression of genes involved in the repair and protection of oxidative DNA damage such as atr, gpx7, or nudt15 and increased the expression of proapoptotic genes such as casp3. In contrast, in the adult brain, genes activated by alcohol were mainly associated with protective mechanisms that prevent cells from oxidative damage. Whatever the age, iterative binge-like episodes provoked the same deleterious effects as those observed after a single binge episode. In adolescent mice, multiple binge ethanol exposure substantially reduced neurogenesis in the dentate gyrus and impaired short-term memory in the novel object and passive avoidance tests. Taken together, our results indicate that alcohol causes deleterious effects in the adolescent brain which are distinct from those observed in adults. These data contribute to explain the greater sensitivity of the adolescent brain to alcohol toxicity. The effects of alcohol exposure were investigated on genes involved in oxidative mechanisms. In adolescent animals, alcohol decreased the expression of genes involved in DNA repair, a potential cause of the observed decrease of neurogenesis. In contrast, in the adult brain, alcohol increased the expression of genes associated with antioxidant mechanisms. Apoptosis was increase in all groups and converged with other biochemical alterations to enhance short-term memory impairment in the adolescent brain. These data contribute to explain the greater sensitivity of the adolescent brain to alcohol toxicity.

  1. 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.

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

    PubMed

    Buscariollo, Daniela L; Fang, Xiefan; Greenwood, Victoria; Xue, Huiling; Rivkees, Scott A; Wendler, Christopher C

    2014-01-01

    Evidence indicates that disruption of normal prenatal development influences an individual's risk of developing obesity and cardiovascular disease as an adult. Thus, understanding how in utero exposure to chemical agents leads to increased susceptibility to adult diseases is a critical health related issue. Our aim was to determine whether adenosine A1 receptors (A1ARs) mediate the long-term effects of in utero caffeine exposure on cardiac function and whether these long-term effects are the result of changes in DNA methylation patterns in adult hearts. Pregnant A1AR knockout mice were treated with caffeine (20 mg/kg) or vehicle (0.09% NaCl) i.p. at embryonic day 8.5. This caffeine treatment results in serum levels equivalent to the consumption of 2-4 cups of coffee in humans. After dams gave birth, offspring were examined at 8-10 weeks of age. A1AR+/+ offspring treated in utero with caffeine were 10% heavier than vehicle controls. Using echocardiography, we observed altered cardiac function and morphology in adult mice exposed to caffeine in utero. Caffeine treatment decreased cardiac output by 11% and increased left ventricular wall thickness by 29% during diastole. Using DNA methylation arrays, we identified altered DNA methylation patterns in A1AR+/+ caffeine treated hearts, including 7719 differentially methylated regions (DMRs) within the genome and an overall decrease in DNA methylation of 26%. Analysis of genes associated with DMRs revealed that many are associated with cardiac hypertrophy. These data demonstrate that A1ARs mediate in utero caffeine effects on cardiac function and growth and that caffeine exposure leads to changes in DNA methylation.

  3. 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

  4. Impact of fasting on the rhythmic expression of myogenic and metabolic factors in skeletal muscle of adult mice.

    PubMed

    Shavlakadze, T; Anwari, T; Soffe, Z; Cozens, G; Mark, P J; Gondro, C; Grounds, M D

    2013-07-01

    Circadian rhythms and metabolism are tightly integrated, and rhythmic expression of metabolic factors is common in homeostatic processes. We measured the temporal changes in the expression of myogenic regulatory factors and expression and activity level of molecules involved in protein metabolism in skeletal muscles and livers in mice and examined the impact of fasting. Tissues were collected over 24 h (at zeitgeber times ZT1, ZT5, ZT9, ZT13, ZT17, ZT21, and ZT1 the following day) from adult male C57Bl/6J mice that had been either freely fed or fasted for 24 h. In skeletal muscle, there was a robust rise in the mRNA expression of the myogenic regulatory factors MyoD and myogenin during dark hours which was strongly suppressed by fasting. Circadian pattern was observed for mRNA of MuRF1, Akt1, and ribosomal protein S6 in muscles in fed and fasted mice and for Fbxo32 in fed mice. Activity (phosphorylation) levels of Akt(Ser473) displayed temporal regulation in fasted (but not fed) mice and were high at ZT9. Fasting caused significant reductions in phosphorylation for both Akt and S6 in muscles, indicative of inactivation. Hepatic phosphorylated Akt(Ser473) and S6(Ser235/236) proteins did not exhibit daily rhythms. Fasting significantly reduced hepatic Akt(473) phosphorylation compared with fed levels, although (unlike in muscle) it did not affect S6(Ser235/236) phosphorylation. This in vivo circadian study addresses for the first time the signaling activities of key molecules related to protein turnover and their possible cross-regulation of expression of genes related to protein degradation.

  5. High-Yield Superovulation in Adult Mice by Anti-Inhibin Serum Treatment Combined with Estrous Cycle Synchronization.

    PubMed

    Hasegawa, Ayumi; Mochida, Keiji; Inoue, Hiroki; Noda, Yoshihiro; Endo, Tamao; Watanabe, Gen; Ogura, Atsuo

    2016-01-01

    Producing many mature oocytes is of great importance for assisted reproductive technologies. In mice, superovulation by consecutive injections of equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG) has been the gold standard for oocyte collection. However, the yield of mature oocytes by this regimen can fluctuate according to the stage of the estrous cycle, strain, and age. Therefore, our objective was to develop a high-yield superovulation protocol to collect higher numbers of oocytes from adult female mice of different strains and ages. First, we aimed to synchronize the estrous cycle using C57BL/6 (B6) female mice. Most (93%) were synchronized to metestrus after two daily injections of progesterone. Second, we found that with the injection of anti-inhibin serum (AIS) instead of eCG, the mean number of ovulated oocytes almost doubled (21 vs. 41 per mouse). Third, by combining estrous cycle synchronization with two AIS injections, we obtained 62 oocytes per mouse, about three times that with the eCG-hCG protocol. Importantly, this approach increased the proportion of mice that ovulated >25 oocytes from about 40% (eCG-hCG) to 90%. The same protocol was also effective in other inbred (BALB/cA), outbred (ICR), and hybrid (B6D2F1) strains. In addition, B6 female mice aged over 1 yr ovulated 1.8-fold more oocytes by this protocol. Thus, estrous cycle synchronization followed by AIS-hCG yielded a broadly applicable, highly efficient superovulation. This protocol should promote the effective use of invaluable female mouse strains and decrease the numbers of animals euthanized.

  6. 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.

  7. High levels of gene expression in the hepatocytes of adult mice, neonatal mice and tree shrews via retro-orbital sinus hydrodynamic injections of naked plasmid DNA.

    PubMed

    Yan, Shaoduo; Fu, Qiuxia; Zhou, Yong; Wang, Jidong; Liu, Ying; Duan, Xiangguo; Jia, Shuaizheng; Peng, Jianchun; Gao, Bo; Du, Juan; Zhou, Qianqian; Li, Yuan; Wang, Xiaohui; Zhan, Linsheng

    2012-08-10

    Hydrodynamic-based gene delivery has emerged as an efficient and simple method for the intracellular transfection of naked plasmid DNA (pDNA) in vivo. In this system, a hydrodynamic injection via the tail vein is the most effective non-viral method of liver-targeted gene delivery. However, this injection is often technically challenging when used in animals whose tail veins are difficult to visualize or too small to operate on. To overcome this limitation, an alternative in vivo gene delivery method, the rapid injection of large volume of pDNA solution through retro-orbital sinus, was established. Using this technique, we successfully delivered pDNA to the tissue of adult mice, neonatal mice and tree shrews. The efficient expression of exogenous genes was specifically detected in the liver of test animals treated with this gene delivery method. This study demonstrates for the first time that the hydrodynamic gene delivery via the retro-orbital sinus can not only reach the same transgene efficiency as a tradition hydrodynamic-based intravascular injection but also be used in animals that are difficult to inject via the tail vein. This method could open up new areas in gene function studies and gene therapy disease treatment.

  8. Long-term voluntary running improves diet-induced adiposity in young adult mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study investigated the effects of long-term voluntary running on diet-induced adiposity in male C57BL/6 mice. Four-week old mice (n = 15 per group) were fed the AIN93G diet or a 45% high-fat diet (% kcal.) with or without access to in-cage activity wheels for 14 weeks. The high-fat die...

  9. LED Color Characteristics

    SciTech Connect

    2012-01-01

    Color quality is an important consideration when evaluating LED-based products for general illumination. This fact sheet reviews the basics regarding light and color and summarizes the most important color issues related to white-light LED systems.

  10. 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

  11. 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.

  12. 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

  13. Translation of fit & strong! For middle-aged and older adults: examining implementation and effectiveness of a lay-led model in central Texas.

    PubMed

    Ory, Marcia G; Lee, Shinduk; Zollinger, Alyson; Bhurtyal, Kiran; Jiang, Luohua; Smith, Matthew Lee

    2014-01-01

    The Fit & Strong! program is an evidence-based, multi-component program promoting physical activity among older adults, particularly those suffering from lower-extremity osteoarthritis. The primary purpose of the study is to examine if the Fit & Strong! program translated into a lay-leader model can produce comparable outcomes to the original program taught by physical therapists and/or certified exercise instructors. A single-group, pre-post study design was employed, and data were collected at the baseline (n = 136 participants) and the intervention conclusion (n = 71) with both baseline and post-intervention data. The measurements included socio-demographic information, health- and behavior-related information, and health-related quality of life. Various statistical tests were used for the program impact analysis and examination of the association between participant characteristics and program completion. As in the original study, there were statistically significant (p < 0.05) improvements in self-efficacy for exercise, aerobic capacity, joint stiffness, level of energy, and amount and intensity of physical activities. The odds of completing the program were significantly lower for the participants from rural areas and those having multiple chronic conditions. Successful adaptation of the Fit & Strong! program to a lay-leader model can increase the likelihood of program dissemination by broadening the selection pool of instructors and, hence, reducing the potential issue of resource limitation. However, high program attrition rates (54.1%) emphasize the importance of adopting evidence-based strategies for improving the retention of the participants from rural areas and those with multiple chronic conditions.

  14. Contractile properties of skinned muscle fibres from young and adult normal and dystrophic (mdx) mice.

    PubMed Central

    Williams, D A; Head, S I; Lynch, G S; Stephenson, D G

    1993-01-01

    1. Single muscle fibres were enzymatically isolated from the soleus and extensor digitorum longus (EDL) muscles of genetically dystrophic mdx and normal (C57BL/10) mice aged 3-6 or 17-23 weeks. 2. Fibres of both muscles were chemically skinned with the non-ionic detergent Triton X-100 (2% v/v). Ca(2+)- and Sr(2+)-activated contractile responses were recorded and comparisons were made between several contractile parameters of various fibre types of normal and dystrophic mice of similar age. 3. There were no significant differences in the following contractile parameters of skinned fibres of normal and mdx mice of the same age: sensitivity to activating Ca2+ (pCa50) or Sr2+ (pSr50) and differential sensitivity to the activating ions (pCa50-pSr50). However the maximum isometric tension (Po) and the frequency of myofibrillar force oscillations in EDL fast-twitch fibres of young mdx mice were significantly lower than those of soleus fast-twitch fibres of the same animals, or fast-twitch fibres (EDL or soleus) of normal mice. 4. Age-related differences were apparent in some contractile parameters of both normal and mdx mice. In particular the steepness of force-pCa and force-pSr curves increased with age in normal mice, yet decreased with age in fibres of mdx mice. 5. A fluorescent probe, ethidium bromide, which interchelates with DNA, was used with laser-scanning confocal microscopy to determine the distribution of myonuclei in fibres. Fibres isolated from either muscle type of normal animals displayed a characteristic peripheral spiral of myonuclei. Fibres from muscles of mdx mice displayed three major patterns of nuclear distribution; the normal peripheral spiral, long central strands of nuclei, and a mixture of these two patterns. 6. The contractile characteristics of mdx fibres were not markedly influenced by the nuclear distribution pattern in that there were no discernible differences in the major contractile parameters (the Hill coefficients nCa and nSr, which

  15. 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

  16. 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice

    PubMed Central

    Liu, Min-Tsai; Kuan, Yung-Hui; Wang, Jingwen; Hen, René; Gershon, Michael D.

    2009-01-01

    Although the mature enteric nervous system (ENS) has been shown to retain stem cells, enteric neurogenesis has not previously been demonstrated in adults. The relative number of enteric neurons in wild-type (WT) mice and those lacking 5-HT4 receptors (KO) was found to be similar at birth; however, the abundance of ENS neurons increased during the first 4 months after birth in WT but not KO littermates. Enteric neurons subsequently decreased in both WT and KO but at 12 months were significantly more numerous in WT. We tested the hypothesis that stimulation of the 5-HT4 receptor promotes enteric neuron survival and/or neurogenesis. In vitro, 5-HT4 agonists increased enteric neuronal development/survival, decreased apoptosis, and activated CREB. In vivo, in WT but not KO mice, 5-HT4 agonists induced bromodeoxyuridine (BrdU) incorporation into cells that expressed markers of neurons (HuC/D, doublecortin), neural precursors (Sox10, nestin, Phox2b), or stem cells (Musashi-1). This is the first demonstration of adult enteric neurogenesis; our results suggest that 5-HT4 receptors are required postnatally for ENS growth and maintenance. PMID:19657021

  17. Melatonin synergizes with citalopram to induce antidepressant-like behavior and to promote hippocampal neurogenesis in adult mice.

    PubMed

    Ramírez-Rodríguez, Gerardo; Vega-Rivera, Nelly Maritza; Oikawa-Sala, Julián; Gómez-Sánchez, Ariadna; Ortiz-López, Leonardo; Estrada-Camarena, Erika

    2014-05-01

    Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here, we found decreased immobility behavior in mice treated with melatonin (<14-33%) and citalopram (<17-30%). Additionally, the MLTCITAL combination also decreased immobility (<22-35%) in comparison with control mice, reflecting an antidepressant-like effect after 14 days of treatment. Moreover, MLTCITAL decreased plasma corticosterone levels (≤13%) and increased cell proliferation (>29%), survival (>39%), and the absolute number of -associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant-like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.

  18. 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.

  19. 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.

  20. 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

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

    PubMed

    Hsiao, Hung-Bo; Chou, Ai-Hsiang; Lin, Su-I; Lien, Shu-Pei; Liu, Chia-Chyi; Chong, Pele; Chen, Chih-Yeh; Tao, Mi-Hua; Liu, Shih-Jen

    2014-01-01

    Enterovirus71 (EV71) is now recognized as an emerging neurotropic virus in Asia and one major causative agent of hand-foot-mouth diseases (HFMD). However potential animal models for vaccine development are limited to young mice. In this study, we used an adeno-associated virus (AAV) vector to introduce the human EV71 receptors P-selectin glycoprotein ligand-1 (hPSGL1) or a scavenger receptor class-B member-2 (hSCARB2) into adult ICR mice to change their susceptibility to EV71 infection. Mice were administered AAV-hSCARB2 or AAV-hPSGL1 through intravenous and oral routes. After three weeks, expression of human SCARB2 and PSGL1 was detected in various organs. After infection with EV71, we found that the EV71 viral load in AAV-hSCARB2- or AAV-hPSGL1-transduced mice was higher than that of the control mice in both the brain and intestines. The presence of EV71 viral particles in tissues was confirmed using immunohistochemistry analysis. Moreover, inflammatory cytokines were induced in the brain and intestines of AAV-hSCARB2- or AAV-hPSGL1-transduced mice after EV71 infection but not in wild-type mice. However, neurological disease was not observed in these animals. Taken together, we successfully infected adult mice with live EV71 and induced local inflammation using an AAV delivery system.

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

    PubMed Central

    Chabout, Jonathan; Sarkar, Abhra; Patel, Sheel R.; Radden, Taylor; Dunson, David B.; Fisher, Simon E.; Jarvis, Erich D.

    2016-01-01

    Development of proficient spoken language skills is disrupted by mutations of the FOXP2 transcription factor. A heterozygous missense mutation in the KE family causes speech apraxia, involving difficulty producing words with complex learned sequences of syllables. Manipulations in songbirds have helped to elucidate the role of this gene in vocal learning, but findings in non-human mammals have been limited or inconclusive. Here, we performed a systematic study of ultrasonic vocalizations (USVs) of adult male mice carrying the KE family mutation. Using novel statistical tools, we found that Foxp2 heterozygous mice did not have detectable changes in USV syllable acoustic structure, but produced shorter sequences and did not shift to more complex syntax in social contexts where wildtype animals did. Heterozygous mice also displayed a shift in the position of their rudimentary laryngeal motor cortex (LMC) layer-5 neurons. Our findings indicate that although mouse USVs are mostly innate, the underlying contributions of FoxP2 to sequencing of vocalizations are conserved with humans. PMID:27812326

  3. 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.

  4. 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

  5. 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.

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

    PubMed

    Tamura, M; Hori, S

    2011-11-01

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

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

    PubMed Central

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

    2016-01-01

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

  8. 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.

  9. Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1G93A Mice and Nonhuman Primates

    PubMed Central

    Borel, Florie; Gernoux, Gwladys; Cardozo, Brynn; Metterville, Jake P.; Toro Cabreja, Gabriela C.; Song, Lina; Su, Qin; Gao, Guang Ping; Elmallah, Mai K.; Brown, Robert H.; Mueller, Christian

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease; survival in ALS is typically 3–5 years. No treatment extends patient survival by more than three months. Approximately 20% of familial ALS and 1–3% of sporadic ALS patients carry a mutation in the gene encoding superoxide dismutase 1 (SOD1). In a transgenic ALS mouse model expressing the mutant SOD1G93A protein, silencing the SOD1 gene prolongs survival. One study reports a therapeutic effect of silencing the SOD1 gene in systemically treated adult ALS mice; this was achieved with a short hairpin RNA, a silencing molecule that has raised multiple safety concerns, and recombinant adeno-associated virus (rAAV) 9. We report here a silencing method based on an artificial microRNA termed miR-SOD1 systemically delivered using adeno-associated virus rAAVrh10, a serotype with a demonstrated safety profile in CNS clinical trials. Silencing of SOD1 in adult SOD1G93A transgenic mice with this construct profoundly delayed both disease onset and death in the SOD1G93A mice, and significantly preserved muscle strength and motor and respiratory functions. We also document that intrathecal delivery of the same rAAVrh10-miR-SOD1 in nonhuman primates significantly and safely silences SOD1 in lower motor neurons. This study supports the view that rAAVrh10-miR-SOD1 merits further development for the treatment of SOD1-linked ALS in humans. PMID:26710998

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

    NASA Astrophysics Data System (ADS)

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

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

  11. Adult-onset deficiency of acyl CoA:monoacylglycerol acyltransferase 2 protects mice from diet-induced obesity and glucose intolerance[S

    PubMed Central

    Banh, Taylor; Nelson, David W.; Gao, Yu; Huang, Ting-Ni; Yen, Mei-I; Yen, Chi-Liang E.

    2015-01-01

    Acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 catalyzes triacylglycerol (TAG) synthesis, required in intestinal fat absorption. We previously demonstrated that mice without a functional MGAT2-coding gene (Mogat2−/−) exhibit increased energy expenditure and resistance to obesity induced by excess calories. One critical question raised is whether lacking MGAT2 during early development is required for the metabolic phenotypes in adult mice. In this study, we found that Mogat2−/− pups grew slower than wild-type littermates during the suckling period. To determine whether inactivating MGAT2 in adult mice is sufficient to confer resistance to diet-induced obesity, we generated mice with an inducible Mogat2-inactivating mutation. Mice with adult-onset MGAT2 deficiency (Mogat2AKO) exhibited a transient decrease in food intake like Mogat2−/− mice when fed a high-fat diet and a moderate increase in energy expenditure after acclimatization. They gained less weight than littermate controls, but the difference was smaller than that between wild-type and Mogat2−/− mice. The moderate reduction in weight gain was associated with reduced hepatic TAG and improved glucose tolerance. Similar protective effects were also observed in mice that had gained weight on a high-fat diet before inactivating MGAT2. These findings suggest that adult-onset MGAT2 deficiency mitigates metabolic disorders induced by high-fat feeding and that MGAT2 modulates early postnatal nutrition and may program metabolism later in life. PMID:25535286

  12. 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

  13. 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

  14. Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young-adult Ts65Dn and disomic mice.

    PubMed

    Kelley, Christy M; Powers, Brian E; Velazquez, Ramon; Ash, Jessica A; Ginsberg, Stephen D; Strupp, Barbara J; Mufson, Elliott J

    2014-04-15

    Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer's disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. Although DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age-related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3-7.5 months of age. Ts65Dn dams were maintained on a choline-supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; post weaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, and brains were sectioned and immunolabeled for choline acetyltransferase (ChAT) or p75-neurotrophin receptor (p75(NTR) ). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn-unsupplemented mice displayed region- and immunolabel-dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal-diet choline supplementation attenuates some of the genotype-dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21.

  15. 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.

  16. Neural precursors (NPCs) from adult L967Q mice display early commitment to "in vitro" neuronal differentiation and hyperexcitability.

    PubMed

    DiFebo, Francesca; Curti, Daniela; Botti, Francesca; Biella, Gerardo; Bigini, Paolo; Mennini, Tiziana; Toselli, Mauro

    2012-08-01

    The pathogenic factors leading to selective degeneration of motoneurons in ALS are not yet understood. However, altered functionality of voltage-dependent Na(+) channels may play a role since cortical hyperexcitability was described in ALS patients and riluzole, the only drug approved to treat ALS, seems to decrease glutamate release via blockade or inactivation of voltage-dependent Na(+) channels. The wobbler mouse, a murine model of motoneuron degeneration, shares some of the clinical features of human ALS. At early stages of the wobbler disease, increased cortical hyperexcitability was observed. Moreover, riluzole reduced motoneuron loss and muscular atrophy in treated wobbler mice. Here, we focussed our attention on specific electrophysiological properties, like voltage-activated Na(+) currents and underlying regenerative electrical activity, as read-outs of the neuronal maturation process of neural stem/progenitor cells (NPCs) isolated from the subventricular zone (SVZ) of adult early symptomatic wobbler mice. In self-renewal conditions, the rate of wobbler NPC proliferation "in vitro" was 30% lower than that of healthy mice. Conversely, the number of wobbler NPCs displaying early neuronal commitment and action potentials was significantly higher. Upon switching from proliferative to differentiative conditions, NPCs underwent significant changes in the key properties of voltage gated Na(+) currents. The most notable finding, in cells with neuronal morphology, was an increase in Na(+) current density that strictly correlated with an increased probability to generate action potentials. This feature was remarkably more pronounced in neurons differentiated from wobbler NPCs that upon sustained stimulation, displayed short trains of pathological facilitation. In agreement with this result, an increase in the number of c-Fos positive cells, a surrogate marker of neuronal network activation, was observed in the mesial cortex of the wobbler mice "in situ". Thus these

  17. 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

  18. 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

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

    PubMed

    Ismail, Nafissa; Blaustein, Jeffrey D

    2013-07-01

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

  20. The subventricular zone continues to generate corpus callosum and rostral migratory stream astroglia in normal adult mice.

    PubMed

    Sohn, Jiho; Orosco, Lori; Guo, Fuzheng; Chung, Seung-Hyuk; Bannerman, Peter; Mills Ko, Emily; Zarbalis, Kostas; Deng, Wenbin; Pleasure, David

    2015-03-04

    Astrocytes are the most abundant cells in the CNS, and have many essential functions, including maintenance of blood-brain barrier integrity, and CNS water, ion, and glutamate homeostasis. Mammalian astrogliogenesis has generally been considered to be completed soon after birth, and to be reactivated in later life only under pathological circumstances. Here, by using genetic fate-mapping, we demonstrate that new corpus callosum astrocytes are continuously generated from nestin(+) subventricular zone (SVZ) neural progenitor cells (NPCs) in normal adult mice. These nestin fate-mapped corpus callosum astrocytes are uniformly postmitotic, express glutamate receptors, and form aquaporin-4(+) perivascular endfeet. The entry of new astrocytes from the SVZ into the corpus callosum appears to be balanced by astroglial apoptosis, because overall numbers of corpus callosum astrocytes remain constant during normal adulthood. Nestin fate-mapped astrocytes also flow anteriorly from the SVZ in association with the rostral migratory stream, but do not penetrate into the deeper layers of the olfactory bulb. Production of new astrocytes from nestin(+) NPCs is absent in the normal adult cortex, striatum, and spinal cord. Our study is the first to demonstrate ongoing SVZ astrogliogenesis in the normal adult mammalian forebrain.

  1. 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.

  2. Glial glycine transporter 1 function is essential for early postnatal survival but dispensable in adult mice.

    PubMed

    Eulenburg, Volker; Retiounskaia, Marina; Papadopoulos, Theofilos; Gomeza, Jesús; Betz, Heinrich

    2010-07-01

    The glycine transporter 1 (GlyT1) is expressed in astrocytes and selected neurons of the mammalian CNS. In newborn mice, GlyT1 is crucial for efficient termination of glycine-mediated inhibitory neurotransmission. Furthermore, GlyT1 has been implicated in the regulation of excitatory N-methyl-D-asparate (NMDA) receptors. To evaluate whether glial and neuronal GlyT1 have distinct roles at inhibitory synapses, we inactivated the GlyT1 gene cell type-specifically using mice carrying floxed GlyT1 alleles GlyT1((+)/+)). GlyT1((+)/(+)) mice expressing Cre recombinase in glial cells developed severe neuromotor deficits during the first postnatal week, which mimicked the phenotype of conventional GlyT1 knock-out mice and are consistent with glycinergic over-inhibition. In contrast, Cre-mediated inactivation of the GlyT1 gene in neuronal cells did not result in detectable motor impairment. Notably, some animals deficient for glial GlyT1 survived the first postnatal week and did not develop neuromotor deficits throughout adulthood, although GlyT1 expression was efficiently reduced. Thus, glial GlyT1 is critical for the regulation of glycine levels at inhibitory synapses only during early postnatal life.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. LED champing: statistically blessed?

    PubMed

    Wang, Zhuo

    2015-06-10

    LED champing (smart mixing of individual LEDs to match the desired color and lumens) and color mixing strategies have been widely used to maintain the color consistency of light engines. Light engines with champed LEDs can easily achieve the color consistency of a couple MacAdam steps with widely distributed LEDs to begin with. From a statistical point of view, the distributions for the color coordinates and the flux after champing are studied. The related statistical parameters are derived, which facilitate process improvements such as Six Sigma and are instrumental to statistical quality control for mass productions.

  8. Inducible ablation of dopamine D2 receptors in adult mice impairs locomotion, motor skill learning and leads to severe parkinsonism.

    PubMed

    Bello, E P; Casas-Cordero, R; Galiñanes, G L; Casey, E; Belluscio, M A; Rodríguez, V; Noaín, D; Murer, M G; Rubinstein, M

    2017-04-01

    Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2(-/-) mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson's disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette's syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.

  9. Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice

    PubMed Central

    Ponti, Giovanna; Obernier, Kirsten; Guinto, Cristina; Jose, Lingu; Bonfanti, Luca; Alvarez-Buylla, Arturo

    2013-01-01

    Proliferating neural stem cells and intermediate progenitors persist in the ventricular-subventricular zone (V-SVZ) of the adult mammalian brain. This extensive germinal layer in the walls of the lateral ventricles is the site of birth of different types of interneurons destined for the olfactory bulb. The cell cycle dynamics of stem cells (B1 cells), intermediate progenitors (C cells), and neuroblasts (A cells) in the V-SVZ and the number of times these cells divide remain unknown. Using whole mounts of the walls of the lateral ventricles of adult mice and three cell cycle analysis methods using thymidine analogs, we determined the proliferation dynamics of B1, C, and A cells in vivo. Achaete-scute complex homolog (Ascl)1+ C cells were heterogeneous with a cell cycle length (TC) of 18–25 h and a long S phase length (TS) of 14–17 h. After C cells, Doublecortin+ A cells were the second-most common dividing cell type in the V-SVZ and had a TC of 18 h and TS of 9 h. Human glial fibrillary acidic protein (hGFAP)::GFP+ B1 cells had a surprisingly short Tc of 17–18 h and a TS of 4 h. Progenitor population analysis suggests that following the initial division of B1 cells, C cells divide three times and A cells once, possibly twice. These data provide essential information on the dynamics of adult progenitor cell proliferation in the V-SVZ and how large numbers of new neurons continue to be produced in the adult mammalian brain. PMID:23431204

  10. Diodes stabilize LED output

    NASA Technical Reports Server (NTRS)

    Deters, R. A.

    1977-01-01

    Small-signal diodes are placed in series with light-emitting diodes (LED's) to stabilize LED output against temperature fluctuations. Simple inexpensive method compensates for thermal fluctuations over a broad temperature range. Requiring few components, technique is particularly useful where circuit-board space is limited.

  11. Repopulation of adult and neonatal mice with human hepatocytes: a chimeric animal model.

    PubMed

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

    2007-12-18

    We report the successful transplantation of human hepatocytes in immunodeficient, fumarylacetoacetate hydrolase-deficient (fah(-/-)) mice. Engraftment occurs over the entire liver acinus upon transplantation. A few weeks after transplantation, increasing concentrations of human proteins (e.g., human albumin and human C3a) can be measured in the blood of the recipient mouse. No fusion between mouse and human hepatocytes can be detected. Three months after transplantation, up to 20% of the mouse liver is repopulated by human hepatocytes, and sustained expression of lentiviral vector transduced gene can be observed. We further report the development of a hepatocyte transplantation method involving a transcutaneous, intrahepatic injection in neonatal mice. Human hepatocytes engraft over the entire injected lobe with an expansion pattern similar to those observed with intrasplenic transplantation.

  12. Novel concept of motor functional analysis for spinal cord injury in adult mice.

    PubMed

    Shinozaki, Munehisa; Takahashi, Yuichiro; Mukaino, Masahiko; Saito, Nobuhito; Toyama, Yoshiaki; Okano, Hideyuki; Nakamura, Masaya

    2011-01-01

    In basic research on spinal cord injury (SCI), behavioral evaluation of the SCI animal model is critical. However, it is difficult to accurately evaluate function in the mouse SCI model due to the small size of mice. Although the open-field scoring scale is an outstanding appraisal method, supplementary objective tests are required. Using a compact SCANET system, in which a mouse carries out free movement for 5 min, we developed a novel method to detect locomotor ability. A SCANET system samples the horizontal coordinates of a mouse every 0.1 s, and both the speed and acceleration of its motion are calculated at each moment. It was found that the maximum speed and acceleration of motion over 5 min varied by injury severity. Moreover, these values were significantly correlated with open-field scores. The maximum speed and acceleration of SCI model mice using a SCANET system are objective, easy to obtain, and reproducible for evaluating locomotive function.

  13. Beta Cell Regeneration in Adult Mice: Controversy Over the Involvement of Stem Cells.

    PubMed

    Yu, Ke; Fischbach, Shane; Xiao, Xiangwei

    2016-01-01

    Islet transplantation is an effective therapy for severe diabetes. Nevertheless, the short supply of donor pancreases constitutes a formidable obstacle to its extensive clinical application. This shortage heightens the need for alternative sources of insulin-producing beta cells. Since mature beta cells have a very slow proliferation rate, which further declines with age, great efforts have been made to identify beta cell progenitors in the adult pancreas. However, the question whether facultative beta cell progenitors indeed exist in the adult pancreas remains largely unresolved. In the current review, we discuss the problems in past studies and review the milestone studies and recent publications.

  14. Beta Cell Regeneration in Adult Mice: Controversy Over the Involvement of Stem Cells

    PubMed Central

    Yu, Ke; Fischbach, Shane; Xiao, Xiangwei

    2016-01-01

    Islet transplantation is an effective therapy for severe diabetes. Nevertheless, the short supply of donor pancreases constitutes a formidable obstacle to its extensive clinical application. This shortage heightens the need for alternative sources of insulin-producing beta cells. Since mature beta cells have a very slow proliferation rate, which further declines with age, great efforts have been made to identify beta cell progenitors in the adult pancreas. However, the question whether facultative beta cell progenitors indeed exist in the adult pancreas remains largely unresolved. In the current review, we discuss the problems in past studies and review the milestone studies and recent publications. PMID:25429702

  15. 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

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  18. Gestational immune activation and Tsc2 haploinsufficiency cooperate to disrupt fetal survival and may perturb social behavior in adult mice.

    PubMed

    Ehninger, D; Sano, Y; de Vries, P J; Dies, K; Franz, D; Geschwind, D H; Kaur, M; Lee, Y-S; Li, W; Lowe, J K; Nakagawa, J A; Sahin, M; Smith, K; Whittemore, V; Silva, A J

    2012-01-01

    Approximately 40-50% of individuals affected by tuberous sclerosis (TSC) develop autism spectrum disorders (ASDs). One possible explanation for this partial penetrance is an interaction between TSC gene mutations and other risk factors such as gestational immune activation. In this study, we report the interactive effects of these two ASD risk factors in a mouse model of TSC. Combined, but not single, exposure had adverse effects on intrauterine survival. Additionally, provisional results suggest that these factors synergize to disrupt social approach behavior in adult mice. Moreover, studies in human populations are consistent with an interaction between high seasonal flu activity in late gestation and TSC mutations in ASD. Taken together, our studies raise the possibility of a gene × environment interaction between heterozygous TSC gene mutations and gestational immune activation in the pathogenesis of TSC-related ASD.

  19. 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

  20. 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

  1. 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.

  2. Relationship between brain accumulation of manganese and aberration of hippocampal adult neurogenesis after oral exposure to manganese chloride in mice.

    PubMed

    Kikuchihara, Yoh; Abe, Hajime; Tanaka, Takeshi; Kato, Mizuho; Wang, Liyun; Ikarashi, Yoshiaki; Yoshida, Toshinori; Shibutani, Makoto

    2015-05-04

    We previously found persistent aberration of hippocampal adult neurogenesis, along with brain manganese (Mn) accumulation, in mouse offspring after developmental exposure to 800-ppm dietary Mn. Reduction of parvalbumin (Pvalb)(+) γ-aminobutyric acid (GABA)-ergic interneurons in the hilus of the dentate gyrus along with promoter region hypermethylation are thought to be responsible for this aberrant neurogenesis. The present study was conducted to examine the relationship between the induction of aberrant neurogenesis and brain Mn accumulation after oral Mn exposure as well as the responsible mechanism in young adult animals. We used two groups of mice with 28- or 56-day exposure periods to oral MnCl2·xH2O at 800 ppm as Mn, a dose sufficient to lead to aberrant neurogenesis after developmental exposure. A third group of mice received intravenous injections of Mn at 5-mg/kg body weight once weekly for 28 days. The 28-day oral Mn exposure did not cause aberrations in neurogenesis. In contrast, 56-day oral exposure caused aberrations in neurogenesis suggestive of reductions in type 2b and type 3 progenitor cells and immature granule cells in the dentate subgranular zone. Brain Mn accumulation in 56-day exposed cases, as well as in directly Mn-injected cases occurred in parallel with reduction of Pvalb(+) GABAergic interneurons in the dentate hilus, suggesting that this may be responsible for aberrant neurogenesis. For reduction of Pvalb(+) interneurons, suppression of brain-derived neurotrophic factor-mediated signaling of mature granule cells may occur via suppression of c-Fos-mediated neuronal plasticity due to direct Mn-toxicity rather than promoter region hypermethylation of Pvalb.

  3. Spatiotemporal expression patterns of Pax6 in the brain of embryonic, newborn, and adult mice.

    PubMed

    Duan, Deyi; Fu, Yuhong; Paxinos, George; Watson, Charles

    2013-03-01

    The transcription factor Pax6 has been reported to specify neural progenitor cell fates during development and maintain neuronal commitments in the adult. The spatiotemporal patterns of Pax6 expression were examined in sagittal and horizontal sections of the embryonic, postnatal, and adult brains using immunohistochemistry and double immunolabeling. The proportion of Pax6-immunopositive cells in various parts of the adult brain was estimated using the isotropic fractionator methodology. It was shown that at embryonic day 11 (E11) Pax6 was robustly expressed in the proliferative neuroepithelia of the ventricular zone in the forebrain and hindbrain, and in the floor and the mesencephalic reticular formation (mRt) in the midbrain. At E12, its expression emerged in the nucleus of the lateral lemniscus in the rhombencephalon and disappeared from the floor of the midbrain. As neurodevelopment proceeds, the expression pattern of Pax6 changes from the mitotic germinal zone in the ventricular zone to become extensively distributed in cell groups in the forebrain and hindbrain, and the expression persisted in the mRt. The majority of Pax6-positive cell groups were maintained until adult life, but the intensity of Pax6 expression became much weaker. Pax6 expression was maintained in the mitotic subventricular zone in the adult brain, but not in the germinal region dentate gyrus in the adult hippocampus. There was no obvious colocalization of Pax6 and NeuN during embryonic development, suggesting Pax6 is found primarily in developing progenitor cells. In the adult brain, however, Pax6 maintains neuronal features of some subtypes of neurons, as indicated by 97.1% of Pax6-positive cells co-expressing NeuN in the cerebellum, 40.7% in the olfactory bulb, 38.3% in the cerebrum, and 73.9% in the remaining brain except the hippocampus. Differentiated tyrosine hydroxylase (TH) neurons were observed in the floor of the E11 midbrain where Pax6 was also expressed, but no obvious

  4. Taurine drinking attenuates the burden of intestinal adult worms and muscle larvae in mice with Trichinella spiralis infection.

    PubMed

    Yu, Yan-Rong; Liu, Xi-Cheng; Zhang, Jin-Sheng; Ji, Chao-Yue; Qi, Yong-Fen

    2013-10-01

    The parasitic nematode Trichinella spiralis can cause trichinellosis, which leads to pathological processes in the intestine and muscle. The intestinal invasion determines the development, subsequent course, and consequences of the disease. Gastrointestinal nematode infection, including with T. spiralis, is accompanied by a rapid and reversible expansion of mucosal mast cell and goblet cell in the intestinal epithelium, which play important roles in the host immune response to parasite and worm expulsion from the intestine. Taurine and its derivatives have anti-infection and anti-inflammatory properties. We investigated whether taurine supplementation in mice could influence the development and pathological processes of infection with T. spiralis. Supplementing 1% taurine in drinking water in mice infected with T. spiralis could alleviate the burden of intestinal adult worms on days 7 and 10 postinfection (all p < 0.01) and the formation of infective muscle larvae in striated muscle during T. spiralis infection (p < 0.01). As compared with T. spiralis infection alone, taurine treatment increased the number of goblet cells on days 7, 10, and 15 (p < 0.01 and p < 0.05) and alleviated intestinal mucosal mast cell hyperplasia on days 10 and 15 (all p < 0.01). So taurine supplementation in drinking water increased infection-induced intestinal goblet cell hyperplasia and ameliorated mucosal mastocytosis. Thus, taurine can ameliorate the pathological processes of trichinellosis and may be of great value for the treatment and prevention of infection with T. spiralis and other gastrointestinal nematodes.

  5. 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.

  6. 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

  7. 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.

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

    PubMed

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

    2014-05-01

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

  9. Beneficial effect of a CNTF tetrapeptide on adult hippocampal neurogenesis, neuronal plasticity, and spatial memory in mice.

    PubMed

    Blanchard, Julie; Chohan, Muhammad Omar; Li, Bin; Liu, Fei; Iqbal, Khalid; Grundke-Iqbal, Inge

    2010-01-01

    A therapeutic strategy against cognitive disorders like Alzheimer's disease is to take advantage of the regenerative ability of the brain and the properties of neurotrophic factors to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity. Although the ciliary neurotrophic factor (CNTF) has some of the required neuroprotective characteristics, its clinical use, due to its side effects, i.e., anorexia, skeletal muscle loss, hyperalgesia, cramps, and muscle pain, has not materialized. In the present study, we report that Peptide 6c (GDDL) that corresponds to CNTF amino acid residues 147-150, enhances the dentate gyrus neurogenesis and neuronal plasticity, and improves cognition without weight loss or any other apparent side effects in mice. Normal adult C57Bl6 mice received subcutaneous implants of extended release depot pellets containing vehicle or Peptide 6c for 30 days of continuous dosing. Dentate gyrus neurogenesis was assessed by stereological analysis of cells expressing neuronal markers, doublecortin and NeuN, and BrdU uptake. We found that Peptide 6c significantly increased early neuronal commitment, differentiation, and survival of newborn progenitor cells. These newborn neurons were functionally integrated into the hippocampal network, since basal expression of c-fos was enhanced and neuronal plasticity was increased, as reflected by higher expression of MAP2a,b and synaptophysin. Consequently, Peptide 6c treatment improved encoding of hippocampal-dependent information in a spatial reference memory task in mice. Overall, these findings demonstrated the therapeutic potential of Peptide 6c for regeneration of the brain and improvement of cognition.

  10. Behavioral and monoamine perturbations in adult male mice with chronic inflammation induced by repeated peripheral lipopolysaccharide administration.

    PubMed

    Krishna, Saritha; Dodd, Celia A; Filipov, Nikolay M

    2016-04-01

    Considering the limited information on the ability of chronic peripheral inflammation to induce behavioral alterations, including on their persistence after inflammatory stimuli termination and on associated neurochemical perturbations, this study assessed the effects of chronic (0.25 mg/kg; i.p.; twice weekly) lipopolysaccharide (LPS) treatment on selected behavioral, neurochemical and molecular measures at different time points in adult male C57BL/6 mice. Behaviorally, LPS-treated mice were hypoactive after 6 weeks, whereas significant hyperactivity was observed after 12 weeks of LPS and 11 weeks after 13 week LPS treatment termination. Similar biphasic responses, i.e., early decrease followed by a delayed increase were observed in the open field test center time, suggestive of, respectively, increased and decreased anxiety. In a forced swim test, mice exhibited increased immobility (depressive behavior) at all times they were tested. Chronic LPS also produced persistent increase in splenic serotonin (5-HT) and time-dependent, brain region-specific alterations in striatal and prefrontocortical dopamine and 5-HT homeostasis. Microglia, but not astrocytes, were activated by LPS early and late, but their activation did not persist after LPS treatment termination. Above findings demonstrate that chronic peripheral inflammation initially causes hypoactivity and increased anxiety, followed by persistent hyperactivity and decreased anxiety. Notably, chronic LPS-induced depressive behavior appears early, persists long after LPS termination, and is associated with increased splenic 5-HT. Collectively, our data highlight the need for a greater focus on the peripheral/central monoamine alterations and lasting behavioral deficits induced by chronic peripheral inflammation as there are many pathological conditions where inflammation of a chronic nature is a hallmark feature.

  11. Behavioral and monoamine perturbations in adult male mice with chronic inflammation induced by repeated peripheral lipopolysaccharide administration

    PubMed Central

    Krishna, Saritha; Dodd, Celia A.; Filipov, Nikolay M.

    2016-01-01

    Considering the limited information on the ability of chronic peripheral inflammation to induce behavioral alterations, including on their persistence after inflammatory stimuli termination and on associated neurochemical perturbations, this study assessed the effects of chronic (0.25 mg/kg; i.p.; twice weekly) lipopolysaccharide (LPS) treatment on selected behavioral, neurochemical and molecular measures at different time points in adult male C57BL/6 mice. Behaviorally, LPS-treated mice were hypoactive after 6 weeks, whereas significant hyperactivity was observed after 12 weeks of LPS and 11 weeks after 13 week LPS treatment termination. Similar biphasic responses, i.e., early decrease followed by a delayed increase were observed in the open field test center time, suggestive of, respectively, increased and decreased anxiety. In a forced swim test, mice exhibited increased immobility (depressive behavior) at all times they were tested. Chronic LPS also produced persistent increase in splenic serotonin (5-HT) and time-dependent, brain region-specific alterations in striatal and prefrontocortical dopamine and 5-HT homeostasis. Microglia, but not astrocytes, were activated by LPS early and late, but their activation did not persist after LPS treatment termination. Above findings demonstrate that chronic peripheral inflammation initially causes hypoactivity and increased anxiety, followed by persistent hyperactivity and decreased anxiety. Notably, chronic LPS-induced depressive behavior appears early, persists long after LPS termination, and is associated with increased splenic 5-HT. Collectively, our data highlight the need for a greater focus on the peripheral/central monoamine alterations and lasting behavioral deficits induced by chronic peripheral inflammation as there are many pathological conditions where inflammation of a chronic nature is a hallmark feature. PMID:26802725

  12. Large area LED package

    NASA Astrophysics Data System (ADS)

    Goullon, L.; Jordan, R.; Braun, T.; Bauer, J.; Becker, F.; Hutter, M.; Schneider-Ramelow, M.; Lang, K.-D.

    2015-03-01

    Solid state lighting using LED-dies is a rapidly growing market. LED-dies with the needed increasing luminous flux per chip area produce a lot of heat. Therefore an appropriate thermal management is required for general lighting with LEDdies. One way to avoid overheating and shorter lifetime is the use of many small LED-dies on a large area heat sink (down to 70 μm edge length), so that heat can spread into a large area while at the same time light also appears on a larger area. The handling with such small LED-dies is very difficult because they are too small to be picked with common equipment. Therefore a new concept called collective transfer bonding using a temporary carrier chip was developed. A further benefit of this new technology is the high precision assembly as well as the plane parallel assembly of the LED-dies which is necessary for wire bonding. It has been shown that hundred functional LED-dies were transferred and soldered at the same time. After the assembly a cost effective established PCB-technology was applied to produce a large-area light source consisting of many small LED-dies and electrically connected on a PCB-substrate. The top contacts of the LED-dies were realized by laminating an adhesive copper sheet followed by LDI structuring as known from PCB-via-technology. This assembly can be completed by adding converting and light forming optical elements. In summary two technologies based on standard SMD and PCB technology have been developed for panel level LED packaging up to 610x 457 mm2 area size.

  13. 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

  14. A pubertal immune challenge alters the antidepressant-like effects of chronic estradiol treatment in inbred and outbred adult female mice

    PubMed Central

    Ismail, Nafissa; Kumlin, Ashley M.; Blaustein, Jeffrey D.

    2012-01-01

    Puberty is a period characterized by brain reorganization that contributes to the development of neural and behavioral responses to gonadal steroids. A single injection of the bacterial endotoxin, lipopolysaccharide (LPS), during the pubertal period decreases sexual receptivity in response to ovarian hormones in adulthood. Because chronic estradiol treatment alleviates depression-like symptoms in ovariectomized adult mice, we investigated the effect of pubertal LPS treatment on estradiol’s antidepressant effects. We hypothesized that pubertal LPS treatment would decrease the antidepressant-like effect of estradiol in adult ovariectomized female mice, as it decreases other behavioral responses to ovarian hormones. As expected, chronic estradiol treatment decreased depression-like behavior, as measured by the duration of immobility, in saline-treated mice from two different strains, as well as in mice treated with LPS in adulthood. In contrast, in mice treated pubertally with LPS, estradiol strikingly increased the duration of immobility. No difference in body weight and in locomotion was found among the groups, suggesting that the differences in depression-like behavior were not due to differences in body weight or locomotor activity between LPS-treated and control mice. These results suggest that exposure to an immune challenge during the pubertal period alters the responsiveness of depression-like behavior to estradiol. PMID:23036617

  15. 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.

  16. 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.

  17. Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice.

    PubMed

    Iggena, Deetje; Winter, York; Steiner, Barbara

    2017-05-01

    Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder "jet lag" disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag-induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8 mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate "jet lag" by shortening the dark period every third day by 6 hours for 3 weeks. We found that "jet lag" simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag-induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to.

  18. LEDs Are Diodes.

    ERIC Educational Resources Information Center

    Lisensky, George C.; Condren, S. Michael; Widstrand, Cynthia G.; Breitzer, Jonathan; Ellis, Arthur B.

    2001-01-01

    Describes an activity comparing incandescent bulbs and LEDs powered by dc and ac voltage sources to illustrate properties of matter and the interactions of energy and matter. Includes both instructor information and student activity sheet. (Author/YDS)

  19. Energy Efficiency of LEDs

    SciTech Connect

    2013-03-01

    Solid-state lighting program technology fact sheet on energy efficiency of LEDs, characterizing the current state of the market and discussing package efficacy, luminaire efficacy, and application efficacy.

  20. White LED performance

    NASA Astrophysics Data System (ADS)

    Gu, Yimin; Narendran, Nadarajah; Freyssinier, Jean Paul

    2004-10-01

    Two life tests were conducted to compare the effects of drive current and ambient temperature on the degradation rate of 5 mm and high-flux white LEDs. Tests of 5 mm white LED arrays showed that junction temperature increases produced by drive current had a greater effect on the rate of light output degradation than junction temperature increases from ambient heat. A preliminary test of high-flux white LEDs showed the opposite effect, with junction temperature increases from ambient heat leading to a faster depreciation. However, a second life test is necessary to verify this finding. The dissimilarity in temperature effect among 5 mm and high-flux LEDs is likely caused by packaging differences between the two device types.

  1. Histone acetyltransferase activity of MOF is required for adult but not early fetal hematopoiesis in mice.

    PubMed

    Valerio, Daria G; Xu, Haiming; Eisold, Meghan E; Woolthuis, Carolien M; Pandita, Tej K; Armstrong, Scott A

    2017-01-05

    K(lysine) acetyltransferase 8 (KAT8, also known as MOF) mediates the acetylation of histone H4 at lysine 16 (H4K16ac) and is crucial for murine embryogenesis. Lysine acetyltransferases have been shown to regulate various stages of normal hematopoiesis. However, the function of MOF in hematopoietic stem cell (HSC) development has not yet been elucidated. We set out to study the role of MOF in general hematopoiesis by using a Vav1-cre-induced conditional murine Mof knockout system and found that MOF is critical for hematopoietic cell maintenance and HSC engraftment capacity in adult hematopoiesis. Rescue experiments with a MOF histone acetyltransferase domain mutant illustrated the requirement for MOF acetyltransferase activity in the clonogenic capacity of HSCs and progenitors. In stark contrast, fetal steady-state hematopoiesis at embryonic day (E) 14.5 was not affected by homozygous Mof deletion despite dramatic loss of global H4K16ac. Hematopoietic defects start manifesting in late gestation at E17.5. The discovery that MOF and its H4K16ac activity are required for adult but not early and midgestational hematopoiesis supports the notion that multiple chromatin regulators may be crucial for hematopoiesis at varying stages of development. MOF is therefore a developmental-stage-specific chromatin regulator found to be essential for adult but not early fetal hematopoiesis.

  2. 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.

  3. 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.

  4. 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

  5. Xylitol affects the intestinal microbiota and metabolism of daidzein in adult male mice.

    PubMed

    Tamura, Motoi; Hoshi, Chigusa; Hori, Sachiko

    2013-12-10

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

  6. Aniracetam Does Not Alter Cognitive and Affective Behavior in Adult C57BL/6J Mice

    PubMed Central

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

    2014-01-01

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

  7. The protective effect of propylthiouracil against hepatotoxicity induced by chromium in adult mice.

    PubMed

    Ben Hamida, Fatma; Troudi, Afef; Sefi, Madiha; Boudawara, Tahia; Zeghal, Najiba

    2016-02-01

    Environmental and occupational exposure to chromium compounds, especially hexavalent chromium (Cr(VI)), is widely recognized as potentially hepatotoxic in humans and animals. Its toxicity is associated with overproduction of free radicals, which induces oxidative damage. This study focused on the possible protective effect of propylthiouracil (PTU) against potassium dichromate (K2Cr2O7). Female mice were divided into four groups (groups I-IV) with seven animals in each group. Group I served as a control, which received tap water; group II received K2Cr2O7 alone (75 mg kg(-1) body weight (b.w.)) via drinking water; group III received both K2Cr2O7 via drinking water and PTU by intramuscular injection at a dose 2.5 mg/100 g(-1) b.w. twice a week, and group IV received PTU alone twice a week for 30 days. Exposure of mice to Cr promoted oxidative stress with an increase in malondialdehyde, protein carbonyl, and advanced oxidation protein product levels. Nonenzymatic antioxidants such as glutathione, nonprotein thiol, vitamin C levels and enzymatic antioxidant activities such as glutathione peroxidase and superoxide dismutase were decreased, while catalase activity was increased. Biomarkers of liver injury such as aspartate and alanine transaminases, lactate dehydrogenase activities, bilirubin, albumin, and glucose levels were increased, while triglyceride and cholesterol levels decreased. Coadministration of PTU restored the above-mentioned parameters to near-normal values. The histological findings confirmed the biochemical results.

  8. In vivo activation of Wnt signaling pathway enhances cognitive function of adult mice and reverses cognitive deficits in an Alzheimer's disease model.

    PubMed

    Vargas, Jessica Y; Fuenzalida, Marco; Inestrosa, Nibaldo C

    2014-02-05

    The role of the Wnt signaling pathway during synaptic development has been well established. In the adult brain, different components of Wnt signaling are expressed, but little is known about its role in mature synapses. Emerging in vitro studies have implicated Wnt signaling in synaptic plasticity. Furthermore, activation of Wnt signaling has shown to protect against amyloid-β-induced synaptic impairment. The present study provides the first evidence that in vivo activation of Wnt signaling improves episodic memory, increases excitatory synaptic transmission, and enhances long-term potentiation in adult wild-type mice. Moreover, the activation of Wnt signaling also rescues memory loss and improves synaptic dysfunction in APP/PS1-transgenic mice that model the amyloid pathology of Alzheimer's diseases. These findings indicate that Wnt signaling modulates cognitive function in the adult brain and could be a novel promising target for Alzheimer's disease therapy.

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

    PubMed

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

    2009-10-01

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

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

    PubMed Central

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

    2009-01-01

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

  11. Effects of a B-vitamin-deficient diet on exploratory activity, motor coordination, and spatial learning in young adult Balb/c mice.

    PubMed

    Lalonde, R; Barraud, H; Ravey, J; Guéant, J-L; Bronowicki, J-P; Strazielle, C

    2008-01-10

    Elevated homocysteine levels resulting from vitamin B deficiencies have been hypothesized to contribute to functional decline. To investigate the effects of elevated serum homocysteine on neurobehavioral performances, young adult Balb/c mice consumed a vitamin-B-deficient diet or a control diet under free-feeding and pair-fed conditions. The B-deficient diet decreased body weight and food intake but increased water ingestion. Relative to either control group, vitamin-B-deficient mice were more active in the open field and in enclosed arms of the elevated plus-maze. However, vitamin-B-deficient mice were not impaired on sensorimotor coordination and spatial learning tests, swimming to a visible platform even faster than either control group. The main effect of this diet restriction was hyperactivity with no change in anxiety, coordination, and memory. It remains to be determined whether severer deficits are demonstrable in older mice.

  12. The influence of chronic stress on anxiety-like behavior and cognitive function in different human GFAP-ApoE transgenic adult male mice.

    PubMed

    Meng, Fan-Tao; Zhao, Jun; Fang, Hui; Liu, Ya-Jing

    2015-01-01

    The apolipoprotein E (ApoE) ɛ4 allele (ApoE4) is an important genetic risk factor for the pathogenesis of Alzheimer's disease (AD). In addition to genetic factors, environmental factors such as stress may play a critical role in AD pathogenesis. This study was designed to investigate the anxiety-like behavioral and cognitive changes in different human glial fibrillary acidic protein (GFAP)-ApoE transgenic adult male mice under chronic stress conditions. On the open field test, anxiety-like behavior was increased in the non-stressed GFAP-ApoE4 transgenic mice relative to the corresponding GFAP-ApoE3 (ApoE ɛ3 allele) mice. Anxiety-like behavior was increased in the stressed GFAP-ApoE3 mice relative to non-stressed GFAP-ApoE3 mice, but was unexpectedly decreased in the stressed GFAP-ApoE4 mice relative to non-stressed GFAP-ApoE4 mice. On the novel object recognition task, both GFAP-ApoE4 and GFAP-ApoE3 mice exhibited long-term non-spatial memory impairment after chronic stress. Interestingly, short-term non-spatial memory impairment (based on the novel object recognition task) was observed only in the stressed GFAP-ApoE4 male mice relative to non-stressed GFAP-ApoE4 transgenic mice. In addition, short-term spatial memory impairment was observed in the stressed GFAP-ApoE3 transgenic male mice relative to non-stressed GFAP-ApoE3 transgenic male mice; however, short-term spatial memory performance of GFAP-ApoE4 transgenic male mice was not reduced compared to non-stressed control mice based on the Y-maze task. In conclusion, our findings suggested that chronic stress affects anxiety-like behavior and spatial and non-spatial memory in GFAP-ApoE transgenic mice in an ApoE isoform-dependent manner.

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. High frequency mechanical ventilation affects respiratory system mechanics differently in C57BL/6J and BALB/c adult mice.

    PubMed

    Hadden, Hélène

    2013-01-15

    We tested the hypothesis that high frequency ventilation affects respiratory system mechanical functions in C57BL/6J and BALB/c mice. We measured respiratory mechanics by the forced oscillation technique over 1h in anesthetized, intubated, ventilated BALB/c and C57BL/6J male mice. We did not detect any change in airway resistance, Rn, tissue damping, G, tissue elastance, H and hysteresivity, eta in BALB/c mice during 1h of ventilation at 150 or at 450 breaths/min; nor did we find a difference between BALB/c mice ventilated at 150 breaths/min compared with 450 breaths/min. Among C57BL/6J mice, except for H, all parameters remained unchanged over 1h of ventilation in mice ventilated at 150 breaths/min. However, after 10 and 30 min of ventilation at 450 breaths/min, Rn, and respiratory system compliance were lower, and eta was higher, than their starting value. We conclude that high frequency mechanical ventilation affects respiratory system mechanics differently in C57BL/6J and BALB/c adult mice.

  18. A multicentre, pragmatic, parallel group, randomised controlled trial to compare the clinical and cost-effectiveness of three physiotherapy-led exercise interventions for knee osteoarthritis in older adults: the BEEP trial protocol (ISRCTN: 93634563)

    PubMed Central

    2014-01-01

    Background Exercise is consistently recommended for older adults with knee pain related to osteoarthritis. However, the effects from exercise are typically small and short-term, likely linked to insufficient individualisation of the exercise programme and limited attention to supporting exercise adherence over time. The BEEP randomised trial aims to improve patients’ short and long-term outcomes from exercise. It will test the overall effectiveness and cost-effectiveness of two physiotherapy-led exercise interventions (Individually Tailored Exercise and Targeted Exercise Adherence) to improve the individual tailoring of, and adherence to exercise, compared with usual physiotherapy care. Methods/design Based on the learning from a pilot study (ISRCTN 23294263), the BEEP trial is a multi-centre, pragmatic, parallel group, individually randomised controlled trial, with embedded longitudinal qualitative interviews. 500 adults in primary care, aged 45 years and over with knee pain will be randomised to 1 of 3 treatment groups delivered by fully trained physiotherapists in up to 6 NHS services. These are: Usual Physiotherapy Care (control group consisting of up to 4 treatment sessions of advice and exercise), Individually Tailored Exercise (an individualised, supervised and progressed lower-limb exercise programme) or Targeted Exercise Adherence (supporting patients to adhere to exercise and to engage in general physical activity over the longer-term). The primary outcomes are pain and function as measured by the Western Ontario and McMaster Osteoarthritis index. A comprehensive range of secondary outcomes are also included. Outcomes are measured at 3, 6 (primary outcome time-point), 9, 18 and 36 months. Data on adverse events will also be collected. Semi-structured, qualitative interviews with a subsample of 30 participants (10 from each treatment group) will be undertaken at two time-points (end of treatment and 12 to 18 months later) and analysed thematically

  19. Light Emitting Diode (LED)

    NASA Technical Reports Server (NTRS)

    1997-01-01

    A special lighting technology was developed for space-based commercial plant growth research on NASA's Space Shuttle. Surgeons have used this technology to treat brain cancer on Earth, in two successful operations. The treatment technique called photodynamic therapy, requires the surgeon to use tiny pinhead-size Light Emitting Diodes (LEDs) (a source releasing long wavelengths of light) to activate light-sensitive, tumor-treating drugs. Laser light has been used for this type of surgery in the past, but the LED light illuminates through all nearby tissues, reaching parts of a tumor that shorter wavelengths of laser light carnot. The new probe is safer because the longer wavelengths of light are cooler than the shorter wavelengths of laser light, making the LED less likely to injure normal brain tissue near the tumor. It can also be used for hours at a time while still remaining cool to the touch. The LED probe consists of 144 tiny pinhead-size diodes, is 9-inches long, and about one-half-inch in diameter. The small balloon aids in even distribution of the light source. The LED light source is compact, about the size of a briefcase, and can be purchased for a fraction of the cost of a laser. The probe was developed for photodynamic cancer therapy by the Marshall Space Flight Center under a NASA Small Business Innovative Research program grant.

  20. Light Emitting Diodes (LEDs)

    NASA Technical Reports Server (NTRS)

    1997-01-01

    A special lighting technology was developed for space-based commercial plant growth research on NASA's Space Shuttle. Surgeons have used this technology to treat brain cancer on Earth, in two successful operations. The treatment technique, called Photodynamic Therapy, requires the surgeon to use tiny, pinhead-size Light Emitting Diodes (LEDs) (a source that releases long wavelengths of light ) to activate light-sensitive, tumor-treating drugs. 'A young woman operated on in May 1999 has fully recovered with no complications and no evidence of the tumor coming back,' said Dr. Harry Whelan, a pediatric neurologist at the Medical Hospital of Wisconsin in Milwaukee. Laser light has been used for this type of surgery in the past, but the LED light illuminates through all nearby tissues, reaching parts of a tumor that shorter wavelengths of laser light carnot. The new probe is safer because the longer wavelengths of light are cooler than the shorter wavelengths of laser light, making the LED less likely to injure normal brain tissue near the tumor. It can be used for hours at a time while still remaining cool to the touch. The LED light source is compact, about the size of a briefcase, and can be purchased for a fraction of the cost of a laser. The LEDs, developed and managed by NASA's Marshall Space Flight Center, have been used on seven Space Shuttle flights inside the Microgravity Astroculture Facility. This technology has also been successfully used to further commercial research in crop growth.

  1. T cell-derived B cell growth and differentiation factors. Dichotomy between the responsiveness of B cells from adult and neonatal mice

    PubMed Central

    1983-01-01

    In these studies we have determined the molecular weights of B cell growth factor (BCGF) (less than 20,000), and B cell differentiation factors (BCDF) that induce immunoglobulin M (IgM) secretion (BCDF mu) (30-60,000) and IgG secretion (BCDF gamma) (less than 20,000). Thus, the molecular weight of BCDF mu is distinct from that of BCGF and BCDF gamma; BCGF and BCDF gamma cannot be distinguished. In addition, BCGF, BCDF mu, and BCDF gamma are distinguishable by their presence or absence in different supernatants from a panel of mitogen-induced T cell clones. These results suggest that the three lymphokines are different. This conclusion is supported by their differential biological effect on B cells from adult and neonatal mice. Thus, treatment with anti-Ig induces B cells from adult mice to proliferate and this proliferation is sustained by BCGF. In contrast, even in the presence of BCGF, anti-Ig does not induce B cells from neonatal mice to proliferate. However, BCDF mu and BCDF gamma induce IgM and IgG secretion in B cells, respectively, from both adult and neonatal mice. Thus, mature B cells can both clonally expand and differentiate in response to anti-Ig, BCGF, and BCDF, whereas immature B cells can only differentiate. The poor response of neonatal B cells to anti-Ig and BCGF may partially explain the relative immunoincompetence of immature B cells. PMID:6600488

  2. [LED lights in dermatology].

    PubMed

    Noé, C; Pelletier-Aouizerate, M; Cartier, H

    2017-04-01

    The use in dermatology of light-emitting diodes (LEDs) continues to be surrounded by controversy. This is due mainly to poor knowledge of the physicochemical phases of a wide range of devices that are difficult to compare to one another, and also to divergences between irrefutable published evidence either at the level of in vitro studies or at the cellular level, and discordant clinical results in a variety of different indications: rejuvenation, acne, wound healing, leg ulcers, and cutaneous inflammatory or autoimmune processes. Therapeutic LEDs can emit wavelengths ranging from the ultraviolet, through visible light, to the near infrared (247-1300 nm), but only certain bands have so far demonstrated any real value. We feel certain that if this article remains factual, then readers will have a different, or at least more nuanced, opinion concerning the use of such LED devices in dermatology.

  3. 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

  4. Tumor necrosis factor-alpha during neonatal brain development affects anxiety- and depression-related behaviors in adult male and female mice.

    PubMed

    Babri, Shirin; Doosti, Mohammad-Hossein; Salari, Ali-Akbar

    2014-03-15

    A nascent literature suggests that neonatal infection is a risk factor for the development of brain, behavior and hypothalamic-pituitary-adrenal axis which can affect anxiety- and depression-related behaviors in later life. It has been documented that neonatal infection raises the concentrations of tumor necrosis factor-alpha (TNF-α) in neonate rodents and such infections may result in neonatal brain injury, at least in part, through pro-inflammatory cytokines. In addition, previous studies have shown that TNF-α is involved in cellular differentiation, neurogenesis and programmed cell death during the development of the central nervous system. We investigated for the first time whether neonatal exposure to TNF-α can affect body weight, stress-induced corticosterone (COR), anxiety- and depression-related behaviors in adult mice. In the present study, neonatal mice were treated to recombinant mouse TNF-α (0.2, 0.4, 0.7 and 1 μg/kg) or saline on postnatal days 3 and 5, then adult male and female mice were exposed to different behavioral tests. The results indicated that neonatal TNF-α treatment reduced body weight in neonatal period in both sexes. In addition, this study presents findings indicating that high doses of TNF- increase stress-induced COR levels, anxiety- and depression-related behaviors in adult males, but increase levels of anxiety without significantly influencing depression in adult female mice [corrected]. Our findings suggest that TNF-α exposure during neonatal period can alter brain and behavior development in a dose and sex-dependent manner in mice.

  5. 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).

  6. 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.

  7. The effect of the anabolic steroid, nandrolone, in conditioned place preference and D1 dopamine receptor expression in adolescent and adult mice.

    PubMed

    Martínez-Rivera, Freddyson J; Natal-Albelo, Eduardo J; Martínez, Namyr A; Orozco-Vega, Roberto A; Muñiz-Seda, Oscar A; Barreto-Estrada, Jennifer L

    2015-04-01

    Adolescents and adults engage in anabolic-androgenic steroid (AAS) misuse seeking their anabolic effects, even though later on, many could develop neuropsychological dependence. Previously, we have shown that nandrolone induces conditioned place preference (CPP) in adult male mice. However, whether nandrolone induces CPP during adolescence remains unknown. In this study, the CPP test was used to determine the rewarding properties of nandrolone (7.5 mg/kg) in adolescent mice. In addition, since D1 dopamine receptors (D1DR) are critical for reward-related processes, the effect of nandrolone on the expression of D1DR in the nucleus accumbens (NAc) was investigated by Western blot analysis. Similar to our previous results, nandrolone induced CPP in adults. However, in adolescents, nandrolone failed to produce place preference. At the molecular level, nandrolone decreased D1DR expression in the NAc only in adult mice. Our data suggest that nandrolone may not be rewarding in adolescents at least during short-term use. The lack of nandrolone rewarding effects in adolescents may be due, in part to differences in D1DR expression during development.

  8. High Fetal Estrogen Concentrations: Correlation with Increased Adult Sexual Activity and Decreased Aggression in Male Mice

    NASA Astrophysics Data System (ADS)

    Vom Saal, Frederick S.; Grant, William M.; McMullen, Carol W.; Laves, Kurt S.

    1983-06-01

    In the house mouse (Mus musculus), fetuses may develop in utero next to siblings of the same or opposite sex. The amniotic fluid of the female fetuses contains higher concentrations of estradiol than that of male fetuses. Male fetuses that developed in utero between female fetuses had higher concentrations of estradiol in their amniotic fluid than males that were located between other male fetusesw during intrauterine development. They were also more sexually active as adults, less aggressive, and had smaller seminal vesicles than males that had developed between other male fetuses in utero. These findings raise the possibility that during fetal life circulating estrogens may interact with circulating androgens both in regulating the development of sex differences between males and females and in producing variation in phenotype among males and among females.

  9. Isolation of intact astrocytes from the optic nerve head of adult mice.

    PubMed

    Choi, Hee Joo; Sun, Daniel; Jakobs, Tatjana C

    2015-08-01

    The astrocytes of the optic nerve head are a specialized subtype of white matter astrocytes that form the direct cellular environment of the unmyelinated ganglion cell axons. Due to their potential involvement in glaucoma, these astrocytes have become a target of research. Due to the heterogeneity of the optic nerve tissue, which also contains other cell types, in some cases it may be desirable to conduct gene expression studies on small numbers of well-characterized astrocytes or even individual cells. Here, we describe a simple method to isolate individual astrocytes. This method permits obtaining astrocytes with intact morphology from the adult mouse optic nerve and reduces contamination of the isolated astrocytes by other cell types. Individual astrocytes can be recognized by their morphology and collected under microscopic control. The whole procedure can be completed in 2-3 h. We also discuss downstream applications like multiplex single-cell PCR and quantitative PCR (qPCR).

  10. 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

  11. Ketogenic Diet Prevents Epileptogenesis and Disease Progression in Adult Mice and Rats

    PubMed Central

    Lusardi, Theresa A.; Akula, Kiran K.; Coffman, Shayla Q.; Ruskin, David; Masino, Susan A.; Boison, Detlev

    2015-01-01

    Epilepsy is a highly prevalent seizure disorder which tends to progress in severity and become refractory to treatment. Yet no therapy is proven to halt disease progression or to prevent the development of epilepsy. Because a high fat low carbohydrate ketogenic diet (KD) augments adenosine signaling in the brain and because adenosine not only suppresses seizures but also affects epileptogenesis, we hypothesized that a ketogenic diet might prevent epileptogenesis through similar mechanisms. Here, we tested this hypothesis in two independent rodent models of epileptogenesis. Using a pentylenetetrazole kindling paradigm in mice, we first show that a KD, but not a conventional antiepileptic drug (valproic acid), suppressed kindling-epileptogenesis. Importantly, after treatment reversal, increased seizure thresholds were maintained in those animals kindled in the presence of a KD, but not in those kindled in the presence of valproic acid. Next, we tested whether a KD can halt disease progression in a clinically relevant model of progressive epilepsy. Epileptic rats that developed spontaneous recurrent seizures after a pilocarpine-induced status epilepticus were treated with a KD or control diet (CD). Whereas seizures progressed in severity and frequency in the CD-fed animals, KD-fed animals showed a prolonged reduction of seizures, which persisted after diet reversal. KD-treatment was associated with increased adenosine and decreased DNA methylation, the latter being maintained after diet discontinuation. Our findings demonstrate that a KD prevented disease progression in two mechanistically different models of epilepsy, and suggest an epigenetic mechanism underlying the therapeutic effects. PMID:26256422

  12. Acute toxicological impact of nano- and submicro-scaled zinc oxide powder on healthy adult mice

    NASA Astrophysics Data System (ADS)

    Wang, Bing; Feng, Weiyue; Wang, Meng; Wang, Tiancheng; Gu, Yiqun; Zhu, Motao; Ouyang, Hong; Shi, Junwen; Zhang, Fang; Zhao, Yuliang; Chai, Zhifang; Wang, Haifang; Wang, Jing

    2008-02-01

    In this work, the acute oral toxicity of 20- and 120-nm ZnO powder at doses of 1-, 2-, 3-, 4-, 5-g/kg body weight was evaluated referred to the OECD guidelines for testing of chemicals. As the results, both 20- and 120-nm ZnO belong to non-toxic chemicals according to the Globally Harmonized Classification System (GHS) for the classification of chemicals. The distribution determination showed that Zn was mainly retained in the bone, kidney and pancreas after 20- and 120-nm ZnO administration. However, the results of blood measurement suggest that the increase in blood viscosity could be induced by low and median dose of 20-nm ZnO but high dose of 120-nm ZnO. The pathological examination showed that the 120-nm ZnO treated mice had dose-effect pathological damages in stomach, liver, heart and spleen, whereas, 20-nm ZnO displayed negative dose-effect damages in liver, spleen and pancreas. Therefore, we conclude that the liver, spleen, heart, pancreas and bone are the target organs for 20- and 120-nm ZnO oral exposure. More attention should be paid on the potential toxicity induced by low dose of 20-nm ZnO oral exposure.

  13. Altered Hippocampal Neurogenesis and Amygdalar Neuronal Activity in Adult Mice with Repeated Experience of Aggression

    PubMed Central

    Smagin, Dmitry A.; Park, June-Hee; Michurina, Tatyana V.; Peunova, Natalia; Glass, Zachary; Sayed, Kasim; Bondar, Natalya P.; Kovalenko, Irina N.; Kudryavtseva, Natalia N.; Enikolopov, Grigori

    2015-01-01

    Repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here, we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos-positive) cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights. PMID:26648838

  14. Increased Efficiency LED

    NASA Technical Reports Server (NTRS)

    Egalon, Claudio O. (Inventor); Rogowski, Robert S. (Inventor)

    1998-01-01

    In an LED a large portion of the light produced is lost due to total internal reflection at the air-semiconductor interface. A reverse taper of the semiconductor is used to change the angle at which light strikes the interface so that a greater portion of the light is transmitted.

  15. Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice

    PubMed Central

    Burns, Monika; Muthupalani, Sureshkumar; Ge, Zhongming; Wang, Timothy C.; Bakthavatchalu, Vasudevan; Cunningham, Catriona; Ennis, Kathleen; Georgieff, Michael; Fox, James G.

    2015-01-01

    of Hp SS1-infected INS-GAS mice will be an appropriate animal model for further study of the effects of concurrent H. pylori infection and anemia on iron homeostasis and adult iron-dependent brain gene expression. PMID:26575645

  16. Helicobacter pylori Infection Induces Anemia, Depletes Serum Iron Storage, and Alters Local Iron-Related and Adult Brain Gene Expression in Male INS-GAS Mice.

    PubMed

    Burns, Monika; Muthupalani, Sureshkumar; Ge, Zhongming; Wang, Timothy C; Bakthavatchalu, Vasudevan; Cunningham, Catriona; Ennis, Kathleen; Georgieff, Michael; Fox, James G

    2015-01-01

    SS1-infected INS-GAS mice will be an appropriate animal model for further study of the effects of concurrent H. pylori infection and anemia on iron homeostasis and adult iron-dependent brain gene expression.

  17. Genetic evidence for p75NTR-dependent tetraploidy in cortical projection neurons from adult mice.

    PubMed

    López-Sánchez, Noelia; Frade, José M

    2013-04-24

    A subpopulation of chick retinal projection neurons becomes tetraploid during development, an event prevented by blocking antibodies against p75 neurotrophin receptor (p75(NTR)). We have used an optimized flow cytometric assay, based on the analysis of unfixed brain cell nuclei, to study whether p75(NTR)-dependent neuronal tetraploidization takes place in the cerebral cortex, giving rise to projection neurons as well. We show that 3% of neurons in both murine neocortex and chick telencephalic derivatives are tetraploid, and that in the mouse ~85% of these neurons express the immediate early genes Erg-1 and c-Fos, indicating that they are functionally active. Tetraploid cortical neurons (65-80%) express CTIP2, a transcription factor specific for subcortical projection neurons in the mouse neocortex. During the period in which these neurons are born, p75(NTR) is detected in differentiating neurons undergoing DNA replication. Accordingly, p75(NTR)-deficient mice contain a reduced proportion of both NeuN and CTIP2-positive neocortical tetraploid neurons, thus providing genetic evidence for the participation of p75(NTR) in the induction of neuronal tetraploidy in the mouse neocortex. In the striatum tetraploidy is mainly associated with long-range projection neurons as well since ~80% of tetraploid neurons in this structure express calbindin, a marker of neostriatal-matrix spiny neurons, known to establish long-range projections to the substantia nigra and globus pallidus. In contrast, only 20% of tetraploid cortical neurons express calbindin, which is mainly expressed in layers II-III, where CTIP2 is absent. We conclude that tetraploidy mainly affects long-range projection neurons, being facilitated by p75(NTR) in the neocortex.

  18. Expression Profiling Reveals Novel Hypoxic Biomarkers in Peripheral Blood of Adult Mice Exposed to Chronic Hypoxia

    PubMed Central

    Zeiger, Ulrike; Khurana, Tejvir S.

    2012-01-01

    Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO) mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX), exposed for two weeks to normobaric chronic hypoxia (CH) or two weeks of CH followed by two weeks of normoxic recovery (REC). Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off), 230 genes were identified and separated into four distinct temporal categories. Class I) contained 1 transcript up-regulated in both CH and REC; Class II) contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III) contained 9 transcripts down-regulated both in CH and REC; Class IV) contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1) by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia. PMID:22629407

  19. Adipogenic healing in adult mice by implantation of hollow devices in muscle.

    PubMed

    Xaymardan, Munira; Gibbins, John R; Zoellner, Hans

    2002-05-01

    In mammals, wound healing is thought to result in the formation of scar tissue, with the exception of bony healing after fractures. Here we describe a previously unknown pattern of wound healing in which adipose rather than scar tissue is formed. Adipogenesis is normally confined to the embryo, although there are several experimental models for adipogenesis with highly specific dietary, cytokine, matrix, sex, or age requirements. The adipogenic healing described in this work provides a simple and reproducible experimental mouse model for adipogenesis without these limitations. Mice received intramuscular implants of nylon mesh material. Fibrinous material impregnated implants and within 4 weeks was replaced with highly vascular granulation tissue, typical of wound healing. Also consistent with wound healing was a reduction in vascularity of the newly formed tissue over time (P < 0.05). Lipoblasts were prevalent in granulation tissue, reaching a maximum in week 2 (P < 0.001) but falling to very low levels by week 9. These cells matured to adipocytes, with intermediate forms being seen. The identity of lipoblasts and adipocytes was confirmed by Oil Red O staining and electron microscopy. Control experiments confirmed that adipogenesis was independent of the materials used as well as of the sex and age of the animals. Rather, adipogenesis appeared to be due to replacement of fibrinous material in a space created within muscle. It is possible that adipogenic healing represents an adaptation for limiting the formation of restrictive scar tissues within muscle, and that this is the basis for the formation of traumatic lipomas in humans. Also, muscle tissue is replaced by adipose cells, seemingly derived from pluripotential satellite cells, in several degenerative muscle conditions, suggesting a role for adipogenic healing in these conditions.

  20. Development of Adult Worms and Granulomatous Pathology Are Collectively Regulated by T- and B-Cells in Mice Infected with Schistosoma japonicum

    PubMed Central

    Tang, Hongbin; Ming, Zhenping; Liu, Rong; Xiong, Tao; Grevelding, Christoph G.; Dong, Huifeng; Jiang, Mingsen

    2013-01-01

    Schistosoma blood flukes, which cause schistosomiasis affecting 200 million people in the world, are dependent on signals from host CD4+ T cells to facilitate parasite growth and development in the mammalian host and to induce Th2-biased inflammatory granulomas. B cells, however, are reported to down-regulate granulomatous pathology in schistosomiasis, but not to affect the development of blood flukes together with CD4+ T lymphocytes. Thus it is not clear whether B cells mediate parasite development, reproduction and egg granuloma formation of schistosomes without the help of CD4+ T lymphocytes. Using mice that have severe combined immunodeficiency (scid) and mice lacking T cells (nude), we found that the absence of B cells can more seriously hamper the development and paring of adult worms, but granuloma formation of Schistosoma japonicum in scid mice was not down-regulated comparing with that in nude mice. The level of IL-10 in the sera of nude mice was significantly higher than of scid mice at 43 days post infection (p.i.). Thus multiple mechanisms of immune modulation seem to be involved in parasite development and reproduction by helminth-induced regulatory B cells. Our findings have significance for understanding the molecular connections between schistosomes and T- and B-cells, indicating that more research is needed to develop efficient vaccine-based therapies for schistosomiasis. PMID:23349889

  1. Voltage-activated Ca2+ channels and their role in the endocrine function of the pituitary gland in newborn and adult mice

    PubMed Central

    Sedej, Simon; Tsujimoto, Tetsuhiro; Zorec, Robert; Rupnik, Marjan

    2004-01-01

    We have prepared fresh pituitary gland slices from adult and, for the first time, from newborn mice to assess modulation of secretory activity via voltage-activated Ca2+ channels (VACCs). Currents through VACCs and membrane capacitance have been measured with the whole-cell patch-clamp technique. Melanotrophs in newborns were significantly larger than in adults. In both newborn and adult melanotrophs activation of VACCs triggered exocytosis. All pharmacologically isolated VACC types contributed equally to the secretory activity. However, the relative proportion of VACCs differed between newborns and adults. In newborn cells L-type channels dominated and, in addition, an exclusive expression of a toxin-resistant R-type-like current was found. The expression of L-type VACCs was up-regulated by the increased oestrogen levels observed in females, and was even more emphasized in the cells of pregnant females and oestrogen-treated adult male mice. We suggest a general mechanism modulating endocrine secretion in the presence of oestrogen and particularly higher sensitivity to treatments with L-type channel blockers during high oestrogen physiological states. PMID:14724188

  2. Modulation of elevated plus maze behavior after chronic exposure to the anabolic steroid 17alpha-methyltestosterone in adult mice.

    PubMed

    Rojas-Ortiz, Yoel Antonio; Rundle-González, Valerie; Rivera-Ramos, Isamar; Jorge, Juan Carlos

    2006-01-01

    Exposure to supraphysiological doses of androgens may disrupt affective components of behavior. In this study, behavior of adult C57Bl/6 male mice was studied after exposure to the anabolic androgenic steroid (AAS) 17alpha-methyltestosterone (17alpha-meT; 7.5 mg/kg) via a subcutaneous osmotic pump for 17 days. Controls received vehicle implants (0.9% NaCl + 30% cyclodextrine). On day 15, experimental animals were challenged with an ethanol (EtOH) injection (i.p.; 1 g/kg) while controls received saline injections. Five minutes after the injection, animals were tested in an automated elevated plus maze (EPM) or in automated activity chambers. In addition, injection-free animals were tested for ethanol consumption on day 16 after an overnight water deprivation period. Whereas chronic exposure to 17alpha-meT did not modulate open arm behavior, EtOH-exposed animals made more entries into the open arms than controls (P < 0.05). A significant reduction of risk assessment behaviors (rearing, flat approach behavior, and stretch attended posture) over the EPM was noted for EtOH-exposed animals whereas a reduction in stretch attended postures was observed among 17alpha-meT-exposed animals. Locomotor activity, and light-dark transitions in activity chambers remained unaltered. Exposure to AAS did not modulate EtOH consumption. Our data suggest that exposure to a supraphysiological dose of 17alpha-meT has minimal effects on exploratory-based anxiety.

  3. In vivo adeno-associated viral vector-mediated genetic engineering of white and brown adipose tissue in adult mice.

    PubMed

    Jimenez, Veronica; Muñoz, Sergio; Casana, Estefania; Mallol, Cristina; Elias, Ivet; Jambrina, Claudia; Ribera, Albert; Ferre, Tura; Franckhauser, Sylvie; Bosch, Fatima

    2013-12-01

    Adipose tissue is pivotal in the regulation of energy homeostasis through the balance of energy storage and expenditure and as an endocrine organ. An inadequate mass and/or alterations in the metabolic and endocrine functions of adipose tissue underlie the development of obesity, insulin resistance, and type 2 diabetes. To fully understand the metabolic and molecular mechanism(s) involved in adipose dysfunction, in vivo genetic modification of adipocytes holds great potential. Here, we demonstrate that adeno-associated viral (AAV) vectors, especially serotypes 8 and 9, mediated efficient transduction of white (WAT) and brown adipose tissue (BAT) in adult lean and obese diabetic mice. The use of short versions of the adipocyte protein 2 or uncoupling protein-1 promoters or micro-RNA target sequences enabled highly specific, long-term AAV-mediated transgene expression in white or brown adipocytes. As proof of concept, delivery of AAV vectors encoding for hexokinase or vascular endothelial growth factor to WAT or BAT resulted in increased glucose uptake or increased vessel density in targeted depots. This method of gene transfer also enabled the secretion of stable high levels of the alkaline phosphatase marker protein into the bloodstream by transduced WAT. Therefore, AAV-mediated genetic engineering of adipose tissue represents a useful tool for the study of adipose pathophysiology and, likely, for the future development of new therapeutic strategies for obesity and diabetes.

  4. 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.

  5. Impact of Environmental Microbes on the Composition of the Gut Microbiota of Adult BALB/c Mice

    PubMed Central

    Li, Na; Bai, Zhiyu; Zhang, Liling; Xue, Zhencheng; Jiang, Haitao; Song, Yuan; Zhou, Dongrui

    2016-01-01

    To investigate the impact of microbes within the living environment on the gut microbiota of adults, we raised three groups of BALB/c mice from 3–4 weeks age in the same specific-pathogen-free animal room for 8 weeks. The control group lived in cages with sterilized bedding (pelletized cardboard), the probiotics group had three probiotics added to the sterilized bedding, and the intestinal microbes (IM) group had the intestinal microbes of a healthy goat added to the bedding. All other variables such as diet, age, genetic background, physiological status, original gut microbiota, and living room were controlled. Using high-throughput sequencing of the 16S rRNA gene, we observed that the control and probiotics groups had similar diversity and richness of gut microbiota. The two groups had significantly lower diversity than the IM group. We also observed that the IM group had a specific structure of gut microbial community compared with the control and probiotics groups. However, the dominate bacteria changed slightly upon exposure to intestinal microbes, and the abundance of the non-dominate species changed significantly. In addition, exposure to intestinal microbes inhibited DNFB-induced elevation of serum IgE levels. Our results provide new evidence in support of the microflora and hygiene hypotheses. PMID:27518814

  6. Exposure to bisphenol A in young adult mice does not alter ovulation but does alter the fertilization ability of oocytes.

    PubMed

    Moore-Ambriz, Teresita Rocio; Acuña-Hernández, Deyanira Guadalupe; Ramos-Robles, Brenda; Sánchez-Gutiérrez, Manuel; Santacruz-Márquez, Ramsés; Sierra-Santoyo, Adolfo; Piña-Guzmán, Belem; Shibayama, Mineko; Hernández-Ochoa, Isabel

    2015-12-15

    Follicle growth culminates in ovulation, which allows for the expulsion of fertilizable oocytes and the formation of corpora lutea. Bisphenol A (BPA) is present in many consumer products, and it has been suggested that BPA impairs ovulation; however, the underlying mechanisms are unknown. Therefore, this study first evaluated whether BPA alters ovulation by affecting folliculogenesis, the number of corpora lutea or eggs shed to the oviduct, ovarian gonadotropin responsiveness, hormone levels, and estrous cyclicity. Because it has been suggested (but not directly confirmed) that BPA exerts toxic effects on the fertilization ability of oocytes, a second aim was to evaluate whether BPA impacts the oocyte fertilization rate using an in vitro fertilization assay and mating. The possible effects on early zygote development were also examined. Young adult female C57BL/6J mice (39 days old) were orally dosed with corn oil (vehicle) or 50 μg/kgbw/day BPA for a period encompassing the first three reproductive cycles (12-15 days). BPA exposure did not alter any parameters related to ovulation. Moreover, BPA exposure reduced the percentage of fertilized oocytes after either in vitro fertilization or mating, but it did not alter the zygotic stages. The data indicate that exposure to the reference dose of BPA does not impact ovulation but that it does influence the oocyte quality in terms of its fertilization ability.

  7. 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

  8. Activation of the Wnt/{beta}-catenin signaling pathway is associated with glial proliferation in the adult spinal cord of ALS transgenic mice

    SciTech Connect

    Chen, Yanchun; Guan, Yingjun; Liu, Huancai; Wu, Xin; Yu, Li; Wang, Shanshan; Zhao, Chunyan; Du, Hongmei; Wang, Xin

    2012-04-06

    Highlights: Black-Right-Pointing-Pointer Wnt3a and Cyclin D1 were upregulated in the spinal cord of the ALS mice. Black-Right-Pointing-Pointer {beta}-catenin translocated from the cell membrane to the nucleus in the ALS mice. Black-Right-Pointing-Pointer Wnt3a, {beta}-catenin and Cyclin D1 co-localized for astrocytes were all increased. Black-Right-Pointing-Pointer BrdU/Cyclin D1 double-positive cells were increased in the spinal cord of ALS mice. Black-Right-Pointing-Pointer BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. -- Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive and fatal loss of motor neurons. In ALS, there is a significant cell proliferation in response to neurodegeneration; however, the exact molecular mechanisms of cell proliferation and differentiation are unclear. The Wnt signaling pathway has been shown to be involved in neurodegenerative processes. Wnt3a, {beta}-catenin, and Cyclin D1 are three key signaling molecules of the Wnt/{beta}-catenin signaling pathway. We determined the expression of Wnt3a, {beta}-catenin, and Cyclin D1 in the adult spinal cord of SOD1{sup G93A} ALS transgenic mice at different stages by RT-PCR, Western blot, and immunofluorescence labeling techniques. We found that the mRNA and protein of Wnt3a and Cyclin D1 in the spinal cord of the ALS mice were upregulated compared to those in wild-type mice. In addition, {beta}-catenin translocated from the cell membrane to the nucleus and subsequently activated transcription of the target gene, Cyclin D1. BrdU and Cyclin D1 double-positive cells were increased in the spinal cord of these mice. Moreover, Wnt3a, {beta}-catenin, and Cyclin D1 were also expressed in both neurons and astrocytes. The expression of Wnt3a, {beta}-catenin or Cyclin D1 in mature GFAP{sup +} astrocytes increased. Moreover, BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. Our findings suggest that

  9. 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

  10. Effect of Anti-Sclerostin Therapy and Osteogenesis Imperfecta on Tissue-level Properties in Growing and Adult Mice While Controlling for Tissue Age

    PubMed Central

    Sinder, Benjamin P.; Lloyd, William R.; Salemi, Joseph D.; Marini, Joan C.; Caird, Michelle S.; Morris, Michael D.; Kozloff, Kenneth M.

    2016-01-01

    Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as Osteogenesis Imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly→Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5 weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2–4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages >3wk) and rapidly growing Brtl/+ (at tissue ages > 4wk) mice compared to WT. At identical tissue ages defined by fluorescent labels adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age

  11. Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age.

    PubMed

    Sinder, Benjamin P; Lloyd, William R; Salemi, Joseph D; Marini, Joan C; Caird, Michelle S; Morris, Michael D; Kozloff, Kenneth M

    2016-03-01

    Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly➔Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages>3wks) and rapidly growing Brtl/+ (at tissue ages>4wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and

  12. Inactivation of Vhl in Osteochondral Progenitor Cells Causes High Bone Mass Phenotype and Protects Against Age-Related Bone Loss in Adult Mice

    PubMed Central

    Weng, Tujun; Xie, Yangli; Huang, Junlan; Luo, Fengtao; Yi, Lingxian; He, Qifen; Chen, Di; Chen, Lin

    2014-01-01

    Previous studies have shown that disruption of von Hippel–Lindau gene (Vhl) coincides with activation of hypoxia-inducible factor α (HIFα) signaling in bone cells and plays an important role in bone development, homeostasis, and regeneration. It is known that activation of HIF1α signaling in mature osteoblasts is central to the coupling between angiogenesis and bone formation. However, the precise mechanisms responsible for the coupling between skeletal angiogenesis and osteogenesis during bone remodeling are only partially elucidated. To evaluate the role of Vhl in bone homeostasis and the coupling between vascular physiology and bone, we generated mice lacking Vhl in osteochondral progenitor cells (referred to as Vhl cKO mice) at postnatal and adult stages in a tamoxifen-inducible manner and changes in skeletal morphology were assessed by micro–computed tomography (µCT), histology, and bone histomorphometry. We found that mice with inactivation of Vhl in osteochondral progenitor cells at the postnatal stage largely phenocopied that of mice lacking Vhl in mature osteoblasts, developing striking and progressive accumulation of cancellous bone with increased microvascular density and bone formation. These were accompanied with a significant increase in osteoblast proliferation, upregulation of differentiation marker Runx2 and osteocalcin, and elevated expression of vascular endothelial growth factor (VEGF) and phosphorylation of Smad1/5/8. In addition, we found that Vhl deletion in osteochondral progenitor cells in adult bone protects mice from aging-induced bone loss. Our data suggest that the VHL-mediated signaling in osteochondral progenitor cells plays a critical role in bone remodeling at postnatal/adult stages through coupling osteogenesis and angiogenesis. © 2014 American Society for Bone and Mineral Research. PMID:23999831

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

    PubMed

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

    2015-10-01

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

  14. Epigallocatechin-3-gallate rescues LPS-impaired adult hippocampal neurogenesis through suppressing the TLR4-NF-κB signaling pathway in mice

    PubMed Central

    Seong, Kyung-Joo; Lee, Hyun-Gwan; Kook, Min Suk; Ko, Hyun-Mi

    2016-01-01

    Adult hippocampal dentate granule neurons are generated from neural stem cells (NSCs) in the mammalian brain, and the fate specification of adult NSCs is precisely controlled by the local niches and environment, such as the subventricular zone (SVZ), dentate gyrus (DG), and Toll-like receptors (TLRs). Epigallocatechin-3-gallate (EGCG) is the main polyphenolic flavonoid in green tea that has neuroprotective activities, but there is no clear understanding of the role of EGCG in adult neurogenesis in the DG after neuroinflammation. Here, we investigate the effect and the mechanism of EGCG on adult neurogenesis impaired by lipopolysaccharides (LPS). LPS-induced neuroinflammation inhibited adult neurogenesis by suppressing the proliferation and differentiation of neural stem cells in the DG, which was indicated by the decreased number of Bromodeoxyuridine (BrdU)-, Doublecortin (DCX)- and Neuronal Nuclei (NeuN)-positive cells. In addition, microglia were recruited with activatingTLR4-NF-κB signaling in the adult hippocampus by LPS injection. Treating LPS-injured mice with EGCG restored the proliferation and differentiation of NSCs in the DG, which were decreased by LPS, and EGCG treatment also ameliorated the apoptosis of NSCs. Moreover, pro-inflammatory cytokine production induced by LPS was attenuated by EGCG treatment through modulating the TLR4-NF-κB pathway. These results illustrate that EGCG has a beneficial effect on impaired adult neurogenesis caused by LPSinduced neuroinflammation, and it may be applicable as a therapeutic agent against neurodegenerative disorders caused by inflammation. PMID:26807022

  15. 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.

  16. Sulforaphane induces Nrf2 target genes and attenuates inflammatory gene expression in microglia from brain of young adult and aged mice

    PubMed Central

    Townsend, Brigitte E.; Johnson, Rodney W.

    2015-01-01

    Increased neuroinflammation and oxidative stress resulting from heightened microglial activation is associated with age-related cognitive impairment. The objectives of this study were to examine the effects of the bioactive sulforaphane (SFN) on the nuclear factor E2-related factor 2 (Nrf2) pathway in BV2 microglia and primary microglia, and to evaluate proinflammatory cytokine expression in lipopolysaccharide (LPS)-stimulated primary microglia from adult and aged mice. BV2 microglia and primary microglia isolated from young adult and aged mice were treated with SFN and LPS. Changes in Nrf2 activity, expression of Nrf2 target genes, and levels of proinflammatory markers were assessed by quantitative PCR and immunoassay. SFN increased Nrf2 DNA-binding activity and upregulated Nrf2 target genes in BV2 microglia, while reducing LPS-induced interleukin (IL-)1β, IL-6, and inducible nitric oxide synthase (iNOS). In primary microglia from adult and aged mice, SFN increased expression of Nrf2 target genes and attenuated IL-1β, IL-6, and iNOS induced by LPS. These data indicate that SFN is a potential beneficial supplement that may be useful for reducing microglial mediated neuroinflammation and oxidative stress associated with aging. PMID:26571201

  17. Ketamine exposure in adult mice leads to increased cell death in C3H, DBA2 and FVB inbred mouse strains

    PubMed Central

    Majewski-Tiedeken, Chalon R.; Rabin, Cara R.; Siegel, Steven J.

    2008-01-01

    Background Drug abuse is common among adolescents and young adults. Although the consequences of intoxication are known, sequelae of drugs emerging on campuses and in clubs nationwide are not. We previously demonstrated that ketamine exposure results in lasting physiological abnormalities in mice. However, the extent to which these deficits reflect neuropathologic changes is not known. Methods The current study examines neuropathologic changes following sub-anesthetic ketamine administration (5 mg/kg i.p. × 5) to three inbred mouse strains. Stereologic quantification of silver stained nuclear and linear profiles as well as activated caspase-3 labeling was used to address: 1) whether or not ketamine increases excitotoxic and apoptotic cell death in hippocampal CA3 and 2) whether or not ketamine-induced cell death varies by genetic background. Results Ketamine increased cell death in hippocampal CA3 of adult C3H, DBA2 and FVB mice. Neither silver staining nor activated caspase-3 labeling varied by strain, nor was there an interaction between ketamine-induced cell death and strain. Conclusions Ketamine exposure among young adults, even in limited amounts, may lead to irreversible changes in both brain function and structure. Loss of CA3 hippocampal cells may underlie persistent ERP changes previously shown in mice and possibly contribute to lasting cognitive deficits among ketamine abusers. PMID:17920787

  18. Characterization of a Unique Cell Population Marked by Transgene Expression in the Adult Cochlea of Nestin-CreERT2/tdTomato-Reporter Mice

    PubMed Central

    Chow, Cynthia L.; Guo, Weixiang; Trivedi, Parul; Zhao, Xinyu; Gubbels, Samuel P.

    2015-01-01

    Hair cells in the adult mammalian cochlea cannot spontaneously regenerate after damage resulting in the permanency of hearing loss. Stem cells have been found to be present in the cochlea of young rodents; however, there has been little evidence for their existence into adulthood. We used nestin-CreERT2/tdTomato-reporter mice to trace the lineage of putative nestin-expressing cells and their progeny in the cochleae of adult mice. Nestin, an intermediate filament found in neural progenitor cells during early development and adulthood, is regarded as a multi-potent and neural stem cell marker. Other investigators have reported its presence in postnatal and young adult rodents; however, there are discrepancies amongst these reports. Using lineage tracing, we documented a robust population of tdTomato-expressing cells and evaluated these cells at a series of adult time points. Upon activation of the nestin promoter, tdTomato was observed just below and medial to the inner hair cell layer. All cells co-localized with the stem cell and cochlear-supporting-cell marker Sox2 as well as the supporting cell and Schwann cell marker Sox10; however, they did not co-localize with the Schwann cell marker Krox20, spiral ganglion marker NF200, or GFAP-expressing supporting cell marker. The cellular identity of this unique population of tdTomato-expressing cells in the adult cochlea of nestin-CreERT2/tdTomato mice remains unclear however these cells may represent a type of supporting cell on the neural aspect of the inner hair cell layer. PMID:25611038

  19. The distribution of PGP9. 5, BDNF and NGF in the vallate papilla of adult and developing mice.

    PubMed

    Chou, H C; Chien, C L; Lu, K S

    2001-08-01

    The development and innervation of vallate papillae and taste buds in mice were studied using antibodies against the neuronal marker, protein gene product 9.5 (PGP 9.5), and against nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). PGP 9.5 immunohistochemical studies revealed that the earliest sign of median vallate papilla formation was an epithelial bulge at embryonic day 13 (E13), and at E14, a dense nerve plexus was found within the connective tissue core of the papilla. Thin nerve fibers penetrated the apical and medial trench wall epithelium of the papilla at E16 and a few of these began to invade the lateral trench wall epithelium at E17. At postnatal day 1 (P1), the newly formed taste buds were recognizable and a small number of PGP 9.5-immunoreactive (IR) cells appeared on the medial trench wall epithelium. The number of PGP 9.5-IR taste bud cells then increased gradually and reached the adult level at postnatal week 2. PGP 9.5 immunoreactivity increased systematically with age. NGF and BDNF immunoreactivity was first seen at the boundary between the columnar cells in the apical epithelium of the developing vallate papilla at E13, then in the medial and lateral trench walls at E15 (BDNF) or E18 (NGF). At P1, BDNF immunoreactivity was exclusively present in the newly formed taste buds of the medial trench wall. The number of BDNF-IR taste bud cells then increased gradually, reaching the adult level at P7. Similar degrees of NGF and BDNF immunoreactivity were seen in the developing vallate papilla. In the present study, we found that the vallate papilla was formed prior to its innervation, and we propose that initiation of papilla formation does not require any direct influence from the specific gustatory nerve. We also suggest that neurotrophins in the early developing vallate papillae might act as local tropic factors for the embryonic growth of nerve fibers to induce differentiation of the taste buds.

  20. 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.

  1. Functional and morphological effects of laser-induced ocular hypertension in retinas of adult albino Swiss mice

    PubMed Central

    Salinas-Navarro, Manuel; Alarcón-Martínez, Luis; Valiente-Soriano, Francisco Javier; Ortín-Martínez, Arturo; Jiménez-López, Manuel; Avilés-Trigueros, Marcelino; Villegas-Pérez, María Paz; de la Villa, Pedro

    2009-01-01

    Purpose To investigate the effects of laser photocoagulation (LP)-induced ocular hypertension (OHT) on the survival and retrograde axonal transport of retinal ganglion cells (RGC), as well as on the function of retinal layers. Methods Adult albino Swiss mice (35–45 g) received laser photocoagulation of limbal and episcleral veins in the left eye. Mice were sacrificed at 8, 17, 35, and 63 days. Intraocular pressure (IOP) in both eyes was measured with a Tono-Lab before LP and at various days after LP. Flash electroretinogram (ERG) scotopic threshold response (STR) and a- and b-wave amplitudes were recorded before LP and at various times after LP. RGCs were labeled with 10% hydroxystilbamidine methanesulfonate (OHSt) applied to both superior colliculi before sacrifice and in some mice, with dextran tetramethylrhodamine (DTMR) applied to the ocular stump of the intraorbitally transected optic nerve. Retinas were immunostained for RT97 or Brn3a. Retinas were prepared as whole-mounts and photographed under a fluorescence microscope. Labeled RGCs were counted using image analysis software, and an isodensity contour plot was generated for each retina. Results IOP increased to twice its basal values by 24 h and was maintained until day 5, after which IOP gradually declined to reach basal values by 1 wk. Similar IOP increases were observed in all groups. The mean total number of OHSt+ RGCs was 13,428±6,295 (n=12), 10,456±14,301 (n=13), 12,622±14,174 (n=21), and 10,451±13,949 (n=13) for groups I, II, III, and IV, respectively; these values represented 28%, 23%, 26%, and 22% of the values found in their contralateral fellow retinas. The mean total population of Brn3a+ RGCs was 24,343±5,739 (n=12) and 10,219±8,887 (n=9), respectively, for groups I and III; these values represented 49% and 20%, respectively, of the values found in their fellow eyes. OHT retinas showed an absence of OHSt+ and DTMR+ RGCs in both focal wedge-shaped and diffuse regions of the retina. By 1

  2. Cilostazol attenuates ischemic brain injury and enhances neurogenesis in the subventricular zone of adult mice after transient focal cerebral ischemia.

    PubMed

    Tanaka, Y; Tanaka, R; Liu, M; Hattori, N; Urabe, T

    2010-12-29

    Evidence suggests that neurogenesis occurs in the adult mammalian brain, and that various stimuli, for example, ischemia/hypoxia, enhance the generation of neural progenitor cells in the subventricular zone (SVZ) and their migration into the olfactory bulb. In a mouse stroke model, focal ischemia results in activation of neural progenitor cells followed by their migration into the ischemic lesion. The present study assessed the in vivo effects of cilostazol, a type 3 phosphodiesterase inhibitor known to activate the cAMP-responsive element binding protein (CREB) signaling, on neurogenesis in the ipsilateral SVZ and peri-infarct area in a mouse model of transient middle cerebral artery occlusion. Mice were divided into sham operated (n=12), vehicle- (n=18) and cilostazol-treated (n=18) groups. Sections stained for 5-bromodeoxyuridine (BrdU) and several neuronal and a glial markers were analyzed at post-ischemia days 1, 3 and 7. Cilostazol reduced brain ischemic volume (P<0.05) and induced earlier recovery of neurologic deficit (P<0.05). Cilostazol significantly increased the density of BrdU-positive newly-formed cells in the SVZ compared with the vehicle group without ischemia. Increased density of doublecortin (DCX)-positive and BrdU/DCX-double positive neural progenitor cells was noted in the ipsilateral SVZ and peri-infarct area at 3 and 7 days after focal ischemia compared with the vehicle group (P<0.05). Cilostazol increased DCX-positive phosphorylated CREB (pCREB)-expressing neural progenitor cells, and increased brain derived neurotrophic factor (BDNF)-expressing astrocytes in the ipsilateral SVZ and peri-infarct area. The results indicated that cilostazol enhanced neural progenitor cell generation in both ipsilateral SVZ and peri-infarct area through CREB-mediated signaling pathway after focal ischemia.

  3. Lithium-induced effects on adult hippocampal neurogenesis are topographically segregated along the dorso-ventral axis of stressed mice.

    PubMed

    O'Leary, Olivia F; O'Connor, Richard M; Cryan, John F

    2012-01-01

    Adult hippocampal neurogenesis is an important process in the regulation of cognition, stress responsivity, and sensitivity to antidepressant and mood stabiliser drugs. Increasing evidence suggests that the hippocampus is functionally divided along its axis with the ventral hippocampus (vHi) playing a preferential role in stress- and anxiety-related processes, while the dorsal hippocampus (dHi) is crucial for spatial learning and memory. However, it is currently unclear whether stress or the medications used to treat stress-related disorders, preferentially affect neurogenesis in the vHi rather than dHi. The aim of this study was to determine whether the mood stabiliser, lithium, preferentially affects cell proliferation and survival in the vHi rather than dHi under stress conditions. To this end, mice of the stress-sensitive strain, BALB/c, underwent chronic exposure to immobilisation stress plus lithium treatment (0.2% lithium-supplemented diet), and the rates of cell proliferation and survival were compared in the dHi and vHi. Lithium preferentially increased cell proliferation in the vHi under stress conditions only. This increase in cell proliferation was secondary to reductions in the survival of newly-born cells. Moreover, lithium-induced decreases in cell survival in the vHi were only observed under stress conditions. Taken together, the data suggest that the turnover of newly-born cells in response to chronic stress and lithium treatment occurs predominantly in the vHi rather than the dHi. This article is part of a Special Issue entitled 'Anxiety and Depression'.

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

    PubMed

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

    2012-06-01

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

  5. ADAM8 is selectively upregulated in endothelial cells and is associated with angiogenesis after spinal cord injury in adult mice

    PubMed Central

    Mahoney, Edward T.; Benton, Richard L.; Maddie, Melissa A.; Whittemore, Scott R.; Hagg, Theo

    2009-01-01

    Endothelial cell (EC) loss and subsequent angiogenesis occurs over the first week after spinal cord injury (SCI). To identify molecular mechanisms that could be targeted with intravenous (i.v.) treatments we determined whether transmembrane A Disintegrin And Metalloprotease (ADAM) proteins are expressed in ECs of the injured spinal cord. ADAMs bind to integrins which are important for EC survival and angiogenesis. Female adult C57Bl/6 mice with a spinal cord contusion had progressively more ADAM8 (CD156) immunostaining in blood vessels and individual ECs between 1 and 28 days following injury. Uninjured spinal cords had little ADAM8 staining. The increase in ADAM8 mRNA and protein was confirmed in spinal cord lysates, and ADAM8 mRNA was present in FACS-enriched ECs. ADAM8 co-localized extensively and exclusively with the EC marker PECAM and also with i.v. injected lectins. I.v. injected isolectin B4 (IB4) labels a subpopulation of blood vessels at and within the injury epicenter 3-7 days after injury, coincident with angiogenesis. Both ADAM8 and the proliferation marker Ki-67 were present in IB4-positive microvessels. ADAM8-positive proliferating cells were seen at the leading end of IB4-positive blood vessels. Angiogenesis was confirmed by BrdU incorporation, binding of i.v. injected nucleolin antibodies, and MT1-MMP immunostaining in a subset of blood vessels. These data suggest that ADAM8 is vascular-selective and plays a role in proliferation and/or migration of ECs during angiogenesis following SCI. PMID:19003792

  6. STEMS pilot trial: a pilot cluster randomised controlled trial to investigate the addition of patient direct access to physiotherapy to usual GP-led primary care for adults with musculoskeletal pain

    PubMed Central

    Ogollah, Reuben O; Jowett, Sue; Kigozi, Jesse; Tooth, Stephanie; Protheroe, Joanne; Hay, Elaine M; Salisbury, Chris; Foster, Nadine E

    2017-01-01

    Introduction Around 17% of general practitioner (GP) consultations are for musculoskeletal conditions, which will rise as the population ages. Patient direct access to physiotherapy provides one solution, yet adoption in the National Health Service (NHS) has been slow. Setting A pilot, pragmatic, non-inferiority, cluster randomised controlled trial (RCT) in general practice and physiotherapy services in the UK. Objectives Investigate feasibility of a main RCT. Participants Adult patients registered in participating practices and consulting with a musculoskeletal problem. Interventions 4 general practices (clusters) randomised to provide GP-led care as usual or the addition of a patient direct access to physiotherapy pathway. Outcomes Process outcomes and exploratory analyses of clinical and cost outcomes. Data collection Participant-level data were collected via questionnaires at identification, 2, 6 and 12 months and through medical records. Blinding The study statistician and research nurses were blinded to practice allocation. Results Of 2696 patients invited to complete study questionnaires, 978 participated (intervention group n=425, control arm n=553) and were analysed. Participant recruitment was completed in 6 months. Follow-up rates were 78% (6 months) and 71% (12 months). No evidence of selection bias was observed. The direct access pathway was used by 90% of patients in intervention practices needing physiotherapy. Some increase in referrals to physiotherapy occurred from one practice, although waiting times for physiotherapy did not increase (28 days before, 26 days after introduction of direct access). No safety issues were identified. Clinical and cost outcomes were similar in both groups. Exploratory estimates of between group effect (using 36-item Short Form Health Survey (SF-36) Physical Component Summary (PCS)) at 6 months was −0.28 (95% CI −1.35 to 0.79) and at 12 months 0.12 (95% CI −1.27 to 1.51). Conclusions A full RCT is

  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. 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

  9. Dual-color STED microscopy reveals a sandwich structure of Bassoon and Piccolo in active zones of adult and aged mice

    PubMed Central

    Nishimune, Hiroshi; Badawi, Yomna; Mori, Shuuichi; Shigemoto, Kazuhiro

    2016-01-01

    Presynaptic active zones play a pivotal role as synaptic vesicle release sites for synaptic transmission, but the molecular architecture of active zones in mammalian neuromuscular junctions (NMJs) at sub-diffraction limited resolution remains unknown. Bassoon and Piccolo are active zone specific cytosolic proteins essential for active zone assembly in NMJs, ribbon synapses, and brain synapses. These proteins are thought to colocalize and share some functions at active zones. Here, we report an unexpected finding of non-overlapping localization of these two proteins in mouse NMJs revealed using dual-color stimulated emission depletion (STED) super resolution microscopy. Piccolo puncta sandwiched Bassoon puncta and aligned in a Piccolo-Bassoon-Piccolo structure in adult NMJs. P/Q-type voltage-gated calcium channel (VGCC) puncta colocalized with Bassoon puncta. The P/Q-type VGCC and Bassoon protein levels decreased significantly in NMJs from aged mouse. In contrast, the Piccolo levels in NMJs from aged mice were comparable to levels in adult mice. This study revealed the molecular architecture of active zones in mouse NMJs at sub-diffraction limited resolution, and described the selective degeneration mechanism of active zone proteins in NMJs from aged mice. Interestingly, the localization pattern of active zone proteins described herein is similar to active zone structures described using electron microscope tomography. PMID:27321892

  10. Schizophrenia-like phenotypes in mice with NMDA receptor ablation in intralaminar thalamic nucleus cells and gene therapy-based reversal in adults.

    PubMed

    Yasuda, K; Hayashi, Y; Yoshida, T; Kashiwagi, M; Nakagawa, N; Michikawa, T; Tanaka, M; Ando, R; Huang, A; Hosoya, T; McHugh, T J; Kuwahara, M; Itohara, S

    2017-02-28

    In understanding the mechanism of schizophrenia pathogenesis, a significant finding is that drug abuse of phencyclidine or its analog ketamine causes symptoms similar to schizophrenia. Such drug effects are triggered even by administration at post-adolescent stages. Both drugs are N-methyl-d-aspartate receptor (NMDAR) antagonists, leading to a major hypothesis that glutamate hypofunction underlies schizophrenia pathogenesis. The precise region that depends on NMDAR function, however, is unclear. Here, we developed a mouse strain in which NMDARs in the intralaminar thalamic nuclei (ILN) were selectively disrupted. The mutant mice exhibited various schizophrenia-like phenotypes, including deficits in working memory, long-term spatial memory, and attention, as well as impulsivity, impaired prepulse inhibition, hyperlocomotion and hyperarousal. The electroencephalography analysis revealed that the mutant mice had a significantly reduced power in a wide range of frequencies including the alpha, beta and gamma bands, both during wake and rapid eye movement (REM) sleep, and a modest decrease of gamma power during non-REM sleep. Notably, restoring NMDARs in the adult ILN rescued some of the behavioral abnormalities. These findings suggest that NMDAR dysfunction in the ILN contributes to the pathophysiology of schizophrenia-related disorders. Furthermore, the reversal of inherent schizophrenia-like phenotypes in the adult mutant mice supports that ILN is a potential target site for a therapeutic strategy.

  11. 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

  12. 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.

  13. Relative Contributions of CYP1A2 and CYP2E1 to the Bioactivation and Clearance of 4-Aminobiphenyl in Adult Mice.

    PubMed

    Wang, Shuang; Bott, Debbie; Tung, Aveline; Sugamori, Kim S; Grant, Denis M

    2015-07-01

    4-Aminobiphenyl (ABP), a prototypical aromatic amine carcinogen in rodents and humans, requires bioactivation to manifest its toxic effects. A traditional model of ABP bioactivation, based on in vitro enzyme kinetic evidence, had postulated initial N-hydroxylation by the cytochrome P450 isoform CYP1A2. This is followed by phase 2 O-conjugation and hydrolysis to form a reactive nitrenium ion that covalently binds to DNA and produces tumor-initiating mutations. However, Cyp1a2(-/-) mice still possess significant liver ABP N-hydroxylation activity, DNA damage, and incidence of ABP-induced liver tumors, and in vivo induction of CYP1A2 paradoxically reduces levels of ABP-induced DNA damage. Competing ABP detoxification pathways can include N-acetylation by arylamine N-acetyltransferase 1 (NAT1) and/or NAT2; however, wild-type and Nat1/2(-/-) mice have similar in vivo ABP clearance rates. Together, these studies suggest the existence of novel ABP bioactivating and clearance/detoxification enzymes. In the present study, we detected similar reductions in Vmax for ABP N-hydroxylation by liver microsomes from Cyp1a2(-/-) and Cyp2e1(-/-) mice when compared with wild-type mice. In addition, recombinant mouse CYP1A2 and CYP2E1 were both able to N-hydroxylate ABP in mouse hepatoma cells. However, the in vivo clearance of ABP was significantly reduced in Cyp1a2(-/-) but not in Cyp2e1(-/-) mice. Our results support a significant role for CYP2E1 as a novel ABP N-oxidizing enzyme in adult mice, and suggest a more important contribution of CYP1A2 to the in vivo plasma clearance and thus detoxification of ABP.

  14. Combination of fluoxetine and extinction treatments forms a unique synaptic protein profile that correlates with long-term fear reduction in adult mice.

    PubMed

    Popova, Dina; Ágústsdóttir, Arna; Lindholm, Jesse; Mazulis, Ulams; Akamine, Yumiko; Castrén, Eero; Karpova, Nina N

    2014-07-01

    The antidepressant fluoxetine induces synaptic plasticity in the visual and fear networks and promotes the structural remodeling of neuronal circuits, which is critical for experience-dependent plasticity in response to an environmental stimulus. We recently demonstrated that chronic fluoxetine administration together with extinction training in adult mice reduced fear in a context-independent manner. Fear conditioning and extinction alter excitatory and inhibitory transmissions within the fear circuitry. In this study, we investigated whether fluoxetine, extinction or their combination produced distinct long-lasting changes in the synaptic protein profile in the amygdala, hippocampus and prefrontal cortex of conditioned mice. We determined that extinction induced synaptophysin expression and down-regulated the GluA1:GluA2 ratio throughout the fear network in water- and fluoxetine-treated mice, suggesting a common fluoxetine-independent mechanism for increased synaptic transmission and re-arrangement of AMPA-receptors by extinction training. In contrast to common changes, the presynaptic vesicular neurotransmitter transporters VGAT and Vglut1 were upregulated after extinction in water- and fluoxetine-treated mice, respectively. The cortical levels of the GABA transporter Gat1 were reduced in high-freezing water-drinking mice, suggesting a maladaptive increase of GABA spillover at cortical inhibitory synapses. Fear conditioning decreased, and extinction induced the expression of GABA-receptor alpha1 and alpha2 subunits in water- and fluoxetine-treated mice, respectively. Only a combination of fluoxetine with extinction enhanced GluN2A expression in the amygdala and hippocampus, emphasizing the role of this NMDA-receptor subunit in the successful erasure of fear memories. Our finding provides novel data that may become helpful in developing beneficial pharmacological fear-reducing treatment strategies.

  15. A Single Mutation in the VP1 of Enterovirus 71 Is Responsible for Increased Virulence and Neurotropism in Adult Interferon-Deficient Mice

    PubMed Central

    Caine, Elizabeth A.; Moncla, Louise H.; Ronderos, Monica D.; Friedrich, Thomas C.

    2016-01-01

    ABSTRACT Hand, foot, and mouth disease (HFMD) has spread throughout the Asia-Pacific region, affecting millions of young children, who develop symptoms ranging from painful blisters around their mouths and hands to neurological complications. Many members of the genus Enterovirus (family Picornaviridae) cause HFMD. Enterovirus 71 (EV71) is one of the primary causative agents and has been linked to severe disease. Vaccine efficacy and pathogenesis studies for EV71 have been limited because there is a lack of suitable animal models. Previously, we generated a mouse-adapted EV71 (mEV71) capable of infecting 12-week-old interferon receptor-deficient AG129 mice and used the model to evaluate the efficacy of candidate HFMD vaccines. Here, we present data investigating the genetic correlates of EV71 adaptation and characterize the virus's tissue tropism in mice. Using reverse genetics, a VP1 mutation (K244E) was shown to be necessary for mEV71 virulence in adult mice. Another VP1 mutation (H37R) was required for mEV71 recovery on rhabdomyosarcoma (RD) cells. Viral loads determined by real-time reverse transcription (RT)-PCR confirmed the presence of mEV71 in the sera and multiple organs of mice. Histological analysis revealed signs of meningitis and encephalitis, characteristic of severe human disease. The further description of this model has provided insight into EV71 pathogenesis and demonstrates the importance of the VP1 region in facilitating mEV71 adaptation. IMPORTANCE EV71 is a reemerging pathogen, and little is known about the genetic determinants involved in its pathogenesis. The absence of animal models has contributed to this lack of knowledge. The data presented here improve upon the existing animal models by characterizing a mouse-adapted strain of EV71. We determined that a VP1 mutation (K244E) was needed for EV71 virulence in adult AG129 mice. While this mutation was found previously for EV71 adaptation in 5-day-old BALB/c mice, neurotropic disease did not

  16. Administration of saccharin to neonatal mice influences body composition of adult males and reduces body weight of females.

    PubMed

    Parlee, Sebastian D; Simon, Becky R; Scheller, Erica L; Alejandro, Emilyn U; Learman, Brian S; Krishnan, Venkatesh; Bernal-Mizrachi, Ernesto; MacDougald, Ormond A

    2014-04-01

    Nutritional or pharmacological perturbations during perinatal growth can cause persistent effects on the function of white adipose tissue, altering susceptibility to obesity later in life. Previous studies have established that saccharin, a nonnutritive sweetener, inhibits lipolysis in mature adipocytes and stimulates adipogenesis. Thus, the current study tested whether neonatal exposure to saccharin via maternal lactation increased susceptibility of mice to diet-induced obesity. Saccharin decreased body weight of female mice beginning postnatal week 3. Decreased liver weights on week 14 corroborated this diminished body weight. Initially, saccharin also reduced male mouse body weight. By week 5, weights transiently rebounded above controls, and by week 14, male body weights did not differ. Body composition analysis revealed that saccharin increased lean and decreased fat mass of male mice, the latter due to decreased adipocyte size and epididymal, perirenal, and sc adipose weights. A mild improvement in glucose tolerance without a change in insulin sensitivity or secretion aligned with this leaner phenotype. Interestingly, microcomputed tomography analysis indicated that saccharin also increased cortical and trabecular bone mass of male mice and modified cortical bone alone in female mice. A modest increase in circulating testosterone may contribute to the leaner phenotype in male mice. Accordingly, the current study established a developmental period in which saccharin at high concentrations reduces adiposity and increases lean and bone mass in male mice while decreasing generalized growth in female mice.

  17. Administration of Saccharin to Neonatal Mice Influences Body Composition of Adult Males and Reduces Body Weight of Females

    PubMed Central

    Parlee, Sebastian D.; Simon, Becky R.; Scheller, Erica L.; Alejandro, Emilyn U.; Learman, Brian S.; Krishnan, Venkatesh; Bernal-Mizrachi, Ernesto

    2014-01-01

    Nutritional or pharmacological perturbations during perinatal growth can cause persistent effects on the function of white adipose tissue, altering susceptibility to obesity later in life. Previous studies have established that saccharin, a nonnutritive sweetener, inhibits lipolysis in mature adipocytes and stimulates adipogenesis. Thus, the current study tested whether neonatal exposure to saccharin via maternal lactation increased susceptibility of mice to diet-induced obesity. Saccharin decreased body weight of female mice beginning postnatal week 3. Decreased liver weights on week 14 corroborated this diminished body weight. Initially, saccharin also reduced male mouse body weight. By week 5, weights transiently rebounded above controls, and by week 14, male body weights did not differ. Body composition analysis revealed that saccharin increased lean and decreased fat mass of male mice, the latter due to decreased adipocyte size and epididymal, perirenal, and sc adipose weights. A mild improvement in glucose tolerance without a change in insulin sensitivity or secretion aligned with this leaner phenotype. Interestingly, microcomputed tomography analysis indicated that saccharin also increased cortical and trabecular bone mass of male mice and modified cortical bone alone in female mice. A modest increase in circulating testosterone may contribute to the leaner phenotype in male mice. Accordingly, the current study established a developmental period in which saccharin at high concentrations reduces adiposity and increases lean and bone mass in male mice while decreasing generalized growth in female mice. PMID:24456165

  18. Long-term consumption of sugar-sweetened beverage during the growth period promotes social aggression in adult mice with proinflammatory responses in the brain.

    PubMed

    Choi, Jung-Yun; Park, Mi-Na; Kim, Chong-Su; Lee, Young-Kwan; Choi, Eun Young; Chun, Woo Young; Shin, Dong-Mi

    2017-04-10

    Overconsumption of sugar-sweetened beverages (SSBs) is known to be a key contributor to the obesity epidemic; however, its effects on behavioral changes are yet to be fully studied. In the present study, we examined the long-term effects of SSB on social aggression in mice. Three-week-old weaned mice started to drink either a 30 w/v% sucrose solution (S30), plain water (CT), or an aspartame solution with sweetness equivalent to the sucrose solution (A30) and continued to drink until they were 11-week-old adults. Aggressive behaviors were assessed by the resident-intruder test. We found that SSB significantly promoted social aggression, accompanied by heightened serum corticosterone and reduced body weight. To understand the underlying mechanism, we performed transcriptome analyses of brain. The profiles of mice on S30 were dramatically different from those on CT or A30. Transcriptional networks related to immunological function were significantly dysregulated by SSB. FACS analysis of mice on S30 revealed increased numbers of inflammatory cells in peripheral blood. Interestingly, the artificial sweetener failed to mimic the effects of sugar on social aggression and inflammatory responses. These results demonstrate that SSB promotes aggressive behaviors and provide evidence that sugar reduction strategies may be useful in efforts to prevent social aggression.

  19. 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.

  20. 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.

  1. Long-term consumption of sugar-sweetened beverage during the growth period promotes social aggression in adult mice with proinflammatory responses in the brain

    PubMed Central

    Choi, Jung-Yun; Park, Mi-Na; Kim, Chong-Su; Lee, Young-Kwan; Choi, Eun Young; Chun, Woo Young; Shin, Dong-Mi

    2017-01-01

    Overconsumption of sugar-sweetened beverages (SSBs) is known to be a key contributor to the obesity epidemic; however, its effects on behavioral changes are yet to be fully studied. In the present study, we examined the long-term effects of SSB on social aggression in mice. Three-week-old weaned mice started to drink either a 30 w/v% sucrose solution (S30), plain water (CT), or an aspartame solution with sweetness equivalent to the sucrose solution (A30) and continued to drink until they were 11-week-old adults. Aggressive beha