Western diet increases wheel running in mice selectively bred for high voluntary wheel running.

Science.gov (United States)

Meek, T H; Eisenmann, J C; Garland, T

2010-06-01

Mice from a long-term selective breeding experiment for high voluntary wheel running offer a unique model to examine the contributions of genetic and environmental factors in determining the aspects of behavior and metabolism relevant to body-weight regulation and obesity. Starting with generation 16 and continuing through to generation 52, mice from the four replicate high runner (HR) lines have run 2.5-3-fold more revolutions per day as compared with four non-selected control (C) lines, but the nature of this apparent selection limit is not understood. We hypothesized that it might involve the availability of dietary lipids. Wheel running, food consumption (Teklad Rodent Diet (W) 8604, 14% kJ from fat; or Harlan Teklad TD.88137 Western Diet (WD), 42% kJ from fat) and body mass were measured over 1-2-week intervals in 100 males for 2 months starting 3 days after weaning. WD was obesogenic for both HR and C, significantly increasing both body mass and retroperitoneal fat pad mass, the latter even when controlling statistically for wheel-running distance and caloric intake. The HR mice had significantly less fat than C mice, explainable statistically by their greater running distance. On adjusting for body mass, HR mice showed higher caloric intake than C mice, also explainable by their higher running. Accounting for body mass and running, WD initially caused increased caloric intake in both HR and C, but this effect was reversed during the last four weeks of the study. Western diet had little or no effect on wheel running in C mice, but increased revolutions per day by as much as 75% in HR mice, mainly through increased time spent running. The remarkable stimulation of wheel running by WD in HR mice may involve fuel usage during prolonged endurance exercise and/or direct behavioral effects on motivation. Their unique behavioral responses to WD may render HR mice an important model for understanding the control of voluntary activity levels.

Selectively bred crossed high-alcohol-preferring mice drink to intoxication and develop functional tolerance, but not locomotor sensitization during free-choice ethanol access.

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Matson, Liana M; Kasten, Chelsea R; Boehm, Stephen L; Grahame, Nicholas J

2014-01-01

Crossed high-alcohol-preferring (cHAP) mice were selectively bred from a cross of the HAP1 × HAP2 replicate lines and demonstrate blood ethanol concentrations (BECs) during free-choice drinking reminiscent of those observed in alcohol-dependent humans. In this report, we investigated the relationship between free-choice drinking, intoxication, tolerance, and sensitization in cHAP mice. We hypothesized that initially mice would become ataxic after drinking alcohol, but that increased drinking over days would be accompanied by increasing tolerance to the ataxic effects of ethanol (EtOH). Male and female cHAP mice had free-choice access to 10% EtOH and water (E), while Water mice (W) had access to water alone. In experiment 1, the first drinking experience was monitored during the dark portion of the cycle. Once E mice reached an average intake rate of ≥1.5 g/kg/h, they, along with W mice, were tested for footslips on a balance beam, and BECs were assessed. In experiments 2, 3, and 4, after varying durations of free-choice 10% EtOH access (0, 3, 14, or 21 days), mice were challenged with 20% EtOH and tested for number of footslips on a balance beam or locomotor stimulant response. Blood was sampled for BEC determination. We found that cHAP mice rapidly acquire alcohol intakes that lead to ataxia. Over time, cHAP mice developed behavioral tolerance to the ataxic effects of alcohol, paralleled by escalating alcohol consumption. However, locomotor sensitization did not develop following 14 days of free-choice EtOH access. Overall, we observed increases in free-choice drinking with extended alcohol access paralleled by increases in functional tolerance, but not locomotor sensitization. These data support our hypothesis that escalating free-choice drinking over days in cHAP mice is driven by tolerance to alcohol's behavioral effects. These data are the first to demonstrate that escalating free-choice consumption is accompanied by increasing alcohol tolerance. In

Gamma radiation-induced heritable mutations at repetitive DNA loci in out-bred mice

International Nuclear Information System (INIS)

Somers, C.M.; Sharma, R.; Quinn, J.S.; Boreham, D.R.

2004-01-01

Recent studies have shown that expanded-simple-tandem-repeat (ESTR) DNA loci are efficient genetic markers for detecting radiation-induced germ line mutations in mice. Dose responses following irradiation, however, have only been characterized in a small number of inbred mouse strains, and no studies have applied Esters to examine potential modifiers of radiation risk, such as adaptive response. We gamma-irradiated groups of male out-bred Swiss-Webster mice with single acute doses of 0.5 and 1.0 Gy, and compared germ line mutation rates at ESTR loci to a sham-irradiated control. To test for evidence of adaptive response we treated a third group with a total dose of 1.1 Gy that was fractionated into a 0.1 Gy adapting dose, followed by a challenge dose of 1.0 Gy 24 h later. Paternal mutation rates were significantly elevated above the control in the 0.5 Gy (2.8-fold) and 1.0 Gy (3.0-fold) groups, but were similar to each other despite the difference in radiation dose. The doubling dose for paternal mutation induction was 0.26 Gy (95% CI = 0.14-0.51 Gy). Males adapted with a 0.1 Gy dose prior to a 1.0 Gy challenge dose had mutation rates that were not significantly elevated above the control, and were 43% reduced compared to those receiving single doses. We conclude that pre-meiotic male germ cells in out-bred Swiss-Webster mice are sensitive to ESTR mutations induced by acute doses of ionizing radiation, but mutation induction may become saturated at a lower dose than in some strains of inbred mice. Reduced mutation rates in the adapted group provide intriguing evidence for suppression of ESTR mutations in the male germline through adaptive response. Repetitive DNA markers may be useful tools for exploration of biological factors affecting the probability of heritable mutations caused by low-dose ionizing radiation exposure. The biological significance of ESTR mutations in terms of radiation risk assessment, however, is still undetermined

Selection for increased voluntary wheel-running affects behavior and brain monoamines in mice

Science.gov (United States)

Waters, R.Parrish; Pringle, R.B.; Forster, G.L.; Renner, K.J.; Malisch, J.L.; Garland, T.; Swallow, J.G.

2013-01-01

Selective-breeding of house mice for increased voluntary wheel-running has resulted in multiple physiological and behavioral changes. Characterizing these differences may lead to experimental models that can elucidate factors involved in human diseases and disorders associated with physical inactivity, or potentially treated by physical activity, such as diabetes, obesity, and depression. Herein, we present ethological data for adult males from a line of mice that has been selectively bred for high levels of voluntary wheel-running and from a non-selected control line, housed with or without wheels. Additionally, we present concentrations of central monoamines in limbic, striatal, and midbrain regions. We monitored wheel-running for 8 weeks, and observed home-cage behavior during the last 5 weeks of the study. Mice from the selected line accumulated more revolutions per day than controls due to increased speed and duration of running. Selected mice exhibited more active behaviors than controls, regardless of wheel access, and exhibited less inactivity and grooming than controls. Selective-breeding also influenced the longitudinal patterns of behavior. We found statistically significant differences in monoamine concentrations and associated metabolites in brain regions that influence exercise and motivational state. These results suggest underlying neurochemical differences between selected and control lines that may influence the observed differences in behavior. Our results bolster the argument that selected mice can provide a useful model of human psychological and physiological diseases and disorders. PMID:23352668

Effects of size, sex, and voluntary running speeds on costs of locomotion in lines of laboratory mice selectively bred for high wheel-running activity.

Science.gov (United States)

Rezende, Enrico L; Kelly, Scott A; Gomes, Fernando R; Chappell, Mark A; Garland, Theodore

2006-01-01

Selective breeding for over 35 generations has led to four replicate (S) lines of laboratory house mice (Mus domesticus) that run voluntarily on wheels about 170% more than four random-bred control (C) lines. We tested whether S lines have evolved higher running performance by increasing running economy (i.e., decreasing energy spent per unit of distance) as a correlated response to selection, using a recently developed method that allows for nearly continuous measurements of oxygen consumption (VO2) and running speed in freely behaving animals. We estimated slope (incremental cost of transport [COT]) and intercept for regressions of power (the dependent variable, VO2/min) on speed for 49 males and 47 females, as well as their maximum VO2 and speeds during wheel running, under conditions mimicking those that these lines face during the selection protocol. For comparison, we also measured COT and maximum aerobic capacity (VO2max) during forced exercise on a motorized treadmill. As in previous studies, the increased wheel running of S lines was mainly attributable to increased average speed, with males also showing a tendency for increased time spent running. On a whole-animal basis, combined analysis of males and females indicated that COT during voluntary wheel running was significantly lower in the S lines (one-tailed P=0.015). However, mice from S lines are significantly smaller and attain higher maximum speeds on the wheels; with either body mass or maximum speed (or both) entered as a covariate, the statistical significance of the difference in COT is lost (one-tailed P> or =0.2). Thus, both body size and behavior are key components of the reduction in COT. Several statistically significant sex differences were observed, including lower COT and higher resting metabolic rate in females. In addition, maximum voluntary running speeds were negatively correlated with COT in females but not in males. Moreover, males (but not females) from the S lines exhibited

Mice divergently selected for high and low basal metabolic rates evolved different cell size and organ mass.

Science.gov (United States)

Maciak, S; Bonda-Ostaszewska, E; Czarnołęski, M; Konarzewski, M; Kozłowski, J

2014-03-01

Evolution of metabolic rates of multicellular organisms is hypothesized to reflect the evolution of their cell architecture. This is likely to stem from a tight link between the sizes of cells and nuclei, which are expected to be inversely related to cell metabolism. Here, we analysed basal metabolic rate (BMR), internal organ masses and the cell/nucleus size in different tissues of laboratory mice divergently selected for high/low mass-corrected BMR and four random-bred mouse lines. Random-bred lines had intermediate levels of BMR as compared to low- and high-BMR lines. Yet, this pattern was only partly consistent with the between-line differences in cell/nucleus sizes. Erythrocytes and skin epithelium cells were smaller in the high-BMR line than in other lines, but the cells of low-BMR and random-bred mice were similar in size. On the other hand, the size of hepatocytes, kidney proximal tubule cells and duodenum enterocytes were larger in high-BMR mice than other lines. All cell and nucleus sizes were positively correlated, which supports the role of the nucleus in cell size regulation. Our results suggest that the evolution of high BMR involves a reduction in cell size in specialized tissues, whose functions are primarily dictated by surface-to-volume ratios, such as erythrocytes. High BMR may, however, also incur an increase in cell size in tissues with an intense transcription and translation, such as hepatocytes. © 2014 The Authors. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

Twenty-three generations of mice bidirectionally selected for open-field thigmotaxis: selection response and repeated exposure to the open field.

Science.gov (United States)

Leppänen, Pia K; Ravaja, N; Ewalds-Kvist, S B M

2006-03-01

We examined: (a) the response to bidirectional selection for open-field (OF) thigmotaxis in mice for 23 generations and (b) the effects of repeated exposure (during 5 days) on different OF behaviors in the selectively bred high OF thigmotaxis (HOFT) and low OF thigmotaxis (LOFT) mice. A total of 2049 mice were used in the study. Prior to the testing in the selection experiment, the mice were exposed to the OF apparatus for approximately 2 min on each of 4 consecutive days. Thus, the selection was based on the scores registered on the 5th day after the four habituation periods. The HOFT mice were more thigmotactic than the LOFT mice in almost each generation. The HOFT mice also tended to rear less than the LOFT mice, which was explained by the inverse relationship between emotionality and exploratory tendencies. The lines did not generally differ in ambulation. Sex differences were found in thigmotaxis, ambulation, and rearing. In the repeated exposure experiment, the development of nine different OF behaviors across the 5 days of testing was addressed. Both lines ambulated, explored, and reared most on the 1st, 4th, and 5th days. Grooming and radial latency decreased and thigmotaxis increased linearly across the testing days. Line differences were found in ambulation, exploration, grooming, and rearing, while sex differences were manifested in ambulation and exploration. The line difference in thigmotaxis was evident only on the 5th day. Temporal changes were partially at variance with the general assumptions. OF thigmotaxis was found to be a powerful characteristic for producing two diverging lines of mice.

Are voluntary wheel running and open-field behavior correlated in mice? Different answers from comparative and artificial selection approaches.

Science.gov (United States)

Careau, Vincent; Bininda-Emonds, Olaf R P; Ordonez, Genesis; Garland, Theodore

2012-09-01

Voluntary wheel running and open-field behavior are probably the two most widely used measures of locomotion in laboratory rodents. We tested whether these two behaviors are correlated in mice using two approaches: the phylogenetic comparative method using inbred strains of mice and an ongoing artificial selection experiment on voluntary wheel running. After taking into account the measurement error and phylogenetic relationships among inbred strains, we obtained a significant positive correlation between distance run on wheels and distance moved in the open-field for both sexes. Thigmotaxis was negatively correlated with distance run on wheels in females but not in males. By contrast, mice from four replicate lines bred for high wheel running did not differ in either distance covered or thigmotaxis in the open field as compared with mice from four non-selected control lines. Overall, results obtained in the selection experiment were generally opposite to those observed among inbred strains. Possible reasons for this discrepancy are discussed.

Myosin heavy chain isoform expression in adult and juvenile mini-muscle mice bred for high-voluntary wheel running.

Science.gov (United States)

Talmadge, Robert J; Acosta, Wendy; Garland, Theodore

2014-11-01

The myosin heavy chain (MyHC) isoform composition of locomotor and non-locomotor muscles of mini-muscle mice were assessed at the protein and mRNA levels in both adult and juvenile (21 day old) mice. Mini-muscle mice are one outcome of a replicated artificial selection experiment in which four lines of mice were bred for high voluntary wheel running (HR lines). Two of the lines responded with an increase in frequency of a single nucleotide polymorphism in an intron in the MyHC-2b gene (myh4) that when homozygous causes a dramatic reduction in triceps surae mass. We found that both locomotor and non-locomotor muscles of adult mini-muscle mice displayed robust reductions, but not elimination, of the MyHC-2b isoform at both the protein and mRNA levels, with commensurate increases in MyHC-2x and sometimes MyHC-2a, as compared with either a line of HR mice that does not display the mini-muscle phenotype or inbred C57Bl6 mice. Immunohistochemical analyses revealed that locomotor muscles of mini-muscle mice contain fibers that express the MyHC-2b isoform, which migrates normally in SDS-PAGE gels. However, these MyHC-2b positive fibers are generally smaller than the surrounding fibers and smaller than the MyHC-2b positive fibers of non-mini-muscle mice, resulting in characteristically fast muscles that lack a substantial MyHC-2b positive (superficial) region. In contrast, the masseter, a non-locomotor muscle of mini-muscle mice contained MyHC-2b positive fibers that stained more lightly for MyHC-2b, but appeared normal in size and distribution. In adults, many of the MyHC-2b positive fibers in the mini-muscle mice also display central nuclei. Only a small proportion of small MyHC-2b fibers in mini-muscle mice stained positive for the neural cell adhesion molecule, suggesting that anatomical innervation was not compromised. In addition, weanling (21 day old), but not 5 day old mice, displayed alterations in MyHC isoform content at both the protein and mRNA levels, including

Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running.

Science.gov (United States)

Johnson, R A; Rhodes, J S; Jeffrey, S L; Garland, T; Mitchell, G S

2003-01-01

Voluntary wheel running in rats increases hippocampal brain-derived neurotrophic factor (BDNF) expression, a neurochemical important for neuronal survival, differentiation, connectivity and synaptic plasticity. Here, we report the effects of wheel running on BDNF and neurotrophin-3 (NT-3) protein levels in normal control mice, and in mice selectively bred (25 generations) for increased voluntary wheel running. We hypothesized that increased voluntary wheel running in selected (S) mice would increase CNS BDNF and NT-3 protein levels more than in control (C) mice. Baseline hippocampal BDNF levels (mice housed without running wheels) were similar in S and C mice. Following seven nights of running, hippocampal BDNF increased significantly more in S versus C mice, and levels were correlated with distance run (considering C and S mice together). Spinal and cerebellar BDNF and hippocampal NT-3 levels were not significantly affected by wheel running in any group, but there was a small, positive correlation between spinal C3-C6 BDNF levels and distance run (considering C and S mice together). This is the first study to demonstrate that mice which choose to run more have greater elevations in hippocampal BDNF, suggesting enhanced potential for exercise-induced hippocampal neuroplasticity.

Responses to cholinergic agonists of rats selectively bred for differential sensitivity to ethanol.

Science.gov (United States)

de Fiebre, C M; Romm, E; Collins, J T; Draski, L J; Deitrich, R A; Collins, A C

1991-03-01

Alcoholics are almost invariably heavy users of tobacco. Both alcoholism and smoking appear to be influenced by genetic factors but it is not known whether the same or different genes regulate the abuse of ethanol and nicotine. Recent studies have demonstrated that the long-sleep (LS) and short-sleep (SS) mouse lines, which were selectively bred for differences in ethanol-induced anesthesia ("sleep-time"), also differ in several effects of nicotine and the muscarinic agonist, oxotremorine. In order to determine whether or not these differences are due to chance, the relative sensitivities of rat lines which were selectively bred for differences in ethanol-induced sleep-time were determined. The high alcohol sensitivity (HAS) rat line was more sensitive to the locomotor and body temperature depressant effects of nicotine than was the low alcohol sensitivity (LAS) rat line. The control line (CAS) was intermediate in sensitivity. The rat lines did not differ in sensitivity to oxotremorine's hypothermia-producing effects. The numbers and affinities of two classes of brain nicotinic receptors were measured in eight brain regions. No differences among the rat lines were detected. These results suggest that ethanol elicits some of its depressant actions via an effect on brain nicotinic systems, but the differences in sensitivity to ethanol and nicotine are probably not due to differences in the number of brain nicotinic receptors. Perhaps this interaction explains the high correlation between alcoholism and smoking in humans.

Co-segregation of hyperactivity, active coping styles, and cognitive dysfunction in mice selectively bred for low levels of anxiety

OpenAIRE

Yen, Yi-Chun; Anderzhanova, Elmira; Bunck, Mirjam; Schuller, Julia; Landgraf, Rainer; Wotjak, Carsten T.

2013-01-01

We established mouse models of extremes in trait anxiety, which are based on selective breeding for low vs. normal vs. high open-arm exploration on the elevated plus-maze. Genetically selected low anxiety-related behavior (LAB) coincided with hyperactivity in the home cage. Given the fact that several psychiatric disorders such as schizophrenia, mania, and attention deficit hyperactivity disorder (ADHD) share hyperactivity symptom, we systematically examined LAB mice with respect to unique an...

Effects of early-life exposure to Western diet and wheel access on metabolic syndrome profiles in mice bred for high voluntary exercise.

Science.gov (United States)

Meek, T H; Eisenmann, J C; Keeney, B K; Hannon, R M; Dlugosz, E M; Garland, T

2014-03-01

Experimental studies manipulating diet and exercise have shown varying effects on metabolic syndrome components in both humans and rodents. To examine the potential interactive effects of diet, exercise and genetic background, we studied mice from four replicate lines bred (52 generations) for high voluntary wheel running (HR lines) and four unselected control lines (C). At weaning, animals were housed for 60 days with or without wheels and fed either a standard chow or Western diet (WD, 42% kcal from fat). Four serial (three juvenile and one adult) blood samples were taken to measure fasting total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides and glucose. Western diet was obesogenic for all mice, even after accounting for the amount of wheel running and kilojoules consumed. Western diet significantly raised glucose as well as TC and HDL-C concentrations. At the level of individual variation (repeatability), there was a modest correlation (r = 0.3-0.5) of blood lipids over time, which was reduced with wheel access and/or WD. Neither genetic selection history nor wheel access had a statistically significant effect on blood lipids. However, HR and C mice had divergent ontogenetic trajectories for body mass and caloric intake. HR mice also had lower adiposity, an effect that was dependent on wheel access. The environmental factors of diet and wheel access had pronounced effects on body mass, food consumption and fasting glucose concentrations, interacting with each other and/or with genetic strain. These data underscore the importance (and often unpredictable nature) of genotype-by-environment and environment-by-environment interactions when studying body weight regulation. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Selective Breeding and Short-Term Access to a Running Wheel Alter Stride Characteristics in House Mice.

Science.gov (United States)

Claghorn, Gerald C; Thompson, Zoe; Kay, Jarren C; Ordonez, Genesis; Hampton, Thomas G; Garland, Theodore

Postural and kinematic aspects of running may have evolved to support high runner (HR) mice to run approximately threefold farther than control mice. Mice from four replicate HR lines selectively bred for high levels of voluntary wheel running show many differences in locomotor behavior and morphology as compared with four nonselected control (C) lines. We hypothesized that HR mice would show stride alterations that have coadapted with locomotor behavior, morphology, and physiology. More specifically, we predicted that HR mice would have stride characteristics that differed from those of C mice in ways that parallel some of the adaptations seen in highly cursorial animals. For example, we predicted that limbs of HR mice would swing closer to the parasagittal plane, resulting in a two-dimensional measurement of narrowed stance width. We also expected that some differences between HR and C mice might be amplified by 6 d of wheel access, as is used to select breeders each generation. We used the DigiGait Imaging System (Mouse Specifics) to capture high-speed videos in ventral view as mice ran on a motorized treadmill across a range of speeds and then to automatically calculate several aspects of strides. Young adults of both sexes were tested both before and after 6 d of wheel access. Stride length, stride frequency, stance width, stance time, brake time, propel time, swing time, duty factor, and paw contact area were analyzed using a nested analysis of covariance, with body mass as a covariate. As expected, body mass and treadmill speed affected nearly every analyzed metric. Six days of wheel access also affected nearly every measure, indicating pervasive training effects, in both HR and C mice. As predicted, stance width was significantly narrower in HR than C mice. Paw contact area and duty factor were significantly greater in minimuscle individuals (subset of HR mice with 50%-reduced hind limb muscle mass) than in normal-muscled HR or C mice. We conclude that

Detecting spatial memory deficits beyond blindness in tg2576 Alzheimer mice.

Science.gov (United States)

Yassine, Nour; Lazaris, Anelise; Dorner-Ciossek, Cornelia; Després, Olivier; Meyer, Laurence; Maitre, Michel; Mensah-Nyagan, Ayikoe Guy; Cassel, Jean-Christophe; Mathis, Chantal

2013-03-01

The retinal degeneration Pde6b(rd1) (rd) mutation can be a major pitfall in behavioral studies using tg2576 mice bred on a B6:SJL genetic background, 1 of the most widely used models of Alzheimer's disease. After a pilot study in wild type mice, performance of 8- and 16-month-old tg2576 mice were assessed in several behavioral tasks with the challenge of selecting 1 or more task(s) showing robust memory deficits on this genetic background. Water maze acquisition was impossible in rd homozygotes, whereas Y-maze alternation, object recognition, and olfactory discrimination were unaffected by both the transgene and the rd mutation. Spatial memory retention of 8- and 16-month-old tg2576 mice, however, was dramatically affected independently of the rd mutation when mice had to recognize a spatial configuration of objects or to perform the Barnes maze. Thus, the latter tasks appear extremely useful to evaluate spatial memory deficits and to test cognitive therapies in tg2576 mice and other mouse models bred on a background susceptible to visual impairment. Copyright © 2013 Elsevier Inc. All rights reserved.

Maximal metabolic rates during voluntary exercise, forced exercise, and cold exposure in house mice selectively bred for high wheel-running.

Science.gov (United States)

Rezende, Enrico L; Chappell, Mark A; Gomes, Fernando R; Malisch, Jessica L; Garland, Theodore

2005-06-01

Selective breeding for high wheel-running activity has generated four lines of laboratory house mice (S lines) that run about 170% more than their control counterparts (C lines) on a daily basis, mostly because they run faster. We tested whether maximum aerobic metabolic rates (V(O2max)) have evolved in concert with wheel-running, using 48 females from generation 35. Voluntary activity and metabolic rates were measured on days 5+6 of wheel access (mimicking conditions during selection), using wheels enclosed in metabolic chambers. Following this, V(O2max) was measured twice on a motorized treadmill and twice during cold-exposure in a heliox atmosphere (HeO2). Almost all measurements, except heliox V(O2max), were significantly repeatable. After accounting for differences in body mass (S running speeds on the treadmill. However, running speeds and V(O2max) during voluntary exercise were significantly higher in S lines. Nevertheless, S mice never voluntarily achieved the V(O2max) elicited during their forced treadmill trials, suggesting that aerobic capacity per se is not limiting the evolution of even higher wheel-running speeds in these lines. Our results support the hypothesis that S mice have genetically higher motivation for wheel-running and they demonstrate that behavior can sometimes evolve independently of performance capacities. We also discuss the possible importance of domestication as a confounding factor to extrapolate results from this animal model to natural populations.

Effects of selective breeding for increased wheel-running behavior on circadian timing of substrate oxidation and ingestive behavior

NARCIS (Netherlands)

Jonas, I.; Vaanholt, L. M.; Doornbos, M.; Garland, T.; Scheurink, A. J. W.; Nyakas, C.; van Dijk, G.; Garland Jr., T.

2010-01-01

Fluctuations in substrate preference and utilization across the circadian cycle may be influenced by the degree of physical activity and nutritional status. In the present study, we assessed these relationships in control mice and in mice from a line selectively bred for high voluntary wheel-running

Behavioral Traits are Affected by Selective Breeding for Increased Wheel-Running Behavior in Mice

NARCIS (Netherlands)

Jonas, I.; Schubert, K. A.; Reijne, A. C.; Scholte, J.; Garland, T.; Gerkema, M. P.; Scheurink, A. J. W.; Nyakas, C.; van Dijk, G.; Garland Jr., T.; Maxson, Stephen

Voluntary physical activity may be related to personality traits. Here, we investigated these relations in two mouse lines selectively bred for high voluntary wheel-running behavior and in one non-selected control line. Selection lines were more explorative and "information gathering" in the

High motivation for exercise is associated with altered chromatin regulators of monoamine receptor gene expression in the striatum of selectively bred mice.

Science.gov (United States)

Saul, M C; Majdak, P; Perez, S; Reilly, M; Garland, T; Rhodes, J S

2017-03-01

Although exercise is critical for health, many lack the motivation to exercise, and it is unclear how motivation might be increased. To uncover the molecular underpinnings of increased motivation for exercise, we analyzed the transcriptome of the striatum in four mouse lines selectively bred for high voluntary wheel running and four non-selected control lines. The striatum was dissected and RNA was extracted and sequenced from four individuals of each line. We found multiple genes and gene systems with strong relationships to both selection and running history over the previous 6 days. Among these genes were Htr1b, a serotonin receptor subunit and Slc38a2, a marker for both glutamatergic and γ-aminobutyric acid (GABA)-ergic signaling. System analysis of the raw results found enrichment of transcriptional regulation and kinase genes. Further, we identified a splice variant affecting the Wnt-related Golgi signaling gene Tmed5. Using coexpression network analysis, we found a cluster of interrelated coexpression modules with relationships to running behavior. From these modules, we built a network correlated with running that predicts a mechanistic relationship between transcriptional regulation by nucleosome structure and Htr1b expression. The Library of Integrated Network-Based Cellular Signatures identified the protein kinase C δ inhibitor, rottlerin, the tyrosine kinase inhibitor, Linifanib and the delta-opioid receptor antagonist 7-benzylidenenaltrexone as potential compounds for increasing the motivation to run. Taken together, our findings support a neurobiological framework of exercise motivation where chromatin state leads to differences in dopamine signaling through modulation of both the primary neurotransmitters glutamate and GABA, and by neuromodulators such as serotonin. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Enhanced sensitivity of postsynaptic serotonin-1A receptors in rats and mice with high trait aggression

NARCIS (Netherlands)

van der Vegt, BJ; de Boer, SF; Buwalda, B; de Ruiter, AJH; de Jong, JG; Koolhaas, JM

2001-01-01

Individual differences in aggressive behaviour have been linked to variability in central serotonergic activity, both in humans and animals. A previous experiment in mice, selectively bred for high or low levels of aggression, showed an up-regulation of postsynaptic serotonin-1A (5-HT1A) receptors,

Application of Bred Vectors To Data Assimilation

Science.gov (United States)

Corazza, M.; Kalnay, E.; Patil, Dj

We introduced a statistic, the BV-dimension, to measure the effective local finite-time dimensionality of the atmosphere. We show that this dimension is often quite low, and suggest that this finding has important implications for data assimilation and the accuracy of weather forecasting (Patil et al, 2001). The original database for this study was the forecasts of the NCEP global ensemble forecasting system. The initial differences between the control forecast and the per- turbed forecasts are called bred vectors. The control and perturbed initial conditions valid at time t=n(t are evolved using the forecast model until time t=(n+1) (t. The differences between the perturbed and the control forecasts are scaled down to their initial amplitude, and constitute the bred vectors valid at (n+1) (t. Their growth rate is typically about 1.5/day. The bred vectors are similar by construction to leading Lya- punov vectors except that they have small but finite amplitude, and they are valid at finite times. The original NCEP ensemble data set has 5 independent bred vectors. We define a local bred vector at each grid point by choosing the 5 by 5 grid points centered at the grid point (a region of about 1100km by 1100km), and using the north-south and east- west velocity components at 500mb pressure level to form a 50 dimensional column vector. Since we have k=5 global bred vectors, we also have k local bred vectors at each grid point. We estimate the effective dimensionality of the subspace spanned by the local bred vectors by performing a singular value decomposition (EOF analysis). The k local bred vector columns form a 50xk matrix M. The singular values s(i) of M measure the extent to which the k column unit vectors making up the matrix M point in the direction of v(i). We define the bred vector dimension as BVDIM={Sum[s(i)]}^2/{Sum[s(i)]^2} For example, if 4 out of the 5 vectors lie along v, and one lies along v, the BV- dimension would be BVDIM[sqrt(4), 1, 0

Effects of a selectively bred novelty-seeking phenotype on the motivation to take cocaine in male and female rats

Directory of Open Access Journals (Sweden)

Cummings Jennifer A

2011-03-01

Full Text Available Abstract Background Gender and enhanced novelty reactivity can predispose certain individuals to drug abuse. Previous research in male and female rats selectively bred for high or low locomotor reactivity to novelty found that bred High Responders (bHRs acquire cocaine self-administration more rapidly than bred Low Responders (bLRs and that bHR females in particular self-administered more cocaine than the other groups. The experiments presented here aimed to determine whether an individual's sex and behavioral phenotype interact to affect motivation to take cocaine. Methods We examined motivation for taking cocaine in two experiments using a range of doses on a progressive ratio (PR schedule of responding in bHR or bLR males and females. Additionally, we included a measure of continuing to respond in the absence of reinforcement, a feature of addiction that has been recently incorporated into tests of animal models on the basis of the criteria for substance use disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Statistical analyses were performed using PASW Statistics 18.0 software. Data were analyzed using repeated-measures analysis of variance followed by a Bonferroni correction post hoc test when applicable. Results We found sex differences as well as effects of novelty reactivity on the motivation to self-administer cocaine. Specifically, females demonstrated higher breaking points on the PR schedule compared with males, regardless of phenotype, and bHR males and females exhibited higher motivation than bLR animals at a number of the doses studied. Conclusions An individual's sex continues to be a predisposing factor with respect to drug abuse liability and can be compounded by additional individual differences such as reactivity to novelty.

Differences in nitrogen and urea metabolism between goats bred for ...

African Journals Online (AJOL)

This experiment was conducted to determine whether selection for fleece weight is accompanied by changes in the efficiency of nitrogen utilization, using Angora and Boer goats as models of animals bred for fleece or meat production respectively. A diet, containing a protein: energy ratio of 12 g CP/ MJ ME, was fed at ...

Blood Protein Polymorphism of Small Cattle Bred in Armenia

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Gayane Marmaryan

2017-05-01

Full Text Available ABSTRACT Biochemical and genetic markers have not yet been used in selection and breeding of agricultural animals in Armenia. The objective behind the experiments was to assess the small cattle bred in Armenia- the semi-coarse wool and semi-fine wool sheep, as well as goats of different genotypes characterized by different milk productivity, polymorphic blood proteins-transferrin, ceruloplasmin, aiming to use them in breeding. Another objective was to study the genetic distance between the researched breeds and crossbreeds aiming to reveal the genetic similarity. The findings of research studies come to show that goats with polymorphic transferrin locus and a big set of genotypes are characterized by higher milk productivity; therefore it is recommended that they be used in selection as a supplementary milk productivity marker. The genetic distance between the researched goats comprised 0,60 which comes to show that semi-fine wool sheep were also bred with the help of semi-coarse wool crossbreeds. The high coefficients of genetic distance of crossbreed goats compared to both the highly milk producing imported breeds and the locals are indicative of inherited high adaptability qualities of locals and high milk producing quality of pure breeds.

Logarithmic bred vectors in spatiotemporal chaos: structure and growth.

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Hallerberg, Sarah; Pazó, Diego; López, Juan M; Rodríguez, Miguel A

2010-06-01

Bred vectors are a type of finite perturbation used in prediction studies of atmospheric models that exhibit spatially extended chaos. We study the structure, spatial correlations, and the growth rates of logarithmic bred vectors (which are constructed by using a given norm). We find that, after a suitable transformation, logarithmic bred vectors are roughly piecewise copies of the leading Lyapunov vector. This fact allows us to deduce a scaling law for the bred vector growth rate as a function of its amplitude. In addition, we relate growth rates with the spectrum of Lyapunov exponents corresponding to the most expanding directions. We illustrate our results with simulations of the Lorenz 1996 model.

Experimental transmission of M. leprae into the testes of mice born from 60Co-irradiated pregnant mice

International Nuclear Information System (INIS)

Sushida, Kiyo; Tanemura, Mutsuko

1979-01-01

R 1 -mice, which were born from pregnant mice (R-P) irradiated with 60 CO 300 R were inoculated with leprosy bacilli into the testis. Recently, the author reported that the skin homograft survival duration in 60 CO-irradiated mice (R-P) was shown to be longer than the duration in the R 1 -F mice. The acid-fast bacilli, the so-called globi, were often found at the inoculated site of R-P mice, but not in the R 1 -F mice. The R 1 -F females bred with normal males and the R 2 -F females bred with normal males were both irradiated with 60 CO 300 R, and the R 2 -F male offspring from this R 1 -F and the R 3 -F male offspring from this R 2 -F showed the same increase in sensitivity to leprosy bacilli as the R-P generation. Acid-fast bacilli (globi, +G) were also found in the testes of the R 2 -F and R 3 -F males. IR-F mice which had received 131 I-Na 100 μci injections and also 60 CO 300 R irradiations during their fetus-term, showed few increase in sensitivity to infection of leprosy bacilli. (author)

BRED: a simple and powerful tool for constructing mutant and recombinant bacteriophage genomes.

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Laura J Marinelli

Full Text Available Advances in DNA sequencing technology have facilitated the determination of hundreds of complete genome sequences both for bacteria and their bacteriophages. Some of these bacteria have well-developed and facile genetic systems for constructing mutants to determine gene function, and recombineering is a particularly effective tool. However, generally applicable methods for constructing defined mutants of bacteriophages are poorly developed, in part because of the inability to use selectable markers such as drug resistance genes during viral lytic growth. Here we describe a method for simple and effective directed mutagenesis of bacteriophage genomes using Bacteriophage Recombineering of Electroporated DNA (BRED, in which a highly efficient recombineering system is utilized directly on electroporated phage DNA; no selection is required and mutants can be readily detected by PCR. We describe the use of BRED to construct unmarked gene deletions, in-frame internal deletions, base substitutions, precise gene replacements, and the addition of gene tags.

Nicotine response and nicotinic receptors in long-sleep and short-sleep mice.

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De Fiebre, C M; Medhurst, L J; Collins, A C

1987-01-01

Nicotine response and nicotinic receptor binding were characterized in long-sleep (LS) and short-sleep (SS) mice which have been selectively bred for differential "sleep-time" following ethanol administration. LS mice are more sensitive than SS mice to nicotine as measured by a battery of behavioral and physiological tests and as measured by sensitivity to nicotine-induced seizures. The greater sensitivity of the LS mice is not due to differences in binding of [3H]nicotine. Unlike inbred mouse strains which differ in sensitivity to nicotine-induced seizures, these selected mouse lines do not differ in levels of binding of [125I]alpha-bungarotoxin (BTX) in the hippocampus. Significant differences in BTX binding were found in the cerebellum and striatum. Although these two mouse lines do not differ in blood levels of nicotine following nicotine administration, they differ slightly in brain levels of nicotine indicating differential distribution of the drug. Since this distribution difference is much smaller than the observed behavioral differences, these mice probably differ in CNS sensitivity to nicotine; however, follow-up studies are necessary to test whether the differential response of these mice is due to subtle differences in distribution of nicotine to the brain.

Reintroduction of captive-bred African Grass-Owls Tyto capensis ...

African Journals Online (AJOL)

This study represents the first attempt to determine post-release survival of a captive-bred owl in Africa. We released six captive-bred African Grass-Owls Tyto capensis into suitable habitat and, using radio telemetry, determined their daytime roost sites. One bird left the study area soon after release and did not yield data.

Rats selectively bred for low levels of play-induced 50 kHz vocalizations as a model for autism spectrum disorders: a role for NMDA receptors.

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Burgdorf, Jeffrey; Moskal, Joseph R; Brudzynski, Stefan M; Panksepp, Jaak

2013-08-15

Early childhood autism is characterized by deficits in social approach and play behaviors, socio-emotional relatedness, and communication/speech abnormalities, as well as repetitive behaviors. These core neuropsychological features of autism can be modeled in laboratory rats, and the results may be useful for drug discovery and therapeutic development. We review data that show that rats selectively bred for low rates of play-related pro-social ultrasonic vocalizations (USVs) can be used to model social deficit symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes, and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR functional glycine site partial agonist, GLYX-13, rescued the deficits in play-induced pro-social 50-kHz USVs and reduced monotonous USVs. Since the NMDA receptor has been implicated in the genesis of autistic symptoms, it is possible that GLYX-13 may be of therapeutic value in the treatment of autism. Copyright © 2013 Elsevier B.V. All rights reserved.

Effects of voluntary exercise on spontaneous physical activity and food consumption in mice: Results from an artificial selection experiment.

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Copes, Lynn E; Schutz, Heidi; Dlugosz, Elizabeth M; Acosta, Wendy; Chappell, Mark A; Garland, Theodore

2015-10-01

We evaluated the effect of voluntary exercise on spontaneous physical activity (SPA) and food consumption in mice from 4 replicate lines bred for 57 generations for high voluntary wheel running (HR) and from 4 non-selected control (C) lines. Beginning at ~24 days of age, mice were housed in standard cages or in cages with attached wheels. Wheel activity and SPA were monitored in 1-min intervals. Data from the 8th week of the experiment were analyzed because mice were sexually mature and had plateaued in body mass, weekly wheel running distance, SPA, and food consumption. Body mass, length, and masses of the retroperitoneal fat pad, liver, and heart were recorded after the 13th week. SPA of both HR and C mice decreased with wheel access, due to reductions in both duration and average intensity of SPA. However, total activity duration (SPA+wheel running; min/day) was ~1/3 greater when mice were housed with wheels, and food consumption was significantly increased. Overall, food consumption in both HR and C mice was more strongly affected by wheel running than by SPA. Duration of wheel running had a stronger effect than average speed, but the opposite was true for SPA. With body mass as a covariate, chronic wheel access significantly reduced fat pad mass and increased heart mass in both HR and C mice. Given that both HR and C mice housed with wheels had increased food consumption, the energetic cost of wheel running was not fully compensated by concomitant reductions in SPA. The experiment demonstrates that both duration and intensity of both wheel running and SPA were significant predictors of food consumption. This sort of detailed analysis of the effects of different aspects of physical activity on food consumption has not previously been reported for a non-human animal, and it sets the stage for longitudinal examination of energy balance and its components in rodent models. Copyright © 2015 Elsevier Inc. All rights reserved.

75 FR 32356 - Pioneer Hi-Bred International, Inc.; Determination of Nonregulated Status for Genetically...

Science.gov (United States)

2010-06-08

...] Pioneer Hi-Bred International, Inc.; Determination of Nonregulated Status for Genetically Engineered High... advising the public of our determination that a soybean line developed by Pioneer Hi-Bred International... engineered organisms. Our determination is based on our evaluation of data submitted by Pioneer Hi-Bred...

The NS1 glycoprotein can generate dramatic antibody-enhanced dengue viral replication in normal out-bred mice resulting in lethal multi-organ disease.

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Andrew K I Falconar

Full Text Available Antibody-enhanced replication (AER of dengue type-2 virus (DENV-2 strains and production of antibody-enhanced disease (AED was tested in out-bred mice. Polyclonal antibodies (PAbs generated against the nonstructural-1 (NS1 glycoprotein candidate vaccine of the New Guinea-C (NG-C or NSx strains reacted strongly and weakly with these antigens, respectively. These PAbs contained the IgG2a subclass, which cross-reacted with the virion-associated envelope (E glycoprotein of the DENV-2 NSx strain, suggesting that they could generate its AER via all mouse Fcγ-receptor classes. Indeed, when these mice were challenged with a low dose (<0.5 LD₅₀ of the DENV-2 NSx strain, but not the NG-C strain, they all generated dramatic and lethal DENV-2 AER/AED. These AER/AED mice developed life-threatening acute respiratory distress syndrome (ARDS, displayed by diffuse alveolar damage (DAD resulting from i dramatic interstitial alveolar septa-thickening with mononuclear cells, ii some hyperplasia of alveolar type-II pneumocytes, iii copious intra-alveolar protein secretion, iv some hyaline membrane-covered alveolar walls, and v DENV-2 antigen-positive alveolar macrophages. These mice also developed meningo-encephalitis, with greater than 90,000-fold DENV-2 AER titers in microglial cells located throughout their brain parenchyma, some of which formed nodules around dead neurons. Their spleens contained infiltrated megakaryocytes with DENV-2 antigen-positive red-pulp macrophages, while their livers displayed extensive necrosis, apoptosis and macro- and micro-steatosis, with DENV-2 antigen-positive Kuppfer cells and hepatocytes. Their infections were confirmed by DENV-2 isolations from their lungs, spleens and livers. These findings accord with those reported in fatal human "severe dengue" cases. This DENV-2 AER/AED was blocked by high concentrations of only the NG-C NS1 glycoprotein. These results imply a potential hazard of DENV NS1 glycoprotein-based vaccines

Measuring nanocurie quantities of tritium bred in metallic lithium and lithium oxide samples

International Nuclear Information System (INIS)

Bertone, P.C.

1985-01-01

The LBM program requires that nanocurie quantities of tritium, bred in both lithium oxide pellets and lithium samples, be measured with an uncertainty not exceeding + or - 6%. Two methods of accurately measuring nanocurie quantities of tritium bred in LBM lithium oxide pellets and one method of accurately measuring nanocurie quantities of tritium bred in lithium samples are described. Potential errors associated with these tritium measurement techniques are also discussed

78 FR 37201 - Pioneer Hi-Bred International, Inc.; Determination of Nonregulated Status of Maize Genetically...

Science.gov (United States)

2013-06-20

...] Pioneer Hi-Bred International, Inc.; Determination of Nonregulated Status of Maize Genetically Engineered... Hi-Bred International Inc., designated as maize event DP-[Oslash][Oslash]4114-3, which has been... by Pioneer Hi-Bred International, Inc., in its petition for a determination of nonregulated status...

78 FR 32231 - Pioneer Hi-Bred International, Inc.; Availability of Plant Pest Risk Assessment, Environmental...

Science.gov (United States)

2013-05-29

...] Pioneer Hi-Bred International, Inc.; Availability of Plant Pest Risk Assessment, Environmental Assessment... has prepared a preliminary determination regarding a request from Pioneer Hi-Bred International, Inc... 340. APHIS received a petition (APHIS Petition Number 11-063-01p) from Pioneer Hi-Bred International...

Development of Ethanol Withdrawal-Related Sensitization and Relapse Drinking in Mice Selected for High or Low Ethanol Preference

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Lopez, Marcelo F.; Grahame, Nicholas J.; Becker, Howard C.

2010-01-01

Background Previous studies have shown that high alcohol consumption is associated with low withdrawal susceptiblility, while at the same time, other studies have shown that exposure to ethanol vapor increases alcohol drinking in rats and mice. In the present studies, we sought to shed light on this seeming contradiction by using mice selectively bred for High- (HAP) and Low- (LAP) Alcohol Preference, first, assessing these lines for differences in signs of ethanol withdrawal and second, for differences in the efficacy of intermittent alcohol vapor exposure on elevating subsequent ethanol intake. Methods Experiment 1 examined whether these lines of mice differed in ethanol withdrawal-induced CNS hyperexcitability and the development of sensitization to this effect following intermittent ethanol vapor exposure. Adult HAP and LAP lines (replicates 1 and 2), and the C3H/HeNcr inbred strain (included as a control genotype for comparison purposes) received intermittent exposure to ethanol vapor and were evaluated for ethanol withdrawal-induced seizures assessed by scoring handling-induced convulsions (HIC). Experiment 2 examined the influence of chronic intermittent ethanol exposure on voluntary ethanol drinking. Adult male and female HAP-2 and LAP-2 mice, along with male C57BL/6J (included as comparative controls) were trained to drink 10% ethanol using a limited access (2 hr/day) 2-bottle choice paradigm. After stable baseline daily intake was established, mice received chronic intermittent ethanol vapor exposure in inhalation chambers. Ethanol intake sessions resumed 72 hr after final ethanol (or air) exposure for 5 consecutive days. Results Following chronic ethanol treatment, LAP mice exhibited overall greater withdrawal seizure activity compared to HAP mice. In Experiment 2, chronic ethanol exposure/withdrawal resulted in a significant increase in ethanol intake in male C57BL/6J, and modestly elevated intake in HAP-2 male mice. Ethanol intake for male control mice

High-Specificity Targeted Functional Profiling in Microbial Communities with ShortBRED.

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James Kaminski

2015-12-01

Full Text Available Profiling microbial community function from metagenomic sequencing data remains a computationally challenging problem. Mapping millions of DNA reads from such samples to reference protein databases requires long run-times, and short read lengths can result in spurious hits to unrelated proteins (loss of specificity. We developed ShortBRED (Short, Better Representative Extract Dataset to address these challenges, facilitating fast, accurate functional profiling of metagenomic samples. ShortBRED consists of two components: (i a method that reduces reference proteins of interest to short, highly representative amino acid sequences ("markers" and (ii a search step that maps reads to these markers to quantify the relative abundance of their associated proteins. After evaluating ShortBRED on synthetic data, we applied it to profile antibiotic resistance protein families in the gut microbiomes of individuals from the United States, China, Malawi, and Venezuela. Our results support antibiotic resistance as a core function in the human gut microbiome, with tetracycline-resistant ribosomal protection proteins and Class A beta-lactamases being the most widely distributed resistance mechanisms worldwide. ShortBRED markers are applicable to other homology-based search tasks, which we demonstrate here by identifying phylogenetic signatures of antibiotic resistance across more than 3,000 microbial isolate genomes. ShortBRED can be applied to profile a wide variety of protein families of interest; the software, source code, and documentation are available for download at http://huttenhower.sph.harvard.edu/shortbred.

Effects of selective breeding for increased wheel-running behavior on circadian timing of substrate oxidation and ingestive behavior.

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Jónás, I; Vaanholt, L M; Doornbos, M; Garland, T; Scheurink, A J W; Nyakas, C; van Dijk, G

2010-04-19

Fluctuations in substrate preference and utilization across the circadian cycle may be influenced by the degree of physical activity and nutritional status. In the present study, we assessed these relationships in control mice and in mice from a line selectively bred for high voluntary wheel-running behavior, either when feeding a carbohydrate-rich/low-fat (LF) or a high-fat (HF) diet. Housed without wheels, selected mice, and in particular the females, exhibited higher cage activity than their non-selected controls during the dark phase and at the onset of the light phase, irrespective of diet. This was associated with increases in energy expenditure in both sexes of the selection line. In selected males, carbohydrate oxidation appeared to be increased compared to controls. In contrast, selected females had profound increases in fat oxidation above the levels in control females to cover the increased energy expenditure during the dark phase. This is remarkable in light of the finding that the selected mice, and in particular the females showed higher preference for the LF diet relative to controls. It is likely that hormonal and/or metabolic signals increase carbohydrate preference in the selected females, which may serve optimal maintenance of cellular metabolism in the presence of augmented fat oxidation. (c) 2010 Elsevier Inc. All rights reserved.

Differential sensitivity of long-sleep and short-sleep mice to high doses of cocaine.

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de Fiebre, C M; Ruth, J A; Collins, A C

1989-12-01

The cocaine sensitivity of male and female long-sleep (LS) and short-sleep (SS) mice, which have been selectively bred for differential ethanol-induced "sleep-time," was examined in a battery of behavioral and physiological tests. Differences between these two mouse lines were subtle and were seen primarily at high doses. At high doses, SS mice were more sensitive than LS mice, particularly to cocaine-induced hypothermia; however, significant hypothermia was not seen except at doses which were very near to the seizure threshold. During a 60-min test of locomotor activity, LS mice showed greater stimulation of Y-maze activity by 20 mg/kg cocaine than SS mice. Consistent with the finding of subtle differences in sensitivity to low doses of cocaine. LS and SS mice did not differ in sensitivity to cocaine inhibition of synaptosomal uptake of [3H]-dopamine, [3H]-norepinephrine or [3H]-5-hydroxytryptamine. However, consistent with the finding of differential sensitivity to high doses of cocaine, SS mice were more sensitive to the seizure-producing effects of the cocaine and lidocaine, a local anesthetic. It is hypothesized that the differential sensitivity of these mouse lines to high doses of cocaine is due to differential sensitivity to cocaine's actions on systems that regulate local anesthetic effects. Selective breeding for differential duration of alcohol-induced "sleep-time" may have resulted in differential ion channel structure or function in these mice.

Cardiac protein expression patterns are associated with distinct inborn exercise capacity in non-selectively bred rats

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L.P. Ribeiro

2018-01-01

Full Text Available In the present study, we successfully demonstrated for the first time the existence of cardiac proteomic differences between non-selectively bred rats with distinct intrinsic exercise capacities. A proteomic approach based on two-dimensional gel electrophoresis coupled to mass spectrometry was used to study the left ventricle (LV tissue proteome of rats with distinct intrinsic exercise capacity. Low running performance (LRP and high running performance (HRP rats were categorized by a treadmill exercise test, according to distance run to exhaustion. The running capacity of HRPs was 3.5-fold greater than LRPs. Protein profiling revealed 29 differences between HRP and LRP rats (15 proteins were identified. We detected alterations in components involved in metabolism, antioxidant and stress response, microfibrillar and cytoskeletal proteins. Contractile proteins were upregulated in the LVs of HRP rats (α-myosin heavy chain-6, myosin light chain-1 and creatine kinase, whereas the LVs of LRP rats exhibited upregulation in proteins associated with stress response (aldehyde dehydrogenase 2, α-crystallin B chain and HSPβ-2. In addition, the cytoskeletal proteins desmin and α-actin were upregulated in LRPs. Taken together, our results suggest that the increased contractile protein levels in HRP rats partly accounted for their improved exercise capacity, and that proteins considered risk factors to the development of cardiovascular disease were expressed in higher amounts in LRP animals.

Generation of mice harbouring a conditional loss-of-function allele of Gata6

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Duncan Stephen A

2006-04-01

Full Text Available Abstract The zinc finger transcription factor GATA6 is believed to have important roles in the development of several organs including the liver, gastrointestinal tract and heart. However, analyses of the contribution of GATA6 toward organogenesis have been hampered because Gata6-/- mice fail to develop beyond gastrulation due to defects in extraembryonic endoderm function. We have therefore generated a mouse line harbouring a conditional loss-of-function allele of Gata6 using Cre/loxP technology. LoxP elements were introduced into introns flanking exon 2 of the Gata6 gene by homologous recombination in ES cells. Mice containing this altered allele were bred to homozygosity and were found to be viable and fertile. To assess the functional integrity of the loxP sites and to confirm that we had generated a Gata6 loss-of-function allele, we bred Gata6 'floxed' mice to EIIa-Cre mice in which Cre is ubiquitously expressed, and to Villin-Cre mice that express Cre in the epithelial cells of the intestine. We conclude that we have generated a line of mice in which GATA6 activity can be ablated in a cell type specific manner by expression of Cre recombinase. This line of mice can be used to establish the role of GATA6 in regulating embryonic development and various aspects of mammalian physiology.

The selectively bred high alcohol sensitivity (HAS) and low alcohol sensitivity (LAS) rats differ in sensitivity to nicotine.

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de Fiebre, NancyEllen C; Dawson, Ralph; de Fiebre, Christopher M

2002-06-01

Studies in rodents selectively bred to differ in alcohol sensitivity have suggested that nicotine and ethanol sensitivities may cosegregate during selective breeding. This suggests that ethanol and nicotine sensitivities may in part be genetically correlated. Male and female high alcohol sensitivity (HAS), control alcohol sensitivity, and low alcohol sensitivity (LAS) rats were tested for nicotine-induced alterations in locomotor activity, body temperature, and seizure activity. Plasma and brain levels of nicotine and its primary metabolite, cotinine, were measured in these animals, as was the binding of [3H]cytisine, [3H]epibatidine, and [125I]alpha-bungarotoxin in eight brain regions. Both replicate HAS lines were more sensitive to nicotine-induced locomotor activity depression than the replicate LAS lines. No consistent HAS/LAS differences were seen on other measures of nicotine sensitivity; however, females were more susceptible to nicotine-induced seizures than males. No HAS/LAS differences in nicotine or cotinine levels were seen, nor were differences seen in the binding of nicotinic ligands. Females had higher levels of plasma cotinine and brain nicotine than males but had lower brain cotinine levels than males. Sensitivity to a specific action of nicotine cosegregates during selective breeding for differential sensitivity to a specific action of ethanol. The differential sensitivity of the HAS/LAS rats is due to differences in central nervous system sensitivity and not to pharmacokinetic differences. The differential central nervous system sensitivity cannot be explained by differences in the numbers of nicotinic receptors labeled in ligand-binding experiments. The apparent genetic correlation between ethanol and nicotine sensitivities suggests that common genes modulate, in part, the actions of both ethanol and nicotine and may explain the frequent coabuse of these agents.

Nesting behavior of house mice (Mus domesticus) selected for increased wheel-running activity.

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Carter, P A; Swallow, J G; Davis, S J; Garland, T

2000-03-01

Nest building was measured in "active" (housed with access to running wheels) and "sedentary" (without wheel access) mice (Mus domesticus) from four replicate lines selected for 10 generations for high voluntary wheel-running behavior, and from four randombred control lines. Based on previous studies of mice bidirectionally selected for thermoregulatory nest building, it was hypothesized that nest building would show a negative correlated response to selection on wheel-running. Such a response could constrain the evolution of high voluntary activity because nesting has also been shown to be positively genetically correlated with successful production of weaned pups. With wheel access, selected mice of both sexes built significantly smaller nests than did control mice. Without wheel access, selected females also built significantly smaller nests than did control females, but only when body mass was excluded from the statistical model, suggesting that body mass mediated this correlated response to selection. Total distance run and mean running speed on wheels was significantly higher in selected mice than in controls, but no differences in amount of time spent running were measured, indicating a complex cause of the response of nesting to selection for voluntary wheel running.

Phenotypic and molecular differences between rats selectively bred to voluntarily run high vs. low nightly distances.

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Roberts, Michael D; Brown, Jacob D; Company, Joseph M; Oberle, Lauren P; Heese, Alexander J; Toedebusch, Ryan G; Wells, Kevin D; Cruthirds, Clayton L; Knouse, John A; Ferreira, J Andries; Childs, Thomas E; Brown, Marybeth; Booth, Frank W

2013-06-01

The purpose of the present study was to partially phenotype male and female rats from generations 8-10 (G8-G10) that had been selectively bred to possess low (LVR) vs. high voluntary running (HVR) behavior. Over the first 6 days with wheels, 34-day-old G8 male and female LVRs ran shorter distances (P HVR counterparts, respectively. HVR and LVR lines consumed similar amounts of standard chow with or without wheels. No inherent difference existed in PGC-1α mRNA in the plantaris and soleus muscles of LVR and HVR nonrunners, although G8 LVR rats inherently possessed less NADH-positive superficial plantaris fibers compared with G8 HVR rats. While day 28 body mass tended to be greater in both sexes of G9-G10 LVR nonrunners vs. G9-G10 HVR nonrunners (P = 0.06), body fat percentage was similar between lines. G9-G10 HVRs had fat mass loss after 6 days of running compared with their prerunning values, while LVR did not lose or gain fat mass during the 6-day voluntary running period. RNA deep sequencing efforts in the nucleus accumbens showed only eight transcripts to be >1.5-fold differentially expressed between lines in HVR and LVR nonrunners. Interestingly, HVRs presented less Oprd1 mRNA, which ties in to potential differences in dopaminergic signaling between lines. This unique animal model provides further evidence as to how exercise may be mechanistically regulated.

Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice.

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Oestreich, A K; Carleton, S M; Yao, X; Gentry, B A; Raw, C E; Brown, M; Pfeiffer, F M; Wang, Y; Phillips, C L

2016-01-01

Mice with osteogenesis imperfecta (+/oim), a disorder of bone fragility, were bred to mice with muscle over growth to test whether increasing muscle mass genetically would improve bone quality and strength. The results demonstrate that femora from mice carrying both mutations have greater mechanical integrity than their +/oim littermates. Osteogenesis imperfecta is a heritable connective tissue disorder due primarily to mutations in the type I collagen genes resulting in skeletal deformity and fragility. Currently, there is no cure, and therapeutic strategies encompass the use of antiresorptive pharmaceuticals and surgical bracing, with limited success and significant potential for adverse effects. Bone, a mechanosensing organ, can respond to high mechanical loads by increasing new bone formation and altering bone geometry to withstand increased forces. Skeletal muscle is a major source of physiological loading on bone, and bone strength is proportional to muscle mass. To test the hypothesis that congenic increases in muscle mass in the osteogenesis imperfecta murine model mouse (oim) will improve their compromised bone quality and strength, heterozygous (+/oim) mice were bred to mice deficient in myostatin (+/mstn), a negative regulator of muscle growth. The resulting adult offspring were evaluated for hindlimb muscle mass, and bone microarchitecture, physiochemistry, and biomechanical integrity. +/oim mice deficient in myostatin (+/mstn +/oim) were generated and demonstrated that myostatin deficiency increased body weight, muscle mass, and biomechanical strength in +/mstn +/oim mice as compared to +/oim mice. Additionally, myostatin deficiency altered the physiochemical properties of the +/oim bone but did not alter bone remodeling. Myostatin deficiency partially improved the reduced femoral bone biomechanical strength of adult +/oim mice by increasing muscle mass with concomitant improvements in bone microarchitecture and physiochemical properties.

Transpiration Response and Growth in Pearl Millet Parental Lines and Hybrids Bred for Contrasting Rainfall Environments

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Susan Medina

2017-10-01

Full Text Available Under conditions of high vapor pressure deficit (VPD and soil drying, restricting transpiration is an important avenue to gain efficiency in water use. The question we raise in this article is whether breeding for agro-ecological environments that differ for the rainfall have selected for traits that control plant water use. These are measured in pearl millet materials bred for zones varying in rainfall (8 combinations of parent and F1-hybrids, 18 F1-hybrids and then 40 F1-hybrids. In all cases, we found an agro-ecological variation in the slope of the transpiration response to increasing VPD, and parental line variation in the transpiration response to soil drying within hybrids/parent combinations. The hybrids adapted to lower rainfall had higher transpiration response curves than those from the highest rainfall zones, but showed no variation in how transpiration responded to soil drying. The genotypes bred for lower rainfall zones showed lower leaf area, dry matter, thicker leaves, root development, and exudation, than the ones bred for high rainfall zone when grown in the low VPD environment of the greenhouse, but there was no difference in their root length neither on the root/shoot index in these genotypes. By contrast, when grown under high VPD conditions outdoors, the lower rainfall hybrids had the highest leaf, tiller, and biomass development. Finally, under soil drying the genotypes from the lower rainfall accumulated less biomass than the ones from higher rainfall zone, and so did the parental lines compared to the hybrids. These differences in the transpiration response and growth clearly showed that breeding for different agro-ecological zones also bred for different genotype strategies in relation to traits related to plant water use.Highlights:• Variation in transpiration response reflected breeding for agro-ecological zones• Different growth strategies depended on the environmental conditions• Different ideotypes reflected

Transpiration Response and Growth in Pearl Millet Parental Lines and Hybrids Bred for Contrasting Rainfall Environments.

Science.gov (United States)

Medina, Susan; Gupta, S K; Vadez, Vincent

2017-01-01

Under conditions of high vapor pressure deficit (VPD) and soil drying, restricting transpiration is an important avenue to gain efficiency in water use. The question we raise in this article is whether breeding for agro-ecological environments that differ for the rainfall have selected for traits that control plant water use. These are measured in pearl millet materials bred for zones varying in rainfall (8 combinations of parent and F 1 -hybrids, 18 F 1 -hybrids and then 40 F 1 -hybrids). In all cases, we found an agro-ecological variation in the slope of the transpiration response to increasing VPD, and parental line variation in the transpiration response to soil drying within hybrids/parent combinations. The hybrids adapted to lower rainfall had higher transpiration response curves than those from the highest rainfall zones, but showed no variation in how transpiration responded to soil drying. The genotypes bred for lower rainfall zones showed lower leaf area, dry matter, thicker leaves, root development, and exudation, than the ones bred for high rainfall zone when grown in the low VPD environment of the greenhouse, but there was no difference in their root length neither on the root/shoot index in these genotypes. By contrast, when grown under high VPD conditions outdoors, the lower rainfall hybrids had the highest leaf, tiller, and biomass development. Finally, under soil drying the genotypes from the lower rainfall accumulated less biomass than the ones from higher rainfall zone, and so did the parental lines compared to the hybrids. These differences in the transpiration response and growth clearly showed that breeding for different agro-ecological zones also bred for different genotype strategies in relation to traits related to plant water use. Highlights : • Variation in transpiration response reflected breeding for agro-ecological zones • Different growth strategies depended on the environmental conditions • Different ideotypes reflected

Cocaine self-administration and reinstatement in female rats selectively bred for high and low voluntary running.

Science.gov (United States)

Smethells, J R; Zlebnik, N E; Miller, D K; Will, M J; Booth, F; Carroll, M E

2016-10-01

Previous research has found that rats behaviorally screened for high (vs. low) wheel running were more vulnerable to cocaine abuse. To assess the extent to which a genetic component is involved in this drug-abuse vulnerability, rats selectively bred for high or low voluntary running (HVR or LVR, respectively) were examined for differences in cocaine seeking in the present study. Female rats were trained to lever press for food and then were assessed for differences in acquisition of cocaine (0.4mg/kg; i.v.) self-administration across 10 sessions. Once acquired, rats self-administered cocaine for a 14-day maintenance phase, followed by a 14-day extinction phase when cocaine was no longer available. Subsequently, reinstatement of cocaine seeking was examined with priming injections of cocaine (5, 10 & 15mg/kg), caffeine (30mg/kg), yohimbine (2.5mg/kg) and cocaine-paired cues. A greater percentage of LVR rats met the acquisition criteria for cocaine self-administration and in fewer sessions than HVR rats. No differences in responding for cocaine were observed between phenotypes during maintenance. However, during extinction LVR rats initially responded at higher rates and persisted in cocaine seeking for a greater number of sessions. No phenotype differences were observed following drug and cue-primed reinstatement of cocaine seeking. In general, LVR rats were more sensitive to the reinforcing effects of cocaine than HVR rats during periods of transition into and out of cocaine self-administration. Thus, LVR rats sometimes showed a greater vulnerability cocaine seeking than HVR rats. Published by Elsevier Ireland Ltd.

Phenotypic and molecular differences between rats selectively bred to voluntarily run high vs. low nightly distances

Science.gov (United States)

Roberts, Michael D.; Brown, Jacob D.; Company, Joseph M.; Oberle, Lauren P.; Heese, Alexander J.; Toedebusch, Ryan G.; Wells, Kevin D.; Cruthirds, Clayton L.; Knouse, John A.; Ferreira, J. Andries; Childs, Thomas E.; Brown, Marybeth

2013-01-01

The purpose of the present study was to partially phenotype male and female rats from generations 8–10 (G8–G10) that had been selectively bred to possess low (LVR) vs. high voluntary running (HVR) behavior. Over the first 6 days with wheels, 34-day-old G8 male and female LVRs ran shorter distances (P HVR counterparts, respectively. HVR and LVR lines consumed similar amounts of standard chow with or without wheels. No inherent difference existed in PGC-1α mRNA in the plantaris and soleus muscles of LVR and HVR nonrunners, although G8 LVR rats inherently possessed less NADH-positive superficial plantaris fibers compared with G8 HVR rats. While day 28 body mass tended to be greater in both sexes of G9–G10 LVR nonrunners vs. G9–G10 HVR nonrunners (P = 0.06), body fat percentage was similar between lines. G9–G10 HVRs had fat mass loss after 6 days of running compared with their prerunning values, while LVR did not lose or gain fat mass during the 6-day voluntary running period. RNA deep sequencing efforts in the nucleus accumbens showed only eight transcripts to be >1.5-fold differentially expressed between lines in HVR and LVR nonrunners. Interestingly, HVRs presented less Oprd1 mRNA, which ties in to potential differences in dopaminergic signaling between lines. This unique animal model provides further evidence as to how exercise may be mechanistically regulated. PMID:23552494

Evaluating genetic traceability methods for captive-bred marine fish and their applications in fisheries management and wildlife forensics

OpenAIRE

Bylemans, Jonas; Maes, Gregory E.; Diopere, Eveline; Cariani, Alessia; Senn, Helen; Taylor, Martin I.; Helyar, Sarah; Bargelloni, Luca; Bonaldo, Alessio; Carvalho, Gary; Guarniero, Ilaria; Komen, Hans; Martinsohn, Jann Th; Eg Nielsen, Einar; Tinti, Fausto

2016-01-01

Growing demands for marine fish products is leading to increased pressure on already depleted wild populations and a rise in aquaculture production. Consequently, more captive-bred fish are released into the wild through accidental escape or deliberate releases. The increased mixing of captive-bred and wild fish may affect the ecological and/or genetic integrity of wild fish populations. Unambiguous identification tools for captive-bred fish will be highly valuable to manage risks (fisheries ...

Morphometry, ultrastructure, myosin isoforms, and metabolic capacities of the "mini muscles" favoured by selection for high activity in house mice.

Science.gov (United States)

Guderley, Helga; Houle-Leroy, Philippe; Diffee, Gary M; Camp, Dana M; Garland, Theodore

2006-07-01

Prolonged selective breeding of mice (Mus musculus) for high levels of voluntary wheel running has favoured an unusual phenotype ("mini muscles"), apparently caused by a single Mendelian recessive allele, in which most hind-limb muscles are markedly reduced in mass, but have increased mass-specific activities of mitochondrial enzymes. We examined whether these changes reflect changes in fibre size, number or ultrastructure in normal and "mini-muscle" mice within the two (of four) selectively bred lines (lab designations L3 and L6) that exhibit the phenotype at generations 26 and 27. In both lines, the gastrocnemius and plantaris muscles are smaller in mass (by >50% and 20%, respectively) in affected individuals. The mass-specific activities of mitochondrial enzymes in the gastrocnemius and plantaris muscles were increased in the mini phenotype in both lines, with stronger effects in the gastrocnemius muscle. In the gastrocnemius, the % myosin heavy chain (MHC) IIb was reduced by 50% in L3 and by 30% in L6, whereas the % MHC IIa and I were higher, particularly in L3. Fibre number in the plantaris muscle did not significantly differ between mini and normal muscles, although muscle mass was a significant positive correlate of fibre number. Small fibres were more abundant in mini than normal muscles in L3. Mitochondrial volume density was significantly higher in mini than normal muscle fibres in L3, but not in L6. Microscopy revealed a surprising attribute of the mini muscles: an abundance of small, minimally differentiated, myofibril-containing cells positioned in a disorderly fashion, particularly in the surface layer. We hypothesise that these unusual cells may be satellite cells or type IIb fibres that did not complete their differentiation. Together, these observations suggest that mice with the mini phenotype have reduced numbers of type IIb fibres in many of their hind-limb muscles, leading to a decrease in mass and an increase in mass-specific aerobic capacity

Low copulatory activity in selectively bred Sardinian alcohol-nonpreferring (sNP) relative to alcohol-preferring (sP) rats

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Karlsson, Oskar; Colombo, Giancarlo

2015-01-01

Background There is a growing consensus that similar neural mechanisms are involved in the reinforcing properties of natural rewards, like food and sex, and drugs of abuse. Rat lines selectively bred for high and low oral alcohol intake and preference have been useful for understanding factors contributing to excessive alcohol intake and may constitute proper animal models for investigating the neurobiological basis of natural rewarding stimuli. Methods The present study evaluated copulatory behavior in alcohol and sexually naïve Sardinian alcohol-preferring (sP) and -nonpreferring (sNP) male rats in three consecutive copulatory behavior tests. Results The main finding was that, under the conditions used in this study, sNP rats were sexually inactive relative to sP rats. To gain more information about the sexual behavior in sP rats, Wistar rats were included as an external reference strain. Only minor differences between sP and Wistar rats were revealed. Conclusions The reason behind the low copulatory activity of sNP rats remains to be elucidated, but may in part be mediated by innate differences in brain transmitter systems. The comparison between sP and Wistar rats may also suggest that the inherent proclivity to excessive alcohol drinking in sP rats may mainly be dependent on its anxiolytic properties, as previously proposed, and not changes in the reward system. PMID:25728453

Emotional reactivity to incentive downshift as a correlated response to selection of high and low alcohol preferring mice and an influencing factor on ethanol intake.

Science.gov (United States)

Matson, Liana M; Grahame, Nicholas J

2015-11-01

Losing a job or significant other are examples of incentive loss that result in negative emotional reactions. The occurrence of negative life events is associated with increased drinking (Keyes, Hatzenbuehler, & Hasin, 2011). Further, certain genotypes are more likely to drink alcohol in response to stressful negative life events (Blomeyer et al., 2008; Covault et al., 2007). Shared genetic factors may contribute to alcohol drinking and emotional reactivity, but this relationship is not currently well understood. We used an incentive downshift paradigm to address whether emotional reactivity is elevated in mice predisposed to drink alcohol. We also investigated if ethanol drinking is influenced in High Alcohol Preferring mice that had been exposed to an incentive downshift. Incentive downshift procedures have been widely utilized to model emotional reactivity, and involve shifting a high reward group to a low reward and comparing the shifted group to a consistently rewarded control group. Here, we show that replicate lines of selectively bred High Alcohol Preferring mice exhibited larger successive negative contrast effects than their corresponding replicate Low Alcohol Preferring lines, providing strong evidence for a genetic association between alcohol drinking and susceptibility to the emotional effects of negative contrast. These mice can be used to study the shared neurological and genetic underpinnings of emotional reactivity and alcohol preference. Unexpectedly, an incentive downshift suppressed ethanol drinking immediately following an incentive downshift. This could be due to a specific effect of negative contrast on ethanol consumption or a suppressive effect on consummatory behavior in general. These data suggest that either alcohol intake does not provide the anticipated negative reinforcement, or that a single test was insufficient for animals to learn to drink following incentive downshift. However, the emotional intensity following incentive

Oxidative costs of reproduction in mouse strains selected for different levels of food intake and which differ in reproductive performance

DEFF Research Database (Denmark)

Jothery, Aqeel H. Al; Vaanholt, Lobke M.; Mody, Nimesh

2016-01-01

bred for high (H) or low (L) food intake, which differ in their reproductive performance, i.e., H mice have increased milk energy output (MEO) and wean larger pups. Levels of oxidative damage were unchanged (liver) or reduced (brain and serum) in R versus N mice, and no differences in multiple measures......Oxidative damage caused by reactive oxygen species has been hypothesised to underpin the trade-off between reproduction and somatic maintenance, i.e., the life-history-oxidative stress theory. Previous tests of this hypothesis have proved equivocal, and it has been suggested that the variation...... in responses may be related to the tissues measured. Here, we measured oxidative damage (protein carbonyls, 8-OHdG) and antioxidant protection (enzymatic antioxidant activity and serum antioxidant capacity) in multiple tissues of reproductive (R) and non-reproductive (N) mice from two mouse strains selectively...

Asymptotic weight and maturing rate in mice selected for body conformation

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Di Masso Ricardo J.

2000-01-01

Full Text Available Growth patterns of four lines of mice selected for body conformation were analyzed with the logistic function, in order to provide baseline information about the relationship between asymptotic weight and maturing rate of body weight. Two lines were divergently selected favoring the phenotypic correlation between body weight and tail length (agonistic selection: CBi+, high body weight and long tail; CBi-, low body weight and short tail, whereas the other two lines were generated by a disruptive selection performed against the correlation between the aforementioned traits (antagonistic selection: CBi/C, high body weight and short tail; CBi/L, low body weight and long tail. The logistic parameters A (asymptotic weight and k (maturing rate behaved in CBi/C and CBi- mice and in CBi+ females as expected in terms of the negative genetic relationship between mature size and earliness of maturing. An altered growth pattern was found in CBi/L mice and in CBi+ males, because in the former genotype, selected for low body weight, the time taken to mature increased, whereas in the latter, selected for high body weight, there was a non-significant increase in the same trait. In accordance with the selective criterion, different sources of genetic variation for body weight could be exploited: one inversely associated with earliness of maturing (agonistic selection, and the other independent of maturing rate (antagonistic selection, showing that genetic variation of A is partly independent of k.

Mice in Bion-M 1 Space Mission: Training and Selection

Science.gov (United States)

Andreev-Andrievskiy, Alexander; Popova, Anfisa; Boyle, Richard; Alberts, Jeffrey; Shenkman, Boris; Vinogradova, Olga; Dolgov, Oleg; Anokhin, Konstantin; Tsvirkun, Darya; Soldatov, Pavel; Nemirovskaya, Tatyana; Ilyin, Eugeniy; Sychev, Vladimir

2014-01-01

After a 16-year hiatus, Russia has resumed its program of biomedical research in space, with the successful 30-day flight of the Bion-M 1 biosatellite (April 19–May 19, 2013). The principal species for biomedical research in this project was the mouse. This paper presents an overview of the scientific goals, the experimental design and the mouse training/selection program. The aim of mice experiments in the Bion-M 1 project was to elucidate cellular and molecular mechanisms, underlying the adaptation of key physiological systems to long-term exposure in microgravity. The studies with mice combined in vivo measurements, both in flight and post-flight (including continuous blood pressure measurement), with extensive in vitro studies carried out shortly after return of the mice and in the end of recovery study. Male C57/BL6 mice group housed in space habitats were flown aboard the Bion-M 1 biosatellite, or remained on ground in the control experiment that replicated environmental and housing conditions in the spacecraft. Vivarium control groups were used to account for housing effects and possible seasonal differences. Mice training included the co-adaptation in housing groups and mice adaptation to paste food diet. The measures taken to co-adapt aggressive male mice in housing groups and the peculiarities of “space” paste food are described. The training program for mice designated for in vivo studies was broader and included behavioral/functional test battery and continuous behavioral measurements in the home-cage. The results of the preliminary tests were used for the selection of homogenous groups. After the flight, mice were in good condition for biomedical studies and displayed signs of pronounced disadaptation to Earth's gravity. The outcomes of the training program for the mice welfare are discussed. We conclude that our training program was effective and that male mice can be successfully employed in space biomedical research. PMID:25133741

Prevalence of Balantidium coli Infection in Bred Rhesus Monkeys (Macaca mulatta in Guangxi, southern China.

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Hai Long Li

2014-03-01

Full Text Available Balantidium coli infects humans, primates and pigs, causing serious diarrhea and dysentery. Little information on the prevalence of B. coli in primates is available in China. This investigation was conducted to determine the prevalence of B. coli infection in bred rhesus monkeys in Guangxi Zhuang Nationality Autonomous Region (GZNAR, southern China.A total of 120 fecal samples were collected from rhesus monkeys bred in cages in GZNAR and B. coli cysts and/or trophozoites were examined microscopically after sedimentation with water in May 2013.(64.2% samples were tested positive. The prevalence was 65% (39/60 and 63.3% (38/60 in female and male monkeys, respectively. 80% (48/60 cages in this nonhuman primate center were positive for B. coli.The present survey revealed high circulation of B. coli in bred rhesus monkeys in GZNAR, which poses potential threats to animal and human health.

Antigenic specificity of serum antibodies in mice fed soy protein

DEFF Research Database (Denmark)

Christensen, Hanne Risager; Bruun, S.W.; Frøkiær, Hanne

2003-01-01

Background: Soybean protein is used in a number of food products but unfortunately is also a common cause of food allergy. Upon ingestion of soy protein, healthy mice like other animals and humans generate a soy-specific antibody response in the absence of signs of illness. Not much is known about...... the relationship between the immunogenic proteins involved in this nondeleterious antibody response and the pathological response associated with food allergy. The objective of the present study was to characterize the antigenic specificity of the soy protein-specific antibody response generated in healthy mice...... ingesting soy protein. Methods: Blood from mice fed a soy-containing diet was analyzed using ELISA and immunoblot for antibody reactivity towards various soy protein fractions and pure soy proteins/subunits. Mice bred on a soy-free diet were used as controls. Results: The detectable antigenic specificity...

Learning and extinction of a passive avoidance response in mice with high levels of predisposition to catalepsy.

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Dubrovina, N I; Zinov'ev, D R; Zinov'eva, D V; Kulikov, A V

2009-06-01

This report presents results obtained from comparative analysis of learning and the dynamics of extinction of a conditioned passive avoidance response in ASC mice, which were bred for a high level of predisposition to catalepsy, and in CBA and AKR mice. The following findings were obtained: 1) impairments to the extinction of the memory of fear represent an important symptom of depression in ASC mice; 2) extinction is delayed in CBA mice; and 3) new inhibitory learning occurs quickly in AKR mice. Prolonged retention of the fear memory in ASC mice appears to be related to increased anxiety on prolonged testing without a punishment. The deficit of inhibition of the fear reaction in ASC mice allows this strain to be regarded as a genetic model of depression.

Acquisition of i.v. cocaine self-administration in adolescent and adult male rats selectively bred for high and low saccharin intake

OpenAIRE

Perry, Jennifer L.; Anderson, Marissa M.; Nelson, Sarah E.; Carroll, Marilyn E.

2007-01-01

Adolescence and excessive intake of saccharin have each been previously associated with enhanced vulnerability to drug abuse. In the present study, we focused on the relationship between these two factors using male adolescent and adult rats bred for high (HiS) and low (LoS) levels of saccharin intake. On postnatal day 25 (adolescents) or 150 (adults), rats were implanted with an intravenous catheter and trained to self-administer cocaine (0.4 mg/kg) using an autoshaping procedure that consis...

Natural selection against a circadian clock gene mutation in mice.

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Spoelstra, Kamiel; Wikelski, Martin; Daan, Serge; Loudon, Andrew S I; Hau, Michaela

2016-01-19

Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness.

50 CFR 23.63 - What factors are considered in making a finding that an animal is bred in captivity?

Science.gov (United States)

2010-10-01

... finding that an animal is bred in captivity? 23.63 Section 23.63 Wildlife and Fisheries UNITED STATES FISH... controlled environment; and has general characteristics that may include artificial housing, waste removal... means an ensemble of captive wildlife used for reproduction. (c) Bred-in-captivity criteria. For a...

Sequence analysis of chromosome 1 revealed different selection patterns between Chinese wild mice and laboratory strains.

Science.gov (United States)

Xu, Fuyi; Hu, Shixian; Chao, Tianzhu; Wang, Maochun; Li, Kai; Zhou, Yuxun; Xu, Hongyan; Xiao, Junhua

2017-10-01

Both natural and artificial selection play a critical role in animals' adaptation to the environment. Detection of the signature of selection in genomic regions can provide insights for understanding the function of specific phenotypes. It is generally assumed that laboratory mice may experience intense artificial selection while wild mice more natural selection. However, the differences of selection signature in the mouse genome and underlying genes between wild and laboratory mice remain unclear. In this study, we used two mouse populations: chromosome 1 (Chr 1) substitution lines (C1SLs) derived from Chinese wild mice and mouse genome project (MGP) sequenced inbred strains and two selection detection statistics: Fst and Tajima's D to identify the signature of selection footprint on Chr 1. For the differentiation between the C1SLs and MGP, 110 candidate selection regions containing 47 protein coding genes were detected. A total of 149 selection regions which encompass 7.215 Mb were identified in the C1SLs by Tajima's D approach. While for the MGP, we identified nearly twice selection regions (243) compared with the C1SLs which accounted for 13.27 Mb Chr 1 sequence. Through functional annotation, we identified several biological processes with significant enrichment including seven genes in the olfactory transduction pathway. In addition, we searched the phenotypes associated with the 47 candidate selection genes identified by Fst. These genes were involved in behavior, growth or body weight, mortality or aging, and immune systems which align well with the phenotypic differences between wild and laboratory mice. Therefore, the findings would be helpful for our understanding of the phenotypic differences between wild and laboratory mice and applications for using this new mouse resource (C1SLs) for further genetics studies.

Hyperhidrosis in naïve purpose-bred beagle dogs (Canis familiaris).

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Carrier, Catherine A; Seeman, Jennifer L; Hoffmann, Guenther

2011-05-01

This case study details the unusual clinical findings in a unique paw-pad disorder that recently emerged among 2 male and 1 female naïve purpose-bred beagle dogs (Canis familiaris) newly received into our facility. During acclimation period physical examinations, the affected dogs demonstrated constantly moist, soft paw pads on all 4 feet. No information was available regarding the epidemiology and pathogenesis of this pad condition in beagle dogs. Here, we report the results of physical examination, clinical chemistry analysis, hematology, histopathology, detailed observations, and novel testing techniques performed during the acclimation period. Histopathology of several sections of affected footpads was compared with that of an age-matched dog with clinically normal paw pads. We describe the morphologic features of a distinctive cutaneous canine footpad condition and discuss the possible differential diagnoses. The histologic and clinical features were most consistent with those of hyperhidrosis; to our knowledge, this report is the first description of hyperhidrosis as a distinct condition in purpose-bred beagle dogs.

Life cycle biological efficiency of mice divergently selected for heat loss.

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Bhatnagar, A S; Nielsen, M K

2014-08-01

Divergent selection in mice for heat loss was conducted in 3 independent replicates creating a high maintenance, high heat loss (MH) and low maintenance, low heat loss (ML) line and unselected control (MC). Improvement in feed efficiency was observed in ML mice due to a reduced maintenance energy requirement but there was also a slight decline in reproductive performance, survivability, and lean content, particularly when compared to MC animals. The objective of this study was to model a life cycle scenario similar to a livestock production system and calculate total inputs and outputs to estimate overall biological efficiency of these lines and determine if reduced feed intake resulted in improved life cycle efficiency. Feed intake, reproductive performance, growth, and body composition were recorded on 21 mating pairs from each line × replicate combination, cohabitated at 7 wk of age and maintained for up to 1 yr unless culled. Proportion of animals at each parity was calculated from survival rates estimated from previous research when enforcing a maximum of 4, 8, or 12 allowed parities. This parity distribution was then combined with values from previous studies to calculate inputs and outputs of mating pairs and offspring produced in a single cycle at equilibrium. Offspring output was defined as kilograms of lean output of offspring at 49 d. Offspring input was defined as megacalories of energy intake for growing offspring from 21 to 49 d. Parent output was defined as kilograms of lean output of culled parents. Parent input was defined as megacalories of energy intake for mating pairs from weaning of one parity to weaning of the next. Offspring output was greatest in MC mice due to superior BW and numbers weaned, while output was lowest in ML mice due to smaller litter sizes and lean content. Parent output did not differ substantially between lines but was greatest in MH mice due to poorer survival rates resulting in more culled animals. Input was greatest in

Isolation, Culture, and Motility Measurements of Epidermal Melanocytes from GFP-Expressing Reporter Mice.

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Dagnino, Lina; Crawford, Melissa

2018-03-27

In this article, we provide a method to isolate primary epidermal melanocytes from reporter mice, which also allow targeted gene inactivation. The mice from which these cells are isolated are bred into a Rosa26 mT/mG reporter background, which results in GFP expression in the targeted melanocytic cell population. These cells are isolated and cultured to >95% purity. The cells can be used for gene expression studies, clonogenic experiments, and biological assays, such as capacity for migration. Melanocytes are slow moving cells, and we also provide a method to measure motility using individual cell tracking and data analysis.

Spatial Frequency Selectivity Is Impaired in Dopamine D2 Receptor Knockout Mice

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Souza, Bruno Oliveira Ferreira; Abou Rjeili, Mira; Quintana, Clémentine; Beaulieu, Jean M.; Casanova, Christian

2018-01-01

Dopamine is a neurotransmitter implicated in several brain functions, including vision. In the present study, we investigated the impacts of the lack of D2 dopamine receptors on the structure and function of the primary visual cortex (V1) of D2-KO mice using optical imaging of intrinsic signals. Retinotopic maps were generated in order to measure anatomo-functional parameters such as V1 shape, cortical magnification factor, scatter, and ocular dominance. Contrast sensitivity and spatial frequency selectivity (SF) functions were computed from responses to drifting gratings. When compared to control mice, none of the parameters of the retinotopic maps were affected by D2 receptor loss of function. While the contrast sensitivity function of D2-KO mice did not differ from their wild-type counterparts, SF selectivity function was significantly affected as the optimal SF and the high cut-off frequency (p D2-KO than in WT mice. These findings show that the lack of function of D2 dopamine receptors had no influence on cortical structure whereas it had a significant impact on the spatial frequency selectivity and high cut-off. Taken together, our results suggest that D2 receptors play a specific role on the processing of spatial features in early visual cortex while they do not seem to participate in its development. PMID:29379422

Preliminary study on influences of radioactivity of residential granite building materials upon parent mice and their offspring

International Nuclear Information System (INIS)

Liang Minyi; Zhang Jinghong; Zhu Weiyun; Li Yinyan; Liang Yongqing; Zhang Songshuan; Zhu Daming; Li Jinlin; Lu Qingpu

2006-01-01

Objective: To observe the effects of radioactivity of the residential granite building materials on the survival and fertility of mice. Methods: The radioactivities of A, B, C, and D granite building materials were measured and screened by gamma-ray spectrometer, and then these materials were placed into the mice cages. The residential radon was measured with solid state nuclear track detector's and 24-hour continuous measurement. Ninety-six healthy and ablactated mice were randomly selected and put into the four animal cages with different levels of radioactivity, and fed for 120 days. Mice mated and bred naturally. The fertilities and survivals of P, F 1 , and F 2 generation were observed and analyzed. Results: External exposures in the four mice cages were higher than those from the internal exposure. The differences of rates of pregnancy, abortion, and infertility between the P and F 1 generations had no statistical significance among all the groups after being fed for 120 days (P>0.05). There was significant difference among each group in the fertility of F 1 generation (P< 0.001), and the survival rates of the offspring were decreased with increase of radioactivity in granite building materials (P<0.001). Conclusion: Compared with the residential radon, the gamma rays released from the granite building materials had a greater influence on animals. The study suggested that different granite building materials had different influences on the survival and fertility of mice. (authors)

Differences in exterior conformation between primitive, Half-bred, and Thoroughbred horses: anatomic-breeding approach.

Science.gov (United States)

Komosa, M; Frackowiak, H; Purzyc, H; Wojnowska, M; Gramacki, A; Gramacki, J

2013-04-01

The study included 249 horses belonging to 3 horse breeds. Konik horses, comprising the first group, is an example of a breed similar to the extinct Tarpan. In our study, these horses were taken to be a primitive anatomical model of the horse body. The other groups comprised the Polish Half-bred horse and Thoroughbred horse. The biometric characteristics of the horses were compared based on 24 indices. The aim of the paper was to find a reduced set of indices that can be used to determine group membership of the horses. To do this, we used statistical methods to find the most important indices that best discriminate breeds from each other. Chi-squared statistics, linear discriminant analysis, logistic regression, and 1-way ANOVA showed that the discrimination among groups of horses is connected with these 5 indices: scapula, smaller trunk (distance between tubercle of humerus and coxal tuber), greater trunk (distance between tubercle of humerus and ischial tuberosity), metacarpus circumference, and hind autopodium-smaller trunk. Thoroughbred and Half-bred horses are clearly different in exterior conformation from Konik horses. The differences between Thoroughbred and Half-bred horses are more subtle. The conformation of Thoroughbreds is jointly determined by relatively small differences in a range of features.

Bull fertility evaluations for Angus service sires bred to Holstein cows

Science.gov (United States)

Sire conception rate (SCR), a phenotypic evaluation of service-sire fertility implemented in August 2008, is based on data from the most recent 4 years, conventional-semen breedings up to 7 services, and cow parities 1 through 5. Many US dairy cows are now being bred to Angus sires because beef pric...

Comparative functional anatomy of the epaxial musculature of dogs (Canis familiaris) bred for sprinting vs. fighting.

Science.gov (United States)

Webster, Emma L; Hudson, Penny E; Channon, Sarah B

2014-09-01

The axial musculoskeletal system of quadrupedal mammals is not currently well understood despite its functional importance in terms of facilitating postural stability and locomotion. Here we examined the detailed architecture of the muscles of the vertebral column of two breeds of dog, the Staffordshire bull terrier (SBT) and the racing greyhound, which have been selectively bred for physical combat and high speed sprint performance, respectively. Dissections of the epaxial musculature of nine racing greyhounds and six SBTs were carried out; muscle mass, length, and fascicle lengths were measured and used to calculate muscle physiological cross-sectional area (PCSA), and to estimate maximum muscle potential for force, work and power production. The longissimus dorsi muscle was found to have a high propensity for force production in both breeds of dog; however, when considered in combination with the iliocostalis lumborum muscle it showed enhanced potential for production of power and facilitating spinal extension during galloping gaits. This was particularly the case in the greyhound, where the m. longissimus dorsi and the m. iliocostalis lumborum were estimated to have the potential to augment hindlimb muscle power by ca. 12%. Breed differences were found within various other muscles of the axial musculoskeletal system, particularly in the cranial cervical muscles and also the deep muscles of the thorax which insert on the ribs. These may also highlight key functional adaptations between the two breeds of dog, which have been selectively bred for particular purposes. Additionally, in both breeds of dog, we illustrate specialisation of muscle function by spinal region, with differences in both mass and PCSA found between muscles at varying levels of the axial musculoskeletal system, and between muscle functional groups. © 2014 Anatomical Society.

Comparison of productive and reproductive performance and hair cortisol levels between Brown Swiss cross-bred and Holstein cows housed in the same barn.

Science.gov (United States)

Endo, Natsumi; Kuroki, Reimi; Tanaka, Tomomi

2017-10-01

The productive and reproductive characteristics of Brown Swiss (B) cross-bred cows were investigated by comparing with those of Holstein (H) cows housed in the same barn. Additionally, their hair cortisol levels were analyzed to evaluate the extent of stress experienced during dry and lactation periods. B cross-bred cows had lower milk yields and higher milk fat rates than H cows. Reproductive records showed that days from parturition to first artificial insemination (AI) in B cross-bred (n = 16) and H (n = 27) cows were not significantly different, but conception rate at first AI of B cross-bred cows tended to be higher than that of H cows. Percentage of B cross-bred cows that resumed ovarian cyclic activity within 45 days after parturition was higher than that of H cows (6/6 (100%) and 5/11 (45.5%), P cows had higher body condition scores at that time. Hair cortisol level at 60 to 90 days after parturition in H cows increased significantly compared with in the dry period, and it was higher than that of B cows during the same period. These results suggest that B cross-bred cows experience less metabolic stress during early lactation, which may result in earlier resumption of reproductive function. © 2017 Japanese Society of Animal Science.

Evolution of Peromyscus leucopus mice in response to a captive environment.

Directory of Open Access Journals (Sweden)

Robert C Lacy

Full Text Available Many wildlife species are propagated in captivity as models for behavioral, physiological, and genetic research or to provide assurance populations to protect threatened species. However, very little is known about how animals evolve in the novel environment of captivity. The histories of most laboratory strains are poorly documented, and protected populations of wildlife species are usually too small and too short-term to allow robust statistical analysis. To document the evolutionary change in captive breeding programs, we monitored reproduction and behavior across 18 generations in six experimental populations of Peromyscusleucopus mice started from a common set of 20 wild-caught founders. The mice were propagated under three breeding protocols: a strategy to retain maximal genetic diversity, artificial selection against stereotypic behaviors that were hypothesized to reflect poor adaptation to captivity, and random bred controls. Two replicates were maintained with each protocol, and inter-replicate crosses at generations 19 and 20 were used to reverse accumulated inbreeding. We found that one of the stereotypic behaviors (repetitive flipping was positively associated with reproductive fitness, while the other (gnawing was relatively invariant. Selection to reduce these stereotypic behaviors caused marked reduction in reproduction, and populations not under artificial selection to reduce these behaviors responded with large increases in flipping. In non-selected populations, there was rapid evolution toward much higher proportion of pairs breeding and more rapid conception. Litter size, pup survival, and weaning mass all declined slowly, to the extent that would be predicted based on inbreeding depression. Inter-crossing between replicate populations reversed these declines in fitness components but did not reverse the changes in behavior or the accelerated breeding. These findings indicate that adaptation to captivity can be rapid

Differences in muscarinic acetylcholine receptor subtypes in the central nervous system of long sleep and short sleep mice

International Nuclear Information System (INIS)

Watson, M.; Ming, X.; McArdle, J.J.

1989-01-01

Differences in voluntary ethanol consumption have been noted in various inbred strains of mice and pharmacogenetic approaches have been used to study the mechanisms of action of many drugs such as ethanol. Long-sleep (LS) and short-sleep (SS) mice, selectively bred for differences in ethanol induced narcosis, provide a method by which a relationship between the differential responsiveness of these geno-types and muscarinic acetylcholine receptors (mAChR) may be evaluated. Sleep times after injection of 3ml ethanol/kg (i.p.) verified the higher sensitivity of LS vs. SS. Mean body weights of LS (26.5g) vs. SS (22g) were also significantly (p 3 H](-) quinuclidinylbenzilate ([ 3 H](-)QNB), a specific but nonsubtype selective mAChR antagonist, [ 3 H]pirenzepine ([ 3 H]PZ), a specific M1 mAChR antagonist and [ 3 H]11-2-[[2-[(diethylamino) methyl]-1-piperidinyl] acetyl]-5,11-dihydro-6H-pyrido (2,3-b) (1,4) benzodiazepine-6-one, ([ 3 H]AF-DX 116), an M2 selective antagonist were performed to determine mAChR affinity (K d ) and density (B max ) in CNS regions such as the cerebral cortex, hippocampus, corpus striatum and other areas. Significantly lower (30-40%) [ 3 H](-)QNB binding suggests that SS have fewer mAChR's than LS in many areas. These differences may relate to their differential ethanol sensitivity

Immune selection of tumor cells in TCR β-chain transgenic mice.

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Silaeva, Yulia Yu; Grinenko, Tatyana S; Vagida, Murad S; Kalinina, Anastasia A; Khromykh, Ludmila M; Kazansky, Dmitry B

2014-10-01

The concept of immunological surveillance implies that immunogenic variants of tumor cells arising in the organism can be recognized by the immune system. Tumor progression is provided by somatic evolution of tumor cells under the pressure of the immune system. The loss of MHC Class I molecules on the surface of tumor cells is one of the most known outcomes of immune selection. This study developed a model of immune selection based on the immune response of TCR 1d1 single β-chain transgenic B10.D2(R101) (K(d)I(d)D(b)) mice to allogeneic EL4 (H-2(b)) thymoma cells. In wild-type B10.D2(R101) mice, immunization with EL4 cells induced a vigorous CTL response targeted to the H-2K(b) molecule and results in full rejection of the tumor cells. In contrast, transgenic mice developed a compromised proliferative response in mixed-lymphocyte response assays and were unable to reject transplanted allogeneic EL4 cells. During the immune response to EL4 cells, CD8(+) T-lymphocytes with endogenous β-chains accumulated predominantly in the spleen of transgenic mice and only a small part of the T-lymphocytes expressing transgenic β-chains became CD8(+)CD44(+)CD62L(-) effectors. Then, instead of a full elimination of tumor cells as in wild-type mice, a reproducible prolonged equilibrium phase and subsequent escape was observed in transgenic mice that resulted in death of 90% of the mice in 40-60 days after grafting. Prolonged exposure of tumor cells to the pressure of the immune system in transgenic mice in vivo resulted in a stable loss of H-2K(b) molecules on the EL4 cell surface. Genetic manipulation of the T-lymphocyte repertoire was sufficient to reproduce the classic pattern of interactions between tumor cells and the immune system, usually observed in reliable syngeneic models of anti-tumor immunity. This newly-developed model could be used in further studies of immunoregulatory circuits common for transplantational and anti-tumor immune responses.

Evolution of the additive genetic variance–covariance matrix under continuous directional selection on a complex behavioural phenotype

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Careau, Vincent; Wolak, Matthew E.; Carter, Patrick A.; Garland, Theodore

2015-01-01

Given the pace at which human-induced environmental changes occur, a pressing challenge is to determine the speed with which selection can drive evolutionary change. A key determinant of adaptive response to multivariate phenotypic selection is the additive genetic variance–covariance matrix (G). Yet knowledge of G in a population experiencing new or altered selection is not sufficient to predict selection response because G itself evolves in ways that are poorly understood. We experimentally evaluated changes in G when closely related behavioural traits experience continuous directional selection. We applied the genetic covariance tensor approach to a large dataset (n = 17 328 individuals) from a replicated, 31-generation artificial selection experiment that bred mice for voluntary wheel running on days 5 and 6 of a 6-day test. Selection on this subset of G induced proportional changes across the matrix for all 6 days of running behaviour within the first four generations. The changes in G induced by selection resulted in a fourfold slower-than-predicted rate of response to selection. Thus, selection exacerbated constraints within G and limited future adaptive response, a phenomenon that could have profound consequences for populations facing rapid environmental change. PMID:26582016

Evolution of the additive genetic variance-covariance matrix under continuous directional selection on a complex behavioural phenotype.

Science.gov (United States)

Careau, Vincent; Wolak, Matthew E; Carter, Patrick A; Garland, Theodore

2015-11-22

Given the pace at which human-induced environmental changes occur, a pressing challenge is to determine the speed with which selection can drive evolutionary change. A key determinant of adaptive response to multivariate phenotypic selection is the additive genetic variance-covariance matrix ( G: ). Yet knowledge of G: in a population experiencing new or altered selection is not sufficient to predict selection response because G: itself evolves in ways that are poorly understood. We experimentally evaluated changes in G: when closely related behavioural traits experience continuous directional selection. We applied the genetic covariance tensor approach to a large dataset (n = 17 328 individuals) from a replicated, 31-generation artificial selection experiment that bred mice for voluntary wheel running on days 5 and 6 of a 6-day test. Selection on this subset of G: induced proportional changes across the matrix for all 6 days of running behaviour within the first four generations. The changes in G: induced by selection resulted in a fourfold slower-than-predicted rate of response to selection. Thus, selection exacerbated constraints within G: and limited future adaptive response, a phenomenon that could have profound consequences for populations facing rapid environmental change. © 2015 The Author(s).

Chemical form of tritium released from solid breeder materials and the influences of it on a bred tritium recovery systems

International Nuclear Information System (INIS)

Furukubo, Y.; Nishikawa, M.; Nishida, Y.; Kinjyo, T.; Tanifuji, Takaaki; Kawamura, Yoshinori; Enoeda, Mikio

2004-01-01

The ratio of HTO in total tritium was measured at release of the bred tritium to the purge gas with hydrogen using the thermal release after irradiation method, where neutron irradiation was performed at JRR-3 reactor in JAERI or KUR reactor in Kyoto University. It is experimentally confirmed in this study that not a small portion of bred tritium is released to the purge gas in the form of HTO form ceramic breeder materials even when hydrogen is added to the purge gas. The chemical composition is to be decided by the competitive reaction at the grain surface of a ceramic breeder material where desorption reaction, isotope exchange reaction 1, isotope exchange reaction 2 and water formation reaction are considered to take part. Observation in this study implies that it is necessary to have a bred tritium recovery system applicable for both HT and HTO form to recover whole bred tritium. The chemical composition also decides the amount of tritium transferable to the cooling water of the electricity generation system through the structural material in the blanket system. Permeation behavior of tritium through some structural materials at various conditions are also discussed. (author)

Born to be free? Assessing the viability of releasing captive-bred wobbegongs to restock depleted populations

Directory of Open Access Journals (Sweden)

Kathryn Asha Lee

2015-04-01

Full Text Available Large predatory fishes, such as sharks, play an important functional role within marine ecosystems. Restocking of depleted populations has been extensively studied for commercially or recreationally important teleost fish species; however, it has, to the best of our knowledge, never been successfully attempted and assessed on sharks. We evaluated whether fifteen captive-bred wobbegongs (Orectolobus maculatus released into a small bay inhabited by wild sharks would survive and remain within a small ‘no-take’ marine reserve. The captive-bred sharks and twelve wild sharks were tagged with acoustic transmitters and their presence was monitored by an array of acoustic receivers. The detection rate of control tags was modelled against environmental variables to predict detection probabilities and account for days when environmental conditions hampered shark detections. The overall detection probability ranged from 28% to 38% and was most affected by wind direction. Wild wobbegongs showed clear seasonal patterns of attendance to the study site, with the highest probability of presence during the summer months. The captive-bred sharks did not display the same seasonal trend in occurrence. The age at which captive-bred sharks were released into the area affected residency periods. Four out of five adults remained in the area for up to three years post release, while all the juveniles permanently left the area within a year post-release. Three of the juveniles were detected on receivers up to 12 km from the study site. Therefore, if restocking of depleted populations of sharks is to be used as a conservation strategy, the age at which sharks are released must be considered.

RADISH CULTIVARS BRED AT VNIISSOK AND THEIR USE

Directory of Open Access Journals (Sweden)

M. I. Fedorova

2016-01-01

Full Text Available On the base of comparative assessment and average data estimation from 2010 to 2015, the characteristics of 11 cultivars bred at VNIISSOK were described regarding yield capacity and its components, variation, interdependencies at two sowing terms winter,spring time, direction of selection and cultivar uses at cultivar maintaining breeding program. Cultivar 'Koroleva Margo' is rather used in breeding program for yield capacity and taste qualities. Cultivar 'Sonata' is a source of such features as early maturity, valuable biochemical content and low nitrate accumulation. Cultivar 'Sofit' is known to bear early maturity and simultaneous seed maturation. 'Ariya' is a source of cylindrical root shape and early maturation. Cultivar 'Teplichnyi Gribovskyi' is used in breeding program for early maturation and simultaneous seed maturation. Cultivar 'Feya' bearsresistance to bolting and valuable biochemical substances. Cultivar 'Variant' has such features as root density, ability to grow under low lighting, short-term storability.  Purple-red with white tips is a newmade cultivar 'Mavr' suitable for breeding program for valuable biochemical content, unusual root color, also bearing male sterile forms (MS for heterosis hybrid breeding. Out of all cultivars regarded, 'Mokhovskiy' is only a genetic source to breed radish forms with edible leaves. The positive weak dependence was revealed between cultivar biochemical characteristics, root weight, dry matter  content, and nitrate content; whereas the positive middle dependence is revealed with sugar contents and negative dependence with ascorbic acid content. According to  iochemical characteristics, the best cultivar population as 'Ariya', 'Sonata' (ascorbic acid; Mavr, Sonata, Variant (dry matter, sugars have been chosen. Cultivars 'Koroleva Margo', Pheya, Sonata, Sophit, Mokhovskiy are the initial breeding accessions for selection of new cultivar population, MS and MF lines needed for heterosis.

Rats bred for high alcohol drinking are more sensitive to delayed and probabilistic outcomes.

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Wilhelm, C J; Mitchell, S H

2008-10-01

Alcoholics and heavy drinkers score higher on measures of impulsivity than nonalcoholics and light drinkers. This may be because of factors that predate drug exposure (e.g. genetics). This study examined the role of genetics by comparing impulsivity measures in ethanol-naive rats selectively bred based on their high [high alcohol drinking (HAD)] or low [low alcohol drinking (LAD)] consumption of ethanol. Replicates 1 and 2 of the HAD and LAD rats, developed by the University of Indiana Alcohol Research Center, completed two different discounting tasks. Delay discounting examines sensitivity to rewards that are delayed in time and is commonly used to assess 'choice' impulsivity. Probability discounting examines sensitivity to the uncertain delivery of rewards and has been used to assess risk taking and risk assessment. High alcohol drinking rats discounted delayed and probabilistic rewards more steeply than LAD rats. Discount rates associated with probabilistic and delayed rewards were weakly correlated, while bias was strongly correlated with discount rate in both delay and probability discounting. The results suggest that selective breeding for high alcohol consumption selects for animals that are more sensitive to delayed and probabilistic outcomes. Sensitivity to delayed or probabilistic outcomes may be predictive of future drinking in genetically predisposed individuals.

Radiation-induced dominant skeletal mutations in mice: mutation rate, characteristics, and usefulness in estimating genetic hazard to humans from radiation

International Nuclear Information System (INIS)

Selby, P.B.

1979-01-01

The work discussed in this paper represents a major advance in the difficult task of trying to estimate the effects that an increase in mutation frequency would have on human health. Male mice were bred to three females prior to being killed and skeleton studies made. Guidelines were instituted for checking progeny mutations. Surprising results showed a mutation frequency of 1.4% per gamete where none would have been expected. It is now clear that mice can be greatly deformed without showing external effects

Inhibition shapes selectivity to vocalizations in the inferior colliculus of awake mice

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Zachary eMayko

2012-10-01

Full Text Available The inferior colliculus (IC is a major center for integration of auditory information as itreceives ascending projections from a variety of brainstem nuclei as well as descending projectionsfrom the thalamus and auditory cortex. The ascending projections are both excitatory andinhibitory and their convergence at the IC results in a microcircuitry that is important forshaping responses to simple, binaural, and modulated sounds in the IC. Here, we examined therole inhibition plays in shaping selectivity to vocalizations in the IC of awake, normal-hearingadult mice (CBA/CaJ strain. Neurons in the IC of mice show selectivity in their responses tovocalizations, and we hypothesized that this selectivity is created by inhibitory microcircuitryin the IC. We compared single unit responses in the IC to pure tones and a variety of ultrasonicmouse vocalizations before and after iontophoretic application of GABAA receptor (GABAARand glycine receptor (GlyR antagonists. The most pronounced effects of blocking GABAAR andGlyR on IC neurons were to increase spike rates and broaden excitatory frequency tuning curvesin response to pure tone stimuli, and to decrease selectivity to vocalizations. Thus, inhibitionplays an important role in creating selectivity to vocalizations in the inferior colliculus.

Classical genetic analyses of responses to sedative-hypnotic drugs in crosses derived from long-sleep and short-sleep mice.

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de Fiebre, C M; Marley, R J; Miner, L L; de Fiebre, N E; Wehner, J M; Collins, A C

1992-06-01

A classical (Mendelian) genetic analysis of responses to eight sedative-hypnotic compounds (ethanol, urethane, trifluoroethanol, chloral hydrate, barbital, paraldehyde, methyprylon, pentobarbital) was conducted in crosses derived from mouse lines that were selectively bred for differential duration of anesthesia following ethanol. The sleep-time responses of these mice, the long-sleep (LS) and short-sleep (SS) mouse lines, as well as the F1, F2 and backcross (F1 x LS, F1 x SS) generations were measured. Generally, differences in responses among the generations were greater for water soluble compounds than were differences for more lipid soluble compounds. Also, the inheritance of responses to water soluble compounds could be explained primarily by additive effects of alleles while the inheritance patterns for more lipid soluble compounds were more complex. Genetic correlation with ethanol response decreased with increasing lipophilicity. These results suggest that the selection of the LS-SS mouse lines was specific for water soluble anesthetic agents. Because several of these agents are known to act at GABA receptors, examination of the interactions of compounds which differ in lipid solubility at GABA receptors from LS and SS mice may prove useful in elucidating the mechanism of the anesthetic actions of ethanol and other drugs.

Incidence and risk factors of milk fever among cross-bred dairy cows ...

African Journals Online (AJOL)

The study was conducted on 206 cross-bred dairy cows in different dairy herds in Khartoum State, Sudan, during the period from March 2003 to June 2004 to determine the prevalence and incidence rate of milk fever (MF) based on clinical and laboratory diagnosis, and to recognize the risk factors associated with the ...

First radioactive ions charge bred in REXEBIS at the REX-ISOLDE accelerator

CERN Document Server

Wolf, B H; Fostner, O; Wenander, F; Ames, F; Reisinger, K; Liljeby, L; Skeppstedt, Ö; Jonson, B; Nyman, G H

2003-01-01

REXEBIS is the charge breeder of the REX-ISOLDE post accelerator. The radioactive 1$^{+}$ ions produced at ISOLDE are accumulated, phase-space cooled and bunched in the REXTRAP, and thereafter injected into the EBIS with an energy up to 60 keV. The REXEBIS produced the first charge bred ions in August 2001 and has been running nearly non-stop during September to December 2001. It has delivered stable $^{39}$K$^{10+}$ and $^{23}$Na$^{6+}$ beams generated in the ion source in front of REXTRAP with a Na$^{7+}$ current exceeding 70 pA (6x10$^{7}$ p/s). Stable $^{27}$Al$^{7+}$ and $^{23}$Na$^{6+}$ from ISOLDE and also the first radioactive $^{26}$Na$^{7+}$ and $^{24}$Na$^{7+}$ beams (just 5x10$^{5}$ p/s) have been charge bred and accelerated for tests of the experimental setup. Despite some problems with the electron gun, which had one breakdown after about 1500 hours of operation and displays slow changes of the emission conditions, the EBIS is working remarkably stable (24 hours / 7 days a week). We will report ...

THE INFLUENCE OF MANNAN OLIGOSACCHARIDES ADDED POLEN ON BRED AREAS

OpenAIRE

OLIMPIA COLIBAR; D. POPOVICI; E. CRAINICEANU; GABRIELA KORODI; P. ONITA

2009-01-01

Probiotics and prebiotics (oligosaccharides and acidifying agents) appeared in the place of the old antibiotics. Mannan -oligosaccharides from Saccharomyces cerevisiae (beer-yeast) are used with success in the nutrition of pigs, chickens and rabbits. The beer-yeast is used also in the bee family’s foraging with a major success. The bee-bred which is the protein source for the honey bees contains also many species of yeast. Our experiment of adding mannan -oligosaccharides in the energetic and...

Altered fibre types in gastrocnemius muscle of high wheel-running selected mice with mini-muscle phenotypes.

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Guderley, Helga; Joanisse, Denis R; Mokas, Sophie; Bilodeau, Geneviève M; Garland, Theodore

2008-03-01

Selective breeding of mice for high voluntary wheel running has favoured characteristics that facilitate sustained, aerobically supported activity, including a "mini-muscle" phenotype with markedly reduced hind limb muscle mass, increased mass-specific activities of oxidative enzymes, decreased % myosin heavy chain IIb, and, in the medial gastrocnemius, reduced twitch speed, reduced mass-specific isotonic power, and increased fatigue resistance. To evaluate whether selection has altered fibre type expression in mice with either "mini" or normal muscle phenotypes, we examined fibre types of red and white gastrocnemius. In both the medial and lateral gastrocnemius, the mini-phenotype increased activities of oxidative enzymes and decreased activities of glycolytic enzymes. In red muscle samples, the mini-phenotype markedly changed fibre types, with the % type I and type IIA fibres and the surface area of type IIA fibres increasing; in addition, mice from selected lines in general had an increased % type IIA fibres and larger type I fibres as compared with mice from control lines. White muscle samples from mini-mice showed dramatic structural alterations, with an atypical distribution of extremely small, unidentifiable fibres surrounded by larger, more oxidative fibres than normally present in white muscle. The increased proportion of oxidative fibres and these atypical small fibres together may explain the reduced mass and increased mitochondrial enzyme activities in mini-muscles. These and previous results demonstrate that extension of selective breeding beyond the time when the response of the selected trait (i.e. distance run) has levelled off can still modify the mechanistic underpinnings of this behaviour.

Caffeine stimulates voluntary wheel running in mice without increasing aerobic capacity.

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Claghorn, Gerald C; Thompson, Zoe; Wi, Kristianna; Van, Lindsay; Garland, Theodore

2017-03-01

The "energy drink" Red Bull and the "sports drink" Gatorade are often marketed to athletes, with claims that they cause performance gains. However, both are high in sugars, and also consumed by non-athletes. Few studies have addressed the effects of these drinks or their biologically active components in rodent exercise models. We used three experiments to test effects on both voluntary exercise behavior and maximal aerobic capacity in lines of mice known to differ in "athletic" traits. Mice from four replicate High Runner (HR) lines have been selectively bred for voluntary running on wheels, and run approximately three times as many revolutions per day as do mice from four non-selected Control (C) lines. HR mice also have higher endurance and maximal oxygen consumption (VO 2 max) during forced treadmill exercise. In Experiment 1, we tested the hypothesis that Gatorade or Red Bull might cause or allow mice to increase their voluntary wheel running. On days 5 and 6 of 6days of wheel access, as is used to select breeders, HR mice ran 3.3-fold more than C, and females ran 1.2-fold more than males, with no linetype by sex interaction. On day 7, mice were administered Gatorade, Red Bull or tap water. During the subsequent 19-hour period, Gatorade had no statistical effect on running, but Red Bull significantly increased distance run by both sexes and in both HR and C lines. The increase in distance run caused by Red Bull was attributable to time spent running, not an increase in mean (or maximum) speed. As previous studies have found that sucrose alone does not generally increase wheel running, we tested two other active ingredients in Red Bull, caffeine and taurine, in Experiment 2. With a similar testing protocol, caffeine alone and caffeine+taurine increased running by about half the magnitude of Red Bull. In Experiment 3, we tested the hypothesis that Red Bull or caffeine alone can increase physiological performance ability during aerobic exercise, measured as VO 2

A cytogenetic study of Korean native goat bred in the nuclear power plant using the micronucleus assay

International Nuclear Information System (INIS)

Kang, Chang-Mo; Ji, Young-Hoon; Lee, Hae-June; Kim, Se-Ra; Kim, Jong-Choon; Kim, Sung-Ho

2005-01-01

Cytogenetic and hematological analysis was performed on the peripheral blood lymphocytes (PBLs) obtained from Korean native goats bred in two nuclear power plants (Wolsong and Uljin) and a control area. The frequencies of gamma-ray-induced micronuclei (MN) in the cytokinesis-blocked (CB) lymphocytes at several doses were measured in three Korean native goats. The measurements performed after irradiation showed dose-related increases in the MN frequency in each of the donors. The results were analyzed using a linear-quadratic model with a line of best fit of y=0.1019D+0.0045D 2 +0.0093 (y=number of MN/GB cells and D=irradiation dose in Gy). The MN rates in the goats from the Wolsong and Uljin nuclear power plant, and the control area were 9.60±2.88, 6.83±1.47 and 9.88±4.32 per 1,000 CB lymphocytes, respectively. The apparent difference is not statistically significant. The MN frequencies of PBLs from goats bred in three areas means that the values are within the background variation in this experiment. The MN frequencies and hematological values were similar regardless of whether the goats were bred in the nuclear power plant or the control area. (author)

Quantitative Autoradiography on [(35)S]TBPS Binding Sites of Gamma- Aminobutyric Acid(A) Receptors in Discrete Brain Regions of High- Alcohol-Drinking and Low-Alcohol- Drinking Rats Selectively Bred forHigh- and Low-Alcohol Preference.

Science.gov (United States)

Hwang, B.H.; Kunkler, P.E.; Lumeng, L.

1997-01-01

It has been documented that ethanol can potentiate brain gamma-aminobutyric acid (GABA)ergic function, and there is a close link between the GABA(A) receptor complex and effects of ethanol, including reinforcement of alcohol which is a fundamental element of alcohol preference. However, it is unknown in what discrete brain regions GABA(A) receptors might be associated with alcohol preference. In the present study, [(35)S]t-butylbicyclophosphorothionate ([(35)S]TBPS) was used to localize GABA(A) receptors in high-alcohol-drinking (HAD) rats and low-alcohol-drinking (LAD) rats which were selectively bred for high and low alcohol preference, respectively. Initial qualitative observations indicated that [(35)S]TBPS binding sites were abundant in many brain areas including the cerebral cortex, hypothalamus and amygdala of HAD and LAD rats. Furthermore, the quantitative autoradiographic analysis revealed fewer [(35)S]TBPS binding sites of GABA(A) receptors in the amygdaloid complex, central medial thalamic nucleus, lateral hypothalamic nucleus and anterior hypothalamic nucleus of HAD rats than LAD rats. Collectively, this study has indicated that HAD rats selectively bred for high alcohol preference possess lower [(35)S]TBPS binding in the brain. Since lower TBPS binding has been proposed to reflect enhanced GABAergic function, as evidenced in rats with seizure or under alcohol withdrawal, the results from the present study suggest that HAD rats might have an enhanced GABAergic function. It is thus likely that enhanced GABAergic function in the brain might be related to high alcohol preference which is characteristic in HAD rats. In addition, the present result showing no difference of [(35)S]TBPS binding in the nucleus accumbens is also in agreement with a notion that [(35)S]TBPS binding may represent only a small spectrum of the GABA(A) receptor complex which is constituted of a sophisticated subunit combination whose functional compositions are still unknown. In

Do wood mice (Apodemus sylvaticus L.) use food selection as a means to reduce heavy metal intake?

International Nuclear Information System (INIS)

Beernaert, Joke; Scheirs, Jan; Brande, Greet van den; Leirs, Herwig; Blust, Ronny; Meulenaer, Bruno de; Camp, John van; Verhagen, Ron

2008-01-01

Food preference of wood mice from two with heavy metals polluted sites and two unpolluted sites was tested under laboratory and field conditions with two-way choice experiments. In the laboratory, wood mice preferred to eat acorns from unpolluted sites over acorns from polluted sites. Previous experience with polluted food had no influence on food choice. Preference was negatively related to acorn metal content. Furthermore, the nutrient content of the acorn endosperm was consistently lower in polluted sites. We therefore conclude that wood mice used absolute metal concentration in the acorn, nutrient content, or both as a food selection cue. The results of the laboratory experiment could not be confirmed under field conditions. We hypothesized that search time constraints due to the presence of predators, competitors and/or other stress factors in the field have prevented the mice to forage selectively. - Wood mice prefer unpolluted food items over polluted food items in laboratory trials but not in field situations

Focal glomerulosclerosis in proviral and c-fms transgenic mice links Vpr expression to HIV-associated nephropathy

International Nuclear Information System (INIS)

Dickie, Peter; Roberts, Amanda; Uwiera, Richard; Witmer, Jennifer; Sharma, Kirti; Kopp, Jeffrey B.

2004-01-01

Clinical and morphologic features of human immunodeficiency virus (HIV)-associated nephropathy (HIVAN), such as proteinuria, sclerosing glomerulopathy, tubular degeneration, and interstitial disease, have been modeled in mice bearing an HIV proviral transgene rendered noninfectious through a deletion in gag/pol. Exploring the genetic basis of HIVAN, HIV transgenic mice bearing mutations in either or both of the accessory genes nef and vpr were created. Proteinuria and focal glomerulosclerosis (FGS) only developed in mice with an intact vpr gene. Transgenic mice bearing a simplified proviral DNA (encoding only Tat and Vpr) developed renal disease characterized by FGS in which Vpr protein was localized to glomerular and tubular epithelia by immunohistochemistry. The dual transgenic progeny of HIV[Tat/Vpr] mice bred to HIV[ΔVpr] proviral transgenic mice displayed a more severe nephropathy with no apparent increase in Vpr expression, implying that multiple viral genes contribute to HIVAN. However, the unique contribution of macrophage-specific Vpr expression in the development of glomerular disease was underscored by the induction of FGS in multiple murine lines bearing a c-fms/vpr transgene

Isolation of hair follicle bulge stem cells from YFP-expressing reporter mice.

Science.gov (United States)

Nakrieko, Kerry-Ann; Irvine, Timothy S; Dagnino, Lina

2013-01-01

In this article we provide a method to isolate hair follicle stem cells that have undergone targeted gene inactivation. The mice from which these cells are isolated are bred into a Rosa26-yellow fluorescent protein (YFP) reporter background, which results in YFP expression in the targeted stem cell population. These cells are isolated and purified by fluorescence-activated cell sorting, using epidermal stem cell-specific markers in conjunction with YFP fluorescence. The purified cells can be used for gene expression studies, clonogenic experiments, and biological assays, such as viability and capacity for directional migration.

Selective Glucocorticoid Receptor (GR-II Antagonist Reduces Body Weight Gain in Mice

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Tomoko Asagami

2011-01-01

Full Text Available Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (=8 received one of the following: CORT 108297 (80 mg/kg QD, CORT 108297 (40 mg/kg BID, mifepristone (30 mg/kg BID, rosiglitazone (10 mg/kg QD, or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.

Selective impairment of subcategories of long-term memory in mice with hippocampal lesions accessed by the olfactory tubing maze.

Science.gov (United States)

Chaillan, F A; Marchetti, E; Soumireu-Mourat, B; Roman, F S

2005-03-30

A new apparatus, the olfactory tubing maze for mice, was developed recently to study learning and memory processes in mice in regard to their ethological abilities. As in humans, BALB/c mice with selective bilateral lesions of the hippocampal formation showed selective impairment of subcategories of long-term memory when tested with the olfactory tubing maze. After three learning sessions, control mice reached a high percentage of correct responses. They consistently made the olfactory-reward associations, but antero-dorsal and postero-ventral hippocampal-lesioned mice did not. However, all lesioned mice learned the paradigm and the timing of the task as fast and as well as control mice. These data suggest that the olfactory tubing maze can be used to study subcategories of memory, such as declarative and non-declarative memory, which are similar in some respects to those observed in humans. Consequently, possible memory effects of classical approaches (i.e., pharmacological or lesion studies) or genetic modifications in transgenic or gene-targeting mice can be effectively analyzed using this new apparatus.

Acute Restraint Stress Alters Wheel-Running Behavior Immediately Following Stress and up to 20 Hours Later in House Mice.

Science.gov (United States)

Malisch, Jessica L; deWolski, Karen; Meek, Thomas H; Acosta, Wendy; Middleton, Kevin M; Crino, Ondi L; Garland, Theodore

In vertebrates, acute stressors-although short in duration-can influence physiology and behavior over a longer time course, which might have important ramifications under natural conditions. In laboratory rats, for example, acute stress has been shown to increase anxiogenic behaviors for days after a stressor. In this study, we quantified voluntary wheel-running behavior for 22 h following a restraint stress and glucocorticoid levels 24 h postrestraint. We utilized mice from four replicate lines that have been selectively bred for high voluntary wheel-running activity (HR mice) for 60 generations and their nonselected control (C) lines to examine potential interactions between exercise propensity and sensitivity to stress. Following 6 d of wheel access on a 12L∶12D photo cycle (0700-1900 hours, as during the routine selective breeding protocol), 80 mice were physically restrained for 40 min, beginning at 1400 hours, while another 80 were left undisturbed. Relative to unrestrained mice, wheel running increased for both HR and C mice during the first hour postrestraint (P Wheel running was also examined at four distinct phases of the photoperiod. Running in the period of 1600-1840 hours was unaffected by restraint stress and did not differ statistically between HR and C mice. During the period of peak wheel running (1920-0140 hours), restrained mice tended to run fewer revolutions (-11%; two-tailed P = 0.0733), while HR mice ran 473% more than C (P = 0.0008), with no restraint × line type interaction. Wheel running declined for all mice in the latter part of the scotophase (0140-0600 hours), restraint had no statistical effect on wheel running, but HR again ran more than C (+467%; P = 0.0122). Finally, during the start of the photophase (0720-1200 hours), restraint increased running by an average of 53% (P = 0.0443) in both line types, but HR and C mice did not differ statistically. Mice from HR lines had statistically higher plasma corticosterone concentrations

Exercise training effects on hypoxic and hypercapnic ventilatory responses in mice selected for increased voluntary wheel running.

Science.gov (United States)

Kelly, Scott A; Rezende, Enrico L; Chappell, Mark A; Gomes, Fernando R; Kolb, Erik M; Malisch, Jessica L; Rhodes, Justin S; Mitchell, Gordon S; Garland, Theodore

2014-02-01

What is the central question of this study? We used experimental evolution to determine how selective breeding for high voluntary wheel running and exercise training (7-11 weeks) affect ventilatory chemoreflexes of laboratory mice at rest. What is the main finding and its importance? Selective breeding, although significantly affecting some traits, did not systematically alter ventilation across gas concentrations. As with most human studies, our findings support the idea that endurance training attenuates resting ventilation. However, little evidence was found for a correlation between ventilatory chemoreflexes and the amount of individual voluntary wheel running. We conclude that exercise 'training' alters respiratory behaviours, but these changes may not be necessary to achieve high levels of wheel running. Ventilatory control is affected by genetics, the environment and gene-environment and gene-gene interactions. Here, we used an experimental evolution approach to test whether 37 generations of selective breeding for high voluntary wheel running (genetic effects) and/or long-term (7-11 weeks) wheel access (training effects) alter acute respiratory behaviour of mice resting in normoxic, hypoxic and hypercapnic conditions. As the four replicate high-runner (HR) lines run much more than the four non-selected control (C) lines, we also examined whether the amount of exercise among individual mice was a quantitative predictor of ventilatory chemoreflexes at rest. Selective breeding and/or wheel access significantly affected several traits. In normoxia, HR mice tended to have lower mass-adjusted rates of oxygen consumption and carbon dioxide production. Chronic wheel access increased oxygen consumption and carbon dioxide production in both HR and C mice during hypercapnia. Breathing frequency and minute ventilation were significantly reduced by chronic wheel access in both HR and C mice during hypoxia. Selection history, while significantly affecting some traits

Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque

Science.gov (United States)

Powell, David R; Gay, Jason P; Smith, Melinda; Wilganowski, Nathaniel; Harris, Angela; Holland, Autumn; Reyes, Maricela; Kirkham, Laura; Kirkpatrick, Laura L; Zambrowicz, Brian; Hansen, Gwenn; Platt, Kenneth A; van Sligtenhorst, Isaac; Ding, Zhi-Ming; Desai, Urvi

2016-01-01

Delta-5 desaturase (D5D) and delta-6 desaturase (D6D), encoded by fatty acid desaturase 1 (FADS1) and FADS2 genes, respectively, are enzymes in the synthetic pathways for ω3, ω6, and ω9 polyunsaturated fatty acids (PUFAs). Although PUFAs appear to be involved in mammalian metabolic pathways, the physiologic effect of isolated D5D deficiency on these pathways is unclear. After generating >4,650 knockouts (KOs) of independent mouse genes and analyzing them in our high-throughput phenotypic screen, we found that Fads1 KO mice were among the leanest of 3,651 chow-fed KO lines analyzed for body composition and were among the most glucose tolerant of 2,489 high-fat-diet-fed KO lines analyzed by oral glucose tolerance test. In confirmatory studies, chow- or high-fat-diet-fed Fads1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 38% and 31% lower in Fads1 male and female KO mice, respectively. Fads1 KO mice also had lower glucose and insulin excursions during oral glucose tolerance tests along with lower fasting glucose, insulin, triglyceride, and total cholesterol levels. In additional studies using a vascular injury model, Fads1 KO mice had significantly decreased femoral artery intima/media ratios consistent with a decreased inflammatory response in their arterial wall. Based on this result, we bred Fads1 KO and WT mice onto an ApoE KO background and fed them a Western diet for 14 weeks; in this atherogenic environment, aortic trees of Fads1 KO mice had 40% less atheromatous plaque compared to WT littermates. Importantly, PUFA levels measured in brain and liver phospholipid fractions of Fads1 KO mice were consistent with decreased D5D activity and normal D6D activity. The beneficial metabolic phenotype demonstrated in Fads1 KO mice suggests that selective D5D inhibitors may be useful in the treatment of human obesity, diabetes, and atherosclerotic cardiovascular disease. PMID:27382320

Changes in pancreatic somatostatin content in spontaneously diabetic mice, as determined by radioimmunoassay and immunohistochemical methods

International Nuclear Information System (INIS)

Makino, H.; Matsushima, Y.; Kanatsuka, A.; Yamamoto, M.; Kumagai, A.; Nishimura, M.

1979-01-01

A specific RIA for somatostatin (SRIF) was used to determine the SRIF content of the pancreas and hypothalamus in spontaneously diabetic C57BL/KsJ dbdb and C57BL/6J obob mice. In addition, SRIF- and glucagon-containing cells were examined in the pancreatic islets with an immunohistochemical technique. In dbdb mice, immunoassayable pancreatic SRIF content was increased, as was the number of SRIF- or glucagon-containing cells. In obob mice, immunoassayable pancreatic SRIF content was also increased, but no increase was noted in the number of SRIF- or glucagon-containing cells. The hypothalamic SRIF content of either strain was not different from that of controls. These results regarding pancreatic SRIF content were in accord with some but not all previous reports. These differences may be related to the age of the mice or to the conditions in which they were bred. The pancreatic SRIF increase in both dbdb and obob mice may be attributable to hyperglucagonemia, hyperglycemia, or a decrease in insulin action. Further work is necessary to clearly delineate the mechanism

Acquisition of i.v. cocaine self-administration in adolescent and adult male rats selectively bred for high and low saccharin intake.

Science.gov (United States)

Perry, Jennifer L; Anderson, Marissa M; Nelson, Sarah E; Carroll, Marilyn E

2007-05-16

Adolescence and excessive intake of saccharin have each been previously associated with enhanced vulnerability to drug abuse. In the present study, we focused on the relationship between these two factors using male adolescent and adult rats selectively bred for high (HiS) and low (LoS) levels of saccharin intake. On postnatal day 25 (adolescents) or 150 (adults), rats were implanted with an intravenous catheter and trained to self-administer cocaine (0.4 mg/kg) using an autoshaping procedure that consisted of two 6-h sessions. In the first 6 h, rats were given non-contingent cocaine infusions at random intervals 10 times per hour, and during the second 6-h session, rats were allowed to self-administer cocaine under a fixed ratio 1 (FR 1) lever-response contingency. Acquisition was defined as a total of at least 250 infusions over 5 consecutive days, and rats were given 30 days to meet the acquisition criterion. Subsequently, saccharin phenotype scores were determined by comparing 24-h saccharin and water consumption in two-bottle tests to verify HiS/LoS status. Adolescent LoS rats had a faster rate of acquisition of cocaine self-administration than adult LoS rats; however, adolescent and adult HiS rats acquired at the same rate. Both HiS and LoS adolescents had significantly higher saccharin phenotype scores than HiS and LoS adults, respectively. Additionally, saccharin score was negatively correlated with the number of days to meet the acquisition criterion for cocaine self-administration, but this was mostly accounted for by the HiS adolescents. These results suggest that during adolescence, compared with adulthood, rats have both an increased avidity for sweets and vulnerability to initiate drug abuse.

Neuropeptide Y deficiency attenuates responses to fasting and high-fat diet in obesity-prone mice.

Science.gov (United States)

Patel, Hiralben R; Qi, Yong; Hawkins, Evan J; Hileman, Stanley M; Elmquist, Joel K; Imai, Yumi; Ahima, Rexford S

2006-11-01

Neuropeptide Y (NPY) stimulates feeding and weight gain, but deletion of the NPY gene does not affect food intake and body weight in mice bred on a mixed genetic background. We reasoned that the orexigenic action of NPY would be evident in C57Bl/6J mice susceptible to obesity. NPY deficiency has no significant effect in mice fed a normal rodent diet. However, energy expenditure is elevated during fasting, and hyperphagia and weight gain are blunted during refeeding. Expression of agouti-related peptide (AGRP) in the hypothalamus is increased in NPY knockout (NPYko) than wild-type mice, but unlike wild type there is no further increase in AGRP when NPYko mice are fasted. Moreover, NPYko mice have higher oxygen consumption and uncoupling protein-1 expression in brown adipose tissue during fasting. The failure of an increase in orexigenic peptides and higher thermogenesis may contribute to attenuation of weight gain when NPYko mice are refed. C57Bl/6J mice lacking NPY are also less susceptible to diet-induced obesity (DIO) as a result of reduced feeding and increased energy expenditure. The resistance to DIO in NPYko mice is associated with a reduction in nocturnal feeding and increased expression of anorexigenic hypothalamic peptides. Insulin, leptin, and triglyceride levels increase with adiposity in both wild-type and NPYko mice.

Selective reward deficit in mice lacking beta-endorphin and enkephalin.

Science.gov (United States)

Hayward, Michael D; Pintar, John E; Low, Malcolm J

2002-09-15

It has been impossible to unequivocally identify which endogenous opioids modulate the incentive value of rewarding stimuli because these peptides are not highly selective for any single opioid receptor subtype. Here, we present evidence based on the measurement of instrumental behavior of beta-endorphin and enkephalin knock-out mice that both opioid peptides play a positive role. A progressive ratio schedule was used to measure how hard an animal would work for food reinforcers. The loss of either opioid reduced responding under this schedule, regardless of the palatability of the three different formulas of reinforcers used. The phenotype of mice lacking both endogenous opioids was nearly identical to the phenotype of mice mutant for either individual opioid. Responses were tested in nondeprived and deprived feeding states but were reduced in beta-endorphin- and enkephalin-deficient mice only when they were maintained under nondeprived conditions. Other operant manipulations ruled out variables that might contribute nonspecifically to this result such as differences in acquisition, early satiation, motor performance deficit, and reduced resistance to extinction. In contrast to the effects on instrumental performance, the loss of either or both endogenous opioids did not influence preference for water flavored with sucrose or saccharin in a two-bottle free-choice drinking paradigm. We conclude that both beta-endorphin and enkephalin positively contribute to the incentive-motivation to acquire food reinforcers. Because the attenuation of operant responding was observed only during a nondeprived motivational state, the hedonics of feeding are likely altered rather than energy homeostasis.

Selective inbreeding does not increase gut microbiota similarity in BALB/c mice

DEFF Research Database (Denmark)

Pang, Wanyong; Stradiotto, Damiano; Krych, Lukasz

2012-01-01

microbiota. BALB/cCrl mice were, however, found to have a mean heterozygosity of only 0.8% in their genome, and selection of breeders with a high similarity in the gut microbiota for three generations did not change the overall gut microbiota similarity, which was 66% in the P generation and 66%, 64% and 63...

Use of the Open Field Maze to measure locomotor and anxiety-like behavior in mice.

Science.gov (United States)

Seibenhener, Michael L; Wooten, Michael C

2015-02-06

Animal models have proven to be invaluable to researchers trying to answer questions regarding the mechanisms of behavior. The Open Field Maze is one of the most commonly used platforms to measure behaviors in animal models. It is a fast and relatively easy test that provides a variety of behavioral information ranging from general ambulatory ability to data regarding the emotionality of the subject animal. As it relates to rodent models, the procedure allows the study of different strains of mice or rats both laboratory bred and wild-captured. The technique also readily lends itself to the investigation of different pharmacological compounds for anxiolytic or anxiogenic effects. Here, a protocol for use of the open field maze to describe mouse behaviors is detailed and a simple analysis of general locomotor ability and anxiety-related emotional behaviors between two strains of C57BL/6 mice is performed. Briefly, using the described protocol we show Wild Type mice exhibited significantly less anxiety related behaviors than did age-matched Knock Out mice while both strains exhibited similar ambulatory ability.

The ovary is an alternative site of origin for high-grade serous ovarian cancer in mice.

Science.gov (United States)

Kim, Jaeyeon; Coffey, Donna M; Ma, Lang; Matzuk, Martin M

2015-06-01

Although named "ovarian cancer," it has been unclear whether the cancer actually arises from the ovary, especially for high-grade serous carcinoma (HGSC), also known as high-grade serous ovarian cancer, the most common and deadliest ovarian cancer. In addition, the tumor suppressor p53 is the most frequently mutated gene in HGSC. However, whether mutated p53 can cause HGSC remains unknown. In this study, we bred a p53 mutation, p53(R172H), into conditional Dicer-Pten double-knockout (DKO) mice, a mouse model duplicating human HGSC, to generate triple-mutant (TKO) mice. Like DKO mice, these TKO mice develop metastatic HGSCs originating from the fallopian tube. Unlike DKO mice, however, even after fallopian tubes are removed in TKO mice, ovaries alone can develop metastatic HGSCs, indicating that a p53 mutation can drive HGSC arising from the ovary. To confirm this, we generated p53(R172H)-Pten double-mutant mice, one of the genetic control lines for TKO mice. As anticipated, these double-mutant mice also develop metastatic HGSCs from the ovary, verifying the HGSC-forming ability of ovaries with a p53 mutation. Our study therefore shows that ovaries harboring a p53 mutation, as well as fallopian tubes, can be a distinct tissue source of high-grade serous ovarian cancer in mice.

Agonistic activity of tamoxifen, a selective estrogen-receptor modulator (SERM), on arthritic ovariectomized mice

Science.gov (United States)

Silva, L.A.S.; Felix, F.B.; Araujo, J.M.D.; Souza, E.V.; Camargo, E.A.; Grespan, R.

2017-01-01

Arthritis is positively associated with the decline of sex hormones, especially estrogen. Tamoxifen (TMX) is a selective estrogen receptor modulator, possessing agonist or antagonistic activity in different tissues. Thus, the objective of this study was to investigate the effect of TMX on the zymosan-induced arthritis model. Female Swiss normal and ovariectomized (OVX) mice were divided into groups and treated for five days with TMX (0.3, 0.9 or 2.7 mg/kg) or 17-β-estradiol (E2, 50 µg/kg). On the fifth day, arthritis was induced and 4 h later, leukocyte migration into joint cavities was evaluated. The neutrophil migration in OVX animals, but not in normal mice, treated with TMX (all tested doses) was significantly decreased compared with mice that received the vehicle (P≤0.05). Similarly, this effect was also demonstrated in the E2-treated group. Therefore, the present study demonstrates that TMX presented agonist effects in inhibiting neutrophil migration and preventing arthritis progression in OVX mice. PMID:29160416

Lipid solubility of sedative-hypnotic drugs influences hypothermic and hypnotic responses of long-sleep and short-sleep mice.

Science.gov (United States)

De Fiebre, N C; Marley, R J; Wehner, J M; Collins, A C

1992-10-01

The anesthetic potency of many agents, including alcohols, barbiturates and other sedative-hypnotic drugs, is influenced by lipid solubility. Previous studies from our laboratory, however, have demonstrated that genetic factors influence this relationship. We have reported that mouse lines selectively bred for differences in duration of ethanol-induced anesthesia, the long-sleep (LS) and short-sleep (SS) mice, differ in sleep-time response to water-soluble, but not lipid-soluble, sedative-hypnotic drugs. The studies described here sought to determine whether this same relationship exists for the hypothermic response produced by 17 sedative-hypnotic drugs in the LS and SS mice. Dose-response and time course relationships for hypothermic actions were determined and were compared with the dose-related anesthetic effects of the drugs. Hypothermic potencies increased along with lipid solubility for both the LS and SS mouse lines, but the rate of change differed for the two mouse lines. LS mice were more responsive to ethanol and other water-soluble drugs whereas the SS were more responsive to lipid-soluble drugs; significant correlations were obtained between lipid solubility (log P-octanol-water partition coefficient) and relative LS-SS responsiveness to both the hypothermic and hypnotic actions of the 17 test drugs. Thus, both hypnotic and hypothermic actions of sedative-hypnotic drugs are correlated with lipid solubility. Possible explanation for these correlations include greater LS central nervous system sensitivity to water-soluble drugs and LS-SS differences in distribution of lipid-soluble drugs.

Behavioral profiles of genetically selected aggressive and nonaggressive male wild house mice in two anxiety tests

NARCIS (Netherlands)

Hogg, S; Wurbel, H; Steimer, T; de Ruiter, A; Koolhaas, J; Sluyter, F; Driscoll, Peter

2000-01-01

Artificially selected aggressive (SAL) and non-aggressive (LAL) male house mice were tested in a hexagonal tunnel maze and light-dark preference (LD) box to determine if the bidirectional selection for aggressive behavior leads to a coselection for different levels of trait anxiety. The tunnel maze

ENU Mutagenesis in Mice Identifies Candidate Genes For Hypogonadism

Science.gov (United States)

Weiss, Jeffrey; Hurley, Lisa A.; Harris, Rebecca M.; Finlayson, Courtney; Tong, Minghan; Fisher, Lisa A.; Moran, Jennifer L.; Beier, David R.; Mason, Christopher; Jameson, J. Larry

2012-01-01

Genome-wide mutagenesis was performed in mice to identify candidate genes for male infertility, for which the predominant causes remain idiopathic. Mice were mutagenized using N-ethyl-N-nitrosourea (ENU), bred, and screened for phenotypes associated with the male urogenital system. Fifteen heritable lines were isolated and chromosomal loci were assigned using low density genome-wide SNP arrays. Ten of the fifteen lines were pursued further using higher resolution SNP analysis to narrow the candidate gene regions. Exon sequencing of candidate genes identified mutations in mice with cystic kidneys (Bicc1), cryptorchidism (Rxfp2), restricted germ cell deficiency (Plk4), and severe germ cell deficiency (Prdm9). In two other lines with severe hypogonadism candidate sequencing failed to identify mutations, suggesting defects in genes with previously undocumented roles in gonadal function. These genomic intervals were sequenced in their entirety and a candidate mutation was identified in SnrpE in one of the two lines. The line harboring the SnrpE variant retains substantial spermatogenesis despite small testis size, an unusual phenotype. In addition to the reproductive defects, heritable phenotypes were observed in mice with ataxia (Myo5a), tremors (Pmp22), growth retardation (unknown gene), and hydrocephalus (unknown gene). These results demonstrate that the ENU screen is an effective tool for identifying potential causes of male infertility. PMID:22258617

High fat diet prevents over-crowding induced decrease of sex ratio in mice.

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Madhukar Shivajirao Dama

Full Text Available Adaptive theory predicts that mothers would be advantaged by adjusting the sex ratio of their offspring in relation to their offspring's future reproductive success. In the present study, we tested the effect of housing mice under crowded condition on the sex ratio and whether the fat content of the diet has any influence on the outcome of pregnancies. Three-week-old mice were placed on the control diet (NFD for 3 weeks. Thereafter the mice were allotted randomly to two groups of 7 cages each with 4, 6, 8, 10, 12, 14, and 16 mice in every cage to create increasing crowding gradient and fed either NFD or high fat diet (HFD. After 4 weeks, dams were bred and outcomes of pregnancy were analyzed. The average dam body weight (DBW at conception, litter size (LS and SR were significantly higher in HFD fed dams. Further, male biased litters declined with increasing crowding in NFD group but not in HFD. The LS and SR in NFD declined significantly with increasing crowding, whereas only LS was reduced in HFD group. We conclude that female mice housed under overcrowding conditions shift offspring SR in favor of daughters in consistent with the TW hypothesis and high fat diet reduces this influence of overcrowding.

Do wood mice (Apodemus sylvaticus L.) use food selection as a means to reduce heavy metal intake?

DEFF Research Database (Denmark)

Beernaert, Joke; Scheirs, Jan; Brande, Greet Van Den

2008-01-01

Food preference of wood mice from two with heavy metals polluted sites and two unpolluted sites was tested under laboratory and field conditions with two-way choice experiments. In the laboratory, wood mice preferred to eat acorns from unpolluted sites over acorns from polluted sites. Previous...... experience with polluted food had no influence on food choice. Preference was negatively related to acorn metal content. Furthermore, the nutrient content of the acorn endosperm was consistently lower in polluted sites. We therefore conclude that wood mice used absolute metal concentration in the acorn...... selectively. Wood mice prefer unpolluted food items over polluted food items in laboratory trials but not in field situations....

The effect of 2 different housing systems on germ-free mice colonized with a complex gut microbiota

DEFF Research Database (Denmark)

Lundberg, Randi; Toft, Martin Fitzner; August, Benjamin

2015-01-01

Translational animal models are essential prerequisites in exploring functions and causality of the microbiome in human health and disease. Animal models targeted at microbiome research can be germ-free mice inoculated either with a monoculture or with defined (gnotobiotic) or undefined bacterial......, but there is a lack of knowledge on the stability of complex bacterial communities in IVCs. Germ-free SW mice were inoculated with a complex murine microbiota, housed in an isolator or in IVCs and bred for two generations, corresponding to a time course of 5 months. The gut microbiota was characterized by 16S...... Biosciences and Innovation Fund Denmark. The project is a collaboration between Taconic Biosciences, University of Copenhagen and the 3G Centre (Gut, Grain and Greens)....

Reference intervals for hematological parameters of animals bred and kept at the vivarium of the Faculty of Medicine of the State University of São Paulo

Directory of Open Access Journals (Sweden)

Marilda Osti Spinelli

2014-03-01

Full Text Available Knowledge of specific hematological parameters of laboratory animals used in experiments is highly relevant to evaluate functional alterations of their vital organs. Hematological reference rates for rats, mice, rabbits and hamsters, bred in conventional healthy conditions and derived from the Vivarium of the FMUSP’s Vivarium Center are established. One hundred and twenty mice of the strains BALB/c, C57BL / 6 and Swiss, 80 Wistar rats, 80 Golden hamsters and 80 New Zealand rabbits, males and females, apparently normal and healthy, over 10-weeks-old, were employed in current experiment. The analysis was determined by flow cytometry process (CELM CC510 involving the separation of erythrocytes and leukocytes, and cell identification by the suspension method and quantification. Hematological derivatives such as hematometric indexes (application of equations and morphological quantification of leukocytes and erythrocytes were determined by scanning/differential (Panótico-commercial, whereas hemoglobin dosage was determined by spectrophotometry (CELM E210D. Results are given as means and standard deviants of hematological profiles in the blood of the animals grouped by species, strain and sex. Data are an important asset for researchers in their analysis of experimental results. CEAU Certificate n.° 251/11 HCFMUSP.

THE INFLUENCE OF MANNAN OLIGOSACCHARIDES ADDED POLEN ON BRED AREAS

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OLIMPIA COLIBAR

2009-05-01

Full Text Available Probiotics and prebiotics (oligosaccharides and acidifying agents appeared in the place of the old antibiotics. Mannan -oligosaccharides from Saccharomyces cerevisiae (beer-yeast are used with success in the nutrition of pigs, chickens and rabbits. The beer-yeast is used also in the bee family’s foraging with a major success. The bee-bred which is the protein source for the honey bees contains also many species of yeast. Our experiment of adding mannan -oligosaccharides in the energetic and protein feed and of using the artificial bee-bread in the place of pollen shows that those methods didn’t lead an increased performance of the frozen pollen, honey energetic and protein feed.

Low Impact of Avian Pox on Captive-Bred Houbara Bustard Breeding Performance.

Science.gov (United States)

Le Loc'h, Guillaume; Souley, Mam-Noury Amadou; Bertagnoli, Stéphane; Paul, Mathilde C

2017-01-01

Avian pox, a disease caused by avipoxviruses, is a major cause of decline of some endangered bird species. While its impact has been assessed in several species in the wild, effects of the disease in conservation breeding have never been studied. Houbara bustard species ( Chlamydotis undulata and Chlamydotis macqueenii ), whose populations declined in the last decades, have been captive bred for conservation purposes for more than 20 years. While mortality and morbidity induced by avipoxviruses can be controlled by appropriate management, the disease might still affect bird breeding performance and jeopardize the production objectives of conservation programs. Impacts of the disease was studied during two outbreaks in captive-bred juvenile Houbara bustards in Morocco in 2009-2010 and 2010-2011, by modeling the effect of the disease on individual breeding performance (male display and female egg production) of 2,797 birds during their first breeding season. Results showed that the impact of avian pox on the ability of birds to reproduce and on the count of displays or eggs is low and mainly non-significant. The absence of strong impact compared to what could be observed in other species in the wild may be explained by the controlled conditions provided by captivity, especially the close veterinary monitoring of each bird. Those results emphasize the importance of individual management to prevent major disease emergence and their effects in captive breeding of endangered species.

Differential Secondary Reconstitution of In Vivo-Selected Human SCID-Repopulating Cells in NOD/SCID versus NOD/SCID/γ chainnull Mice

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Shanbao Cai

2011-01-01

Full Text Available Humanized bone-marrow xenograft models that can monitor the long-term impact of gene-therapy strategies will help facilitate evaluation of clinical utility. The ability of the murine bone-marrow microenvironment in NOD/SCID versus NOD/SCID/γ chainnull mice to support long-term engraftment of MGMTP140K-transduced human-hematopoietic cells following alkylator-mediated in vivo selection was investigated. Mice were transplanted with MGMTP140K-transduced CD34+ cells and transduced cells selected in vivo. At 4 months after transplantation, levels of human-cell engraftment, and MGMTP140K-transduced cells in the bone marrow of NOD/SCID versus NSG mice varied slightly in vehicle- and drug-treated mice. In secondary transplants, although equal numbers of MGMTP140K-transduced human cells were transplanted, engraftment was significantly higher in NOD/SCID/γ chainnull mice compared to NOD/SCID mice at 2 months after transplantation. These data indicate that reconstitution of NOD/SCID/γ chainnull mice with human-hematopoietic cells represents a more promising model in which to test for genotoxicity and efficacy of strategies that focus on manipulation of long-term repopulating cells of human origin.

Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice.

Science.gov (United States)

Lambert, G; Sakai, N; Vaisman, B L; Neufeld, E B; Marteyn, B; Chan, C C; Paigen, B; Lupia, E; Thomas, A; Striker, L J; Blanchette-Mackie, J; Csako, G; Brady, J N; Costello, R; Striker, G E; Remaley, A T; Brewer, H B; Santamarina-Fojo, S

2001-05-04

To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.

The Genetic Variability of Floral and Agronomic Characteristics of Newly-Bred Cytoplasmic Male Sterile Rice

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Raafat El-Namaky

2018-05-01

Full Text Available Male sterility enabled commercialization of heterosis in rice but low seed set remains a constraint on hybrid dissemination. We evaluated 216 F6 maintainer lines for agronomic and floral characteristics in augmented design and selected 15 maintainer lines, which were testcrossed with IR58025A. Five backcrosses were conducted to transfer cytoplasmic male sterility (CMS to select maintainer lines. Newly-bred BC5:6 CMS lines were evaluated for outcrossing rates and agronomic characteristics. There were highly significant differences among 216 F6 maintainer lines for characteristics whose genotypic variance was higher than environmental variance. The phenotypic coefficient of variation was almost the same as the genotypic coefficient of variation, indicating that most phenotypic variation was due to genetics. There were highly significant differences among CMS lines for number of days to 50% flowering and maturity; stigma exertion; panicle exertion, length and weight; spikelet fertility; tillers per plant; plant height; grains per panicle; grain yield per plant; and 1000-grain weight, but not for pollen and panicle sterility during dry and wet seasons. Three CMS lines (CMS3, CMS12, and CMS14, exhibited high outcrossing rates (56.17%, 51.42% and 48.44%, respectively, which had a highly significant, positive correlation with stigma exertion (0.97, spikelet opening angle (0.82, and panicle exertion (0.95.

The effect of natural hot environment on survival and peripheral blood lymphocytes in γ-irradiated mice

International Nuclear Information System (INIS)

Zhou Meijuan; Zheng Li; Ding Zhenhua

2004-01-01

Objective: To study the effect of natural hot environment (NHE) on survival and peripheral blood lymphocytes in γ-irradiated in mice. Methods: After γ-irradiation at the dosage of 6.5 or 9.0 Gy, the mice were exposed to NHE for 0, 3, 6, 9 h or 30 days. After exposure to NHE, mice of the 6 h and 9 h groups, were then bred at room temperature. The survival and peripheral blood lymphocytes were observed for 30 days. Results: There were obvious differences in survival time between the groups that were exposed to NHE for 9 h and 30 d and that of the 0 h group, the mice of these three groups having been irradiated with 6.5 Gy. For 9.0 Gy-irradiated mice, the survival times of the 6, 9 h and 30 d groups were all significantly shorter than that of the 0 h group. The descending rate of peripheral blood lymphocytes in 0 h group is smaller than that of all NHE groups. There was no lymphocyte fluctuate resuscitation in all NHE groups as seen in the 0 h group. Conclusion: There is a significant decrease of survival indexes and a faster descending rate of peripheral blood lymphocytes in mice exposed to after γ-irradiation. (authors)

Monoamines and sexual function in rats bred for increased catatonic reactivity.

Science.gov (United States)

Klochkov, D V; Alekhina, T A; Kuznetsova, E G; Barykina, N N

2009-07-01

Body weight, ovary and uterus weight, the nature of estral cycles, and hypothalamus dopamine and noradrenaline levels and plasma testosterone levels were studied in female GC rats, bred for increased catatonic reactivity, at different stages of the estral cycle (estrus, proestrus). The outbred Wistar strain served as controls. On the background of decreased body weight, GC females showed impairments to the morphological cyclical changes in the ovaries and uterus, with a reduction in ovary weight in diestrus (p rats showed higher levels of these monoamines in estrus and lower levels in diestrus. Plasma testosterone levels in female GC rats were higher in diestrus than in estrus and in Wistar rats.

Developmental and growth defects in mice with combined deficiency of CK2 catalytic genes.

Science.gov (United States)

Landesman-Bollag, Esther; Belkina, Anna; Hovey, Beth; Connors, Edward; Cox, Charles; Seldin, David C

2011-10-01

The CK2 α and α' catalytic gene products have overlapping biochemical activity, but in vivo, their functions are very different. Deletion of both alleles of CK2α leads to mid-gestational embryonic lethality, while deletion of both alleles of CK2α' does not interfere with viability or development of embryos; however, adult CK2α'-/-males are infertile. To further elucidate developmental roles of CK2, and analyze functional overlap between the two catalytic genes, mice with combined knockouts were bred. Mice bearing any two CK2 catalytic alleles were phenotypically normal. However, inheritance of a single CK2α allele, without either CK2α' allele, resulted in partial embryonic lethality. Such mice that survived through embryogenesis were smaller at birth than littermate controls, and weighed less throughout life. However, their cardiac function and lifespan were normal. Fibroblasts derived from CK2α+/-CK2α'-/- embryos grew poorly in culture. These experiments demonstrate that combined loss of one CK2α allele and both CK2α' alleles leads to unique abnormalities of growth and development.

Evaluating genetic traceability methods for captive-bred marine fish and their applications in fisheries management and wildlife forensics

DEFF Research Database (Denmark)

Bylemans, Jonas; Maes, Gregory E.; Diopere, Eveline

2016-01-01

Growing demands for marine fish products is leading to increased pressure on already depleted wild populations and a rise in aquaculture production. Consequently, more captive-bred fish are released into the wild through accidental escape or deliberate releases. The increased mixing of captive-br...

Chemopreventive Effects of RXR-Selective Rexinoid Bexarotene on Intestinal Neoplasia of ApcMin/+ Mice

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Naveena B. Janakiram

2012-02-01

Full Text Available Retinoid X receptor (RXR has been implicated in several neoplastic diseases. Previously, we have shown that RXR-α is downregulated in human and rodent colonic tumors, suggesting a potential target for colon cancer prevention (http://www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/colorectal-cancer-key-statistics. Experiments were designed to assess the chemopreventive efficacy of the selective RXR agonist bexarotene for the suppression of intestinal tumorigenesis in ApcMin/+ mice. Before the efficacy studies, we determined that the maximal tolerated dose in C57BL/6J mice was less than 400 ppm. For the efficacy study, 6-week-old male and female C57BL/6J-ApcMin/+ mice (nine mice per group were fed diets containing 0, 30, and 60 ppm of bexarotene or 200 ppm of bexarotene for 80 days before intestinal tumors were evaluated. Dietary administration of 30 and 60 ppm of bexarotene suppressed the intestinal polyp formation by 38% (P < .015 and 60% (P < .0001 in males, respectively, and by 8.5% and 37% (P < .007 in females, respectively. Also, significant inhibition (50%–100% of colonic tumor formation was observed in both male and female mice with bexarotene treatment. Administration of 200 ppm of bexarotene showed significant suppression of tumor formation (66%, P < .0001; however, it had significant toxicity. Intestinal tumors of bexarotene-fed mice showed significantly reduced expression of proliferating cell nuclear antigen (60%, P < .0001, cyclin D1, and cyclooxygenase 2 and increased RXR-α messenger RNA and uptake of oleate (34%, P < .01. Also, bexarotene-fed mice showed dose-dependent suppression of serum triglycerides (25%–72%, P < .0001 and inflammatory cytokines.

Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice.

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Perusini, Jennifer N; Cajigas, Stephanie A; Cohensedgh, Omid; Lim, Sean C; Pavlova, Ina P; Donaldson, Zoe R; Denny, Christine A

2017-10-01

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. APPswe/PS1dE9 (APP/PS1) mice have been developed as an AD model and are characterized by plaque formation at 4-6 months of age. Here, we sought to better understand AD-related cognitive decline by characterizing various types of memory. In order to better understand how memory declines with AD, APP/PS1 mice were bred with ArcCreER T2 mice. In this line, neural ensembles activated during memory encoding can be indelibly tagged and directly compared with neural ensembles activated during memory retrieval (i.e., memory traces/engrams). We first administered a battery of tests examining depressive- and anxiety-like behaviors, as well as spatial, social, and cognitive memory to APP/PS1 × ArcCreER T2 × channelrhodopsin (ChR2)-enhanced yellow fluorescent protein (EYFP) mice. Dentate gyrus (DG) neural ensembles were then optogenetically stimulated in these mice to improve memory impairment. AD mice had the most extensive differences in fear memory, as assessed by contextual fear conditioning (CFC), which was accompanied by impaired DG memory traces. Optogenetic stimulation of DG neural ensembles representing a CFC memory increased memory retrieval in the appropriate context in AD mice when compared with control (Ctrl) mice. Moreover, optogenetic stimulation facilitated reactivation of the neural ensembles that were previously activated during memory encoding. These data suggest that activating previously learned DG memory traces can rescue cognitive impairments and point to DG manipulation as a potential target to treat memory loss commonly seen in AD. © 2017 Wiley Periodicals, Inc.

Parasitological and immunological diagnoses from feces of captive-bred snakes at Vital Brazil Institute

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Janaína Lima de Souza

Full Text Available Fecal samples from 56 snakes at the Vital Brazil Institute, in the city of Niterói, Rio de Janeiro, were tested using the sedimentation and flotation techniques to investigate the evolutionary forms of parasites such as helminths and protozoa, and using enzyme immunoassay techniques to detect antigens of Cryptosporidium sp. and Giardiasp. Among the animals tested, 80.3% were positive for parasites. Out of these, there were 16 Bothrops jararaca, 16 B. jararacussu and 13 Crotalus durissus. The prevalence of parasitic nematodes was 41.1%, and nematodes were found in all three snake species. Among these, the most frequent finding was eggs of Kalicephalus sp., which were diagnosed in 25% of the snakes. The positivity for protozoa detected using parasite concentration techniques was 75%, including oocysts of Caryospora sp. in 75%, cysts with morphology similar to Giardia sp. 3.6%, amoeboid cysts in 41.1% and unsporulated coccidia oocysts in 8.9%. Immunoassays for Cryptosporidium sp. antigens produced positive findings in 60.7%. Pseudoparasites were detected in 64.3%. These results show that there is a need to improve the sanitary handling of captive-bred snakes, and also for the animal house that supplies rodents to feed them. The results also highlight that diagnostic tests should be performed periodically on stool specimens from captive-bred snakes.

Parasitological and immunological diagnoses from feces of captive-bred snakes at Vital Brazil Institute.

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Souza, Janaína Lima de; Barbosa, Alynne da Silva; Vazon, Adriana Prado; Uchôa, Claudia Maria Antunes; Nunes, Beatriz Coronato; Cortez, Myrian Bandeira Vianna; Silva, Valmir Laurentino da; Más, Leonora Brazil; Melgarejo, Aníbal Rafael; Bastos, Otilio Machado Pereira

2014-01-01

Fecal samples from 56 snakes at the Vital Brazil Institute, in the city of Niterói, Rio de Janeiro, were tested using the sedimentation and flotation techniques to investigate the evolutionary forms of parasites such as helminths and protozoa, and using enzyme immunoassay techniques to detect antigens of Cryptosporidium sp. and Giardia sp. Among the animals tested, 80.3% were positive for parasites. Out of these, there were 16 Bothrops jararaca, 16 B. jararacussu and 13 Crotalus durissus. The prevalence of parasitic nematodes was 41.1%, and nematodes were found in all three snake species. Among these, the most frequent finding was eggs of Kalicephalus sp., which were diagnosed in 25% of the snakes. The positivity for protozoa detected using parasite concentration techniques was 75%, including oocysts of Caryospora sp. in 75%, cysts with morphology similar to Giardia sp. 3.6%, amoeboid cysts in 41.1% and unsporulated coccidia oocysts in 8.9%. Immunoassays for Cryptosporidium sp. antigens produced positive findings in 60.7%. Pseudoparasites were detected in 64.3%. These results show that there is a need to improve the sanitary handling of captive-bred snakes, and also for the animal house that supplies rodents to feed them. The results also highlight that diagnostic tests should be performed periodically on stool specimens from captive-bred snakes.

Prepartum and postpartum open-field behavior and maternal responsiveness in mice bidirectionally selected for open-field thigmotaxis.

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Leppänen, Pia K; Ravaja, Niklas; Ewalds-Kvist, S Béatrice M

2008-01-01

The authors examined pre- and postpartum open-field (OF) behavior and maternal responsiveness in mice that they bidirectionally selected for OF thigmotaxis. The authors tested 40 female mice under 3 conditions: prepartum OF, postpartum OF, and a pup retrieval test. In both OF conditions, the high OF thigmotaxis (HOFT) mice were more thigmotactic but explored and reared less than the low OF thigmotaxis (LOFT) mice, indicating that the HOFT mice were more emotional. In the postpartum condition, the HOFT mothers also defecated more and ambulated less than the LOFT mothers. The increase in grooming after parturition was more conspicuous among the LOFT mothers than among the HOFT mothers. The LOFT mothers were also more attracted to their pups in the OF, but the retrieval test did not show any substantial line differences. The results suggested that the line difference in emotionality was more pronounced during lactation than during pregnancy, although parturition exerted no effect on thigmotaxis.

Effect of dietary restriction on immune response of laboratory mice divergently selected for basal metabolic rate.

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Książek, Aneta; Konarzewski, Marek

2012-01-01

To study whether dietary restriction (DR; 70% of ad lib. feeding)-elicited immunosuppression results from the trade-off between the costs of mounting an immune response and the metabolic costs of maintenance, we subjected mice from two divergent lines selected for high basal metabolic rate (H-BMR) and low BMR (L-BMR) to 4 wk of DR and then challenged them with keyhole limpet hemocyanin (KLH) antigen. Those line types differ genetically with respect to BMR and to the mass of metabolically expensive internal organs, which are larger in H-BMR mice. In mice of both line types, DR resulted in a significant reduction of body mass, an immune response, and the downsizing of spleen, lymph nodes, thymus, heart, and kidneys but not small intestines. DR resulted in a greater reduction of the spleen and lymph nodes in mice of the H-BMR line type, whereas the thymus was more affected in L-BMR line type. In contrast, immunization resulted in an increase of liver mass in DR mice of both line types. A comparison of the results of current and earlier studies on the same mouse line types suggests that metabolic trade-offs involving the costs of an immune response are more apparent when animals are forced to increase energy demands (e.g., by cold exposure) compared to when energy demands are decreased through DR. Our findings also suggest that divelrgent selection on BMR resulted in between-line-type differences in T-cell- and B-cell-mediated types of an immune response. More generally, our results indicate that production of a wide repertoire of antibodies is not correlated with high BMR.

Ultrasonographic reproductive tract measures and pelvis measures as predictors of pregnancy failure and anestrus in restricted bred beef heifers

NARCIS (Netherlands)

Holm, Dietmar E; Nielen, Mirjam; Jorritsma, Ruurd; Irons, Peter C; Thompson, Peter N

Previous reports have shown that reproductive tract score (RTS) can predict reproduction outcomes in seasonally bred beef heifers, although the accuracy can vary. Some ultrasonographic measures of the female reproductive tract and pelvis area have also been associated with reproductive outcome in

A selective sweep in a microsporidian parasite Nosema-tolerant honeybee population, Apis mellifera

DEFF Research Database (Denmark)

Huang, Q.; Lattorff, H. M. G.; Kryger, P.

2014-01-01

Nosema is a microsporidian parasite of the honeybee, which infects the epithelial cells of the gut. In Denmark, honeybee colonies have been selectively bred for the absence of Nosema over decades, resulting in a breeding line that is tolerant toward Nosema infections. As the tolerance toward the ...

Selective Attention to Visual Stimuli Using Auditory Distractors Is Altered in Alpha-9 Nicotinic Receptor Subunit Knock-Out Mice.

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Terreros, Gonzalo; Jorratt, Pascal; Aedo, Cristian; Elgoyhen, Ana Belén; Delano, Paul H

2016-07-06

During selective attention, subjects voluntarily focus their cognitive resources on a specific stimulus while ignoring others. Top-down filtering of peripheral sensory responses by higher structures of the brain has been proposed as one of the mechanisms responsible for selective attention. A prerequisite to accomplish top-down modulation of the activity of peripheral structures is the presence of corticofugal pathways. The mammalian auditory efferent system is a unique neural network that originates in the auditory cortex and projects to the cochlear receptor through the olivocochlear bundle, and it has been proposed to function as a top-down filter of peripheral auditory responses during attention to cross-modal stimuli. However, to date, there is no conclusive evidence of the involvement of olivocochlear neurons in selective attention paradigms. Here, we trained wild-type and α-9 nicotinic receptor subunit knock-out (KO) mice, which lack cholinergic transmission between medial olivocochlear neurons and outer hair cells, in a two-choice visual discrimination task and studied the behavioral consequences of adding different types of auditory distractors. In addition, we evaluated the effects of contralateral noise on auditory nerve responses as a measure of the individual strength of the olivocochlear reflex. We demonstrate that KO mice have a reduced olivocochlear reflex strength and perform poorly in a visual selective attention paradigm. These results confirm that an intact medial olivocochlear transmission aids in ignoring auditory distraction during selective attention to visual stimuli. The auditory efferent system is a neural network that originates in the auditory cortex and projects to the cochlear receptor through the olivocochlear system. It has been proposed to function as a top-down filter of peripheral auditory responses during attention to cross-modal stimuli. However, to date, there is no conclusive evidence of the involvement of olivocochlear

Myocardial KRAS(G12D) expression does not cause cardiomyopathy in mice.

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Dalin, Martin G; Zou, Zhiyuan; Scharin-Täng, Margareta; Safari, Roghaiyeh; Karlsson, Christin; Bergo, Martin O

2014-02-01

Germ-line mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) pathway cause developmental disorders called RASopathies. Hypertrophic cardiomyopathy (HCM) is the most common myocardial pathology and a leading cause of death in RASopathy patients. KRAS mutations are found in Noonan and cardio-facio-cutaneous syndromes. KRAS mutations, unlike mutations of RAF1 and HRAS, are rarely associated with HCM. This has been attributed to the fact that germ-line KRAS mutations cause only a moderate up-regulation of the MAPK pathway. Highly bioactive KRAS mutations have been hypothesized to cause severe cardiomyopathy incompatible with life. The aim of this study was to define the impact of KRAS(G12D) expression in the heart. To generate mice with endogenous cardiomyocyte-specific KRAS(G12D) expression (cKRAS(G12D) mice), we bred mice with a Cre-inducible allele expressing KRAS(G12D) from its endogenous promoter (Kras2(LSL)) to mice expressing Cre under control of the cardiomyocyte-specific α-myosin heavy chain promoter (αMHC-Cre). cKRAS(G12D) mice showed high levels of myocardial ERK and AKT signalling. However, surprisingly, cKRAS(G12D) mice were born in Mendelian ratios, appeared healthy, and had normal function, size, and histology of the heart. Mice with cardiomyocyte-specific KRAS(G12D) expression do not develop heart pathology. These results challenge the view that the level of MAPK activation correlates with the severity of HCM in RASopathies and suggests that MAPK-independent strategies may be of interest in the development of new treatments for these syndromes.

Voronoi-based spatial analysis reveals selective interneuron changes in the cortex of FALS mice.

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Minciacchi, Diego; Kassa, Roman M; Del Tongo, Claudia; Mariotti, Raffaella; Bentivoglio, Marina

2009-01-01

The neurodegenerative disease amyotrophic lateral sclerosis affects lower motoneurons and corticospinal cells. Mice expressing human mutant superoxide dismutase (SOD)1 provide widely investigated models of the familial form of disease, but information on cortical changes in these mice is still limited. We here analyzed the spatial organization of interneurons characterized by parvalbumin immunoreactivity in the motor, somatosensory, and visual cortical areas of SOD1(G93A) mice. Cell number and sociological spatial behavior were assessed by digital charts of cell location in cortical samples, cell counts, and generation of two-dimensional Voronoi diagrams. In end-stage SOD1-mutant mice, an increase of parvalbumin-containing cortical interneurons was found in the motor and somatosensory areas (about 35% and 20%, respectively) with respect to wild-type littermates. Changes in cell spatial distribution, as documented by Voronoi-derived coefficients of variation, indicated increased tendency of parvalbumin cells to aggregate into clusters in the same areas of the SOD1-mutant cortex. Counts and coefficients of variation of parvalbumin cells in the visual cortex gave instead similar results in SOD1-mutant and wild-type mice. Analyses of motor and somatosensory areas in presymptomatic SOD1-mutant mice provided findings very similar to those obtained at end-stage, indicating early changes of interneurons in these cortical areas during the pathology. Altogether the data reveal in the SOD1-mutant mouse cortex an altered architectonic pattern of interneurons, which selectively affects areas involved in motor control. The findings, which can be interpreted as pathogenic factors or early disease-related adaptations, point to changes in the cortical regulation and modulation of the motor circuit during motoneuron disease.

Transgenerational Inheritance of Increased Fat Depot Size, Stem Cell Reprogramming, and Hepatic Steatosis Elicited by Prenatal Exposure to the Obesogen Tributyltin in Mice

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Chamorro-García, Raquel; Sahu, Margaret; Abbey, Rachelle J.; Laude, Jhyme; Pham, Nhieu

2013-01-01

Background: We have previously shown that exposure to tributyltin (TBT) modulates critical steps of adipogenesis through RXR/PPARγ and that prenatal TBT exposure predisposes multipotent mesenchymal stem cells (MSCs) to become adipocytes by epigenetic imprinting into the memory of the MSC compartment. Objective: We tested whether the effects of prenatal TBT exposure were heritable in F2 and F3 generations. Methods: We exposed C57BL/6J female mice (F0) to DMSO vehicle, the pharmaceutical obesogen rosiglitazone (ROSI), or TBT (5.42, 54.2, or 542 nM) throughout pregnancy via the drinking water. F1 offspring were bred to yield F2, and F2 mice were bred to produce F3. F1 animals were exposed in utero and F2 mice were potentially exposed as germ cells in the F1, but F3 animals were never exposed to the chemicals. We analyzed the effects of these exposures on fat depot weights, adipocyte number, adipocyte size, MSC programming, hepatic lipid accumulation, and hepatic gene expression in all three generations. Discussion: Prenatal TBT exposure increased most white adipose tissue (WAT) depot weights, adipocyte size, and adipocyte number, and reprogrammed MSCs toward the adipocyte lineage at the expense of bone in all three generations. Prenatal TBT exposure led to hepatic lipid accumulation and up-regulated hepatic expression of genes involved in lipid storage/transport, lipogenesis, and lipolysis in all three subsequent generations. Conclusions: Prenatal TBT exposure produced transgenerational effects on fat depots and induced a phenotype resembling nonalcoholic fatty liver disease through at least the F3 generation. These results show that early-life obesogen exposure can have lasting effects. PMID:23322813

Reversing hypomyelination in BACE1-null mice with Akt-DD overexpression.

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Hu, Xiangyou; Schlanger, Rita; He, Wanxia; Macklin, Wendy B; Yan, Riqiang

2013-05-01

β-Site amyloid precursor protein convertase enzyme 1 (BACE1), a type I transmembrane aspartyl protease required to cleave amyloid precursor protein for releasing a toxic amyloid peptide, also cleaves type I and type III neuregulin-1 (Nrg-1). BACE1 deficiency in mice causes hypomyelination during development and impairs remyelination if injured. In BACE1-null mice, the abolished cleavage of neuregulin-1 by BACE1 is speculated to cause reduced myelin sheath thickness in both the central nervous system and peripheral nervous system because reduced cleavage of Nrg-1 correlates with reduced Akt phosphorylation, a downstream signaling molecule of the Nrg-1/ErbB pathway. Here we tested specifically whether increasing Akt activity alone in oligodendrocytes would be sufficient to reverse the hypomyelination phenotype in BACE1-null mice. BACE1-null mice were bred with transgenic mice expressing constitutively active Akt (Akt-DD; mutations with D(308)T and D(473)S) in oligodendrocytes. Relative to littermate BACE1-null controls, BACE1(-/-)/Akt-DD mice exhibited enhanced expression of myelin basic protein and promoter of proteolipid protein. The elevated expression of myelin proteins correlated with a thicker myelin sheath in optic nerves; comparison of quantified g ratios with statistic significance was used to confirm this reversion. However, it appeared that myelin sheath thickness in the sciatic nerves was not increased in BACE1(-/-)/Akt-DD mice, as the g ratio was not significantly different from the control. Hence, increased Akt activity in BACE1-null myelinating cells only compensates for the loss of BACE1 activity in the central nervous system, which is consistent with the observation that overexpression of Akt-DD in Schwann cells did not induce hypermyelination. Our results suggest that signaling activity other than Akt may also contribute to proper myelination in peripheral nerves.

Evaluation of antitrypanosomal and anti inflammatory activities of selected Nigerian medicinal plants in mice.

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Adelodun, Victoria O; Elusiyan, C A; Olorunmola, F O; Adewoyin, F B; Omisore, N O; Adepiti, A O; Agbedahunsi, J M; Adewunmi, C O

2013-01-01

The extracts of nine selected Nigerian medicinal plants were investigated on Trypanosoma brucei brucei infected mice. The anti-inflammatory properties of hexane fraction of the most promising U. chamae extract was assessed by acute oedema of the mice paw model while the modulatory effect of the extract on Delayed-Type Hypersensitivity (DTH) response on in vivo leucocytes mobilization was evaluated. 'Dose-probing acute toxicity tests' established an oral and intraperitoneal LD50 for T. ivorensis stem bark as >1600 5000 mg/kg. Extracts of Khaya senegalensis, Harungana madagascariensis, Terminalia ivorensis, Curcuma longa, Ocimum gratissimum and Alcornea cordifolia showed weak anti-trypanosomal effect and did not exhibit significant clearance in parasitemia at the test dose administered compared with the positive control (Diminal®). However, the leaf extract of U. chamae and its hexane fraction demonstrated a significant response (P < 0.01). The fraction at 1000 mg/kg inhibited oedema by 107%. Uvaria. chamae demonstrated both antitrypanosomal and anti-inflammatory properties by increasing the survival time of infected mice due to reduction in parasitemia caused by T. brucei brucei.

Effect of maternal dietary cow’s milk on the immune response to beta-lactoglobulin in the offspring: A four generation study in mice

DEFF Research Database (Denmark)

Pedersen, Susanne Brix; Christensen, Hanne Risager; Barkholt, Vibeke

2005-01-01

deviated from the response observed in the F0 and F2/F3 generations. Importantly, trace amounts of BLG detected in the commercial milk-free diet did not induce oral tolerance. CONCLUSIONS: The study showed that breeding mice on an antigen-free diet for at least two generations is required to attain animals......Evaluation of immune responses to food proteins in animal models requires that the animals are not already sensitized or orally tolerized against the proteins in question. Since maternal transfer of specific immune responses has been observed, breeding of animals on an antigen-free diet for several...... generations may be necessary to obtain immunologically naive animals. METHODS: To determine the most appropriate breeding conditions of mice to be used in immunological studies on food proteins, we examined immune responses towards beta-lactoglobulin (BLG) in mice bred on a milk-containing diet (F0...

Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors.

Directory of Open Access Journals (Sweden)

Carolina R den Hartog

Full Text Available Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs. In this study, we determined how expression of a mutant GluN1 subunit (F639A that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; i.p. increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg. In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol.

Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors.

Science.gov (United States)

den Hartog, Carolina R; Beckley, Jacob T; Smothers, Thetford C; Lench, Daniel H; Holseberg, Zack L; Fedarovich, Hleb; Gilstrap, Meghin J; Homanics, Gregg E; Woodward, John J

2013-01-01

Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined how expression of a mutant GluN1 subunit (F639A) that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl) significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; i.p.) increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg) reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg). In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg) as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol.

Economic values and selection index in different Angus-Nellore cross-bred production systems.

Science.gov (United States)

Fernandes, G M; Savegnago, R P; El Faro, L; Mosaquatro Roso, V; de Paz, C C P

2018-06-01

Bioeconomic models were developed to calculate economic values (EV) for economically important traits in beef cattle, to evaluate the impact of these traits on production profitability, to assess possible market changes with a payment system and to develop economic selection indexes for Angus cattle for two production systems. Two beef cattle production systems were simulated as follows: a cow-calf cycle (CC) and a complete cycle (CoC). Following selection, positive changes in the EV were observed. In the CC, each 1.0% increment in weaning weight (WW), weaning rate (WR) and pregnancy rate (PR) resulted in increases in US$ 1.30, US$ 3.68 and US$ 3.55 per cow/year in profit, respectively. In the CoC, EV of US$ 1.01, US$ 1.79, US$ 1.19, US$ 1.34, US$ 6.84 and US$ 7.86 per cow/year were obtained for WW, year weight, yearling weight, final weight, WR and PR, respectively. The payment system for carcass quality showed that the scenario considering that 100% of the animals displayed uniform carcasses exhibited the highest EV and was considered optimal. Considering the sensitivity analysis, the price paid per animal was the factor that most affected the EV in both systems. The selection indexes obtained may be used in similar production systems, and the use of EV and selection indexes are important tools for any production system with positive change in profit after selection. © 2018 Blackwell Verlag GmbH.

Cisgenic Rvi6 scab-resistant apple lines show no differences in Rvi6 transcription when compared with conventionally bred cultivars.

Science.gov (United States)

Chizzali, Cornelia; Gusberti, Michele; Schouten, Henk J; Gessler, Cesare; Broggini, Giovanni A L

2016-03-01

The expression of the apple scab resistance gene Rvi6 in different apple cultivars and lines is not modulated by biotic or abiotic factors. All commercially important apple cultivars are susceptible to Venturia inaequalis, the causal organism of apple scab. A limited number of apple cultivars were bred to express the resistance gene Vf from the wild apple genotype Malus floribunda 821. Positional cloning of the Vf locus allowed the identification of the Rvi6 (formerly HcrVf2) scab resistance gene that was subsequently used to generate cisgenic apple lines. It is important to understand and compare how this resistance gene is transcribed and modulated during infection in conventionally bred cultivars and in cisgenic lines. The aim of this work was to study the transcription pattern of Rvi6 in three classically bred apple cultivars and six lines of 'Gala' genetically modified to express Rvi6. Rvi6 transcription was analyzed at two time points using quantitative real-time PCR (RT-qPCR) following inoculation with V. inaequalis conidia or water. Rvi6 transcription was assessed in relation to five reference genes. β-Actin, RNAPol, and UBC were the most suited to performing RT-qPCR experiments on Malus × domestica. Inoculation with V. inaequalis conidia under conditions conducive to scab infection failed to produce any significant changes to the transcription level of Rvi6. Rvi6 expression levels were inconsistent in response to external treatments in the different apple cultivars, and transgenic, intragenic or cisgenic lines.

Use of milk progesterone for determining the reproductive status of cross-bred swamp buffaloes and cattle

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Cuong Le Xuan; Tan Luu Van; Trieu Cao Van; Dung Chung Anh; Canh Tran Tich; Quynh Vuong Dac

1990-01-01

Eighteen cross-bred buffaloes (F 1 , local breed x Murrah) and 19 cross-bred cows (F 1 , local breed x Holstein Friesian), 4-6 years of age, were used in the study to determine the potential of milk progesterone measurement as an aid in characterizing the onset of postpartum ovarian activity and for early pregnancy diagnosis. The first oestrous cycle, based on milk progesterone, commenced between days 40-50 postpartum in 17% of the buffaloes but between days 25-35 postpartum in 21% of the cows. At days 61-100 postpartum, 33% of the buffaloes had cycling ovaries with progesterone concentrations of 3.23-4.02 ng/mL, while 53% of the cows had cycling ovaries during the same period with progesterone concentrations of 3.52-4.16 ng/mL. During the oestrous cycle, the progesterone level showed peak elevations on day 15 in buffaloes and on day 9 in cows. The milk progesterone profiles of the buffalo took longer to reach peak levels, but declined faster than those in the cow. The accuracy of positive pregnancy diagnosis was 78% in buffaloes and 83.3% in cows, but the accuracy of diagnosing non-pregnancy was 100% in both species. (author). 4 refs, 2 figs, 1 tab

The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice.

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Lopez, Marcelo F; Moorman, David E; Aston-Jones, Gary; Becker, Howard C

2016-04-01

The orexin/hypocretin (ORX) system plays a major role in motivation for natural and drug rewards. In particular, a number of studies have shown that ORX signaling through the orexin 1 receptor (OX1R) regulates alcohol seeking and consumption. Despite the association between ORX signaling and motivation for alcohol, no study to date has investigated what role the ORX system plays in alcohol dependence, an understanding of which would have significant clinical relevance. This study was designed to evaluate the effect of the highly selective OX1R antagonist GSK1059865 on voluntary ethanol intake in ethanol-dependent and control non-dependent mice. Mice were subjected to a protocol in which they were evaluated for baseline ethanol intake and then exposed to intermittent ethanol or air exposure in inhalation chambers. Each cycle of chronic intermittent ethanol (CIE), or air, exposure was followed by a test of ethanol intake. Once the expected effect of increased voluntary ethanol intake was obtained in ethanol dependent mice, mice were tested for the effect of GSK1059865 on ethanol and sucrose intake. Treatment with GSK1059865 significantly decreased ethanol drinking in a dose-dependent manner in CIE-exposed mice. In contrast GSK1059865 decreased drinking in air-exposed mice only at the highest dose used. There was no effect of GSK1059865 on sucrose intake. Thus, ORX signaling through the OX1R, using a highly-selective antagonist, has a profound influence on high levels of alcohol drinking induced in a dependence paradigm, but limited or no influence on moderate alcohol drinking or sucrose drinking. These results indicate that the ORX system may be an important target system for treating disorders of compulsive reward seeking such as alcoholism and other addictions in which motivation is strongly elevated. Copyright © 2016 Elsevier B.V. All rights reserved.

Chronic free-choice drinking in crossed high alcohol preferring mice leads to sustained blood ethanol levels and metabolic tolerance without evidence of liver damage.

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Matson, Liana; Liangpunsakul, Suthat; Crabb, David; Buckingham, Amy; Ross, Ruth Ann; Halcomb, Meredith; Grahame, Nicholas

2013-02-01

Crossed high alcohol preferring (cHAP) mice were selectively bred from a cross of the HAP1 × HAP2 replicate lines, and we demonstrate blood ethanol concentrations (BECs) during free-choice drinking that are reminiscent of those observed in alcohol-dependent humans. Therefore, this line may provide an unprecedented opportunity to learn about the consequences of excessive voluntary ethanol (EtOH) consumption, including metabolic tolerance and liver pathology. Cytochrome p450 2E1 (CYP2E1) induction plays a prominent role in driving both metabolic tolerance and EtOH-induced liver injury. In this report, we sought to characterize cHAP drinking by assessing whether pharmacologically relevant BEC levels are sustained throughout the active portion of the light-dark cycle. Given that cHAP intakes and BECs are similar to those observed in mice given an EtOH liquid diet, we assessed whether free-choice exposure results in metabolic tolerance, hepatic enzyme induction, and hepatic steatosis. In experiment 1, blood samples were taken across the dark portion of a 12:12 light-dark cycle to examine the pattern of EtOH accumulation in these mice. In experiments 1 and 2, mice were injected with EtOH following 3 to 4 weeks of access to water or 10% EtOH and water, and blood samples were taken to assess metabolic tolerance. In experiment 3, 24 mice had 4 weeks of access to 10% EtOH and water or water alone, followed by necropsy and hepatological assessment. In experiment 1, cHAP mice mean BEC values exceeded 80 mg/dl at all sampling points and approached 200 mg/dl during the middle of the dark cycle. In experiments 1 and 2, EtOH-exposed mice metabolized EtOH faster than EtOH-naïve mice, demonstrating metabolic tolerance (p alcohol dehydrogenase and aldehyde dehydrogenase. These results demonstrate that excessive intake by cHAP mice results in sustained BECs throughout the active period, leading to the development of metabolic tolerance and evidence of CYP2E1 induction

Select cognitive deficits in Vasoactive Intestinal Peptide deficient mice

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Hagopian Arkady

2008-07-01

Full Text Available Abstract Background The neuropeptide vasoactive intestinal peptide (VIP is widely distributed in the adult central nervous system where this peptide functions to regulate synaptic transmission and neural excitability. The expression of VIP and its receptors in brain regions implicated in learning and memory functions, including the hippocampus, cortex, and amygdala, raise the possibility that this peptide may function to modulate learned behaviors. Among other actions, the loss of VIP has a profound effect on circadian timing and may specifically influence the temporal regulation of learning and memory functions. Results In the present study, we utilized transgenic VIP-deficient mice and the contextual fear conditioning paradigm to explore the impact of the loss of this peptide on a learned behavior. We found that VIP-deficient mice exhibited normal shock-evoked freezing behavior and increases in corticosterone. Similarly, these mutant mice exhibited no deficits in the acquisition or recall of the fear-conditioned behavior when tested 24-hours after training. The VIP-deficient mice exhibited a significant reduction in recall when tested 48-hours or longer after training. Surprisingly, we found that the VIP-deficient mice continued to express circadian rhythms in the recall of the training even in those individual mice whose wheel running wheel activity was arrhythmic. One mechanistic explanation is suggested by the finding that daily rhythms in the expression of the clock gene Period2 continue in the hippocampus of VIP-deficient mice. Conclusion Together these data suggest that the neuropeptide VIP regulates the recall of at least one learned behavior but does not impact the circadian regulation of this behavior.

Intrathymic selection of NK1.1+α/β T cell antigen receptor (TCR)+ cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-Ad

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Iwabuchi, Chikako; Iwabuchi, Kazuya; Nakagawa, Ken-ichi; Takayanagi, Toshiaki; Nishihori, Hiroki; Tone, Saori; Ogasawara, Kazumasa; Good, Robert A.; Onoé, Kazunori

1998-01-01

Generation and negative selection of NK1.1+α/β T cell receptor (TCR)+ thymocytes were analyzed using TCR-transgenic (B10.D2 × DO10)F1 and (C57BL/6 × DO10)F1 mice and Rag-1−/−/DO10 mice, which had been established by breeding and backcrossing between Rag-1−/− and DO10 mice. Almost all T cells from these mice were shown to bear Vα13/Vβ8.2 that is specific for chicken ovalbumin (cOVA) and restricted to I-Ad. A normal proportion of the NK1.1+ Vα13/Vβ8.2+ thymocytes was generated in these mice. However, the actual cell number of both NK1.1+ and NK1.1− thymocytes in I-Ad/d mice (positive selecting background) was larger than that in I-Ab/d mice (negative selecting background). Markedly low but significant proportions of NK1.1+ Vα13/Vβ8.2+ cells were detected in the spleens from I-Ad/d and I-Ab/d mice. It was shown that the splenic NK1.1+ T cells of the I-Ab/d mice were anergized against stimulation through TCR. When (B10.D2 × DO10)F1 and (C57BL/6 × DO10)F1 mice were given cOVA, extensive or intermediate elimination of NK1.1+α/βTCR+ thymocytes was induced in I-Ad/d or I-Ab/d mice, respectively. However, the clonal elimination was not as complete as that seen in the major NK1.1− thymocyte population. The present findings indicate that normal generation of NK1.1+α/βTCR+ thymocytes occurs in the absence of Vα14-Jα281 and that substantial negative selection operates on the NK1.1+α/βTCR+ cells. PMID:9653164

Spontaneous neural tube defects in splotch mice supplemented with selected micronutrients

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Wlodarczyk, Bogdan J.; Tang, Louisa S.; Triplett, Aleata; Aleman, Frank; Finnell, Richard H.

2006-01-01

Splotch (Sp/Sp) mice homozygous for a mutation in the Pax3 gene inevitably present with neural tube defects (NTDs), along with other associated congenital anomalies. The affected mutant embryos usually die by gestation days (E) 12-13. In the present study, the effect of modifier genes from a new genetic background (CXL-Sp) and periconceptional supplementation with selected micronutrients (folic acid, 5-formyltetrahydrofolate, 5-methyltetrahydrofolate, methionine, myoinositol, thiamine, thymidine, and α-tocopherol) was determined with respect to the incidence of NTDs. In order to explore how different exposure parameters (time, dose, and route of compound administration) modulate the beneficial effects of micronutrient supplementation, female mice received either short- or long-term nutrient supplements via enteral or parenteral routes. Embryos were collected on E12.5 and examined for the presence of anterior or posterior NTDs. Additionally, whole mount in situ hybridization studies were conducted in order to reveal/confirm normal expression patterns of the Pax3 gene during neurulation in the wild-type and Sp/Sp homozygous mutant mouse embryos utilized in this study. A strong Pax3 signal was demonstrated in CXL-Sp embryos during neural tube closure (E9.5 to E10.5). The intensity and spatial pattern of expression were similar to other Splotch mutant mice. Of all the micronutrients tested, only supplementation with folic acid or 5-methyltetrahydrofolate rescued the normal phenotype in Sp/Sp embryos. When the folate supplementation dose was increased to 200 mg/kg in the diet, the incidence of rescued splotch homozygotes reached 30%; however, this was accompanied by six-fold increased resorption rate

The cost of feeding bred dairy heifers on native warm-season grasses and harvested feedstuffs.

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Lowe, J K; Boyer, C N; Griffith, A P; Waller, J C; Bates, G E; Keyser, P D; Larson, J A; Holcomb, E

2016-01-01

Heifer rearing is one of the largest production expenses for dairy cattle operations, which is one reason milking operations outsource heifer rearing to custom developers. The cost of harvested feedstuffs is a major expense in heifer rearing. A possible way to lower feed costs is to graze dairy heifers, but little research exists on this topic in the mid-south United States. The objectives of this research were to determine the cost of feeding bred dairy heifers grazing native warm-season grasses (NWSG), with and without legumes, and compare the cost of grazing with the cost of rearing heifers using 3 traditional rations. The 3 rations were corn silage with soybean meal, corn silage with dry distillers grain, and a wet distillers grain-based ration. Bred Holstein heifers between 15- and 20-mo-old continuously grazed switchgrass (SG), SG with red clover (SG+RC), a big bluestem and Indiangrass mixture (BBIG), and BBIG with red clover (BBIG+RC) in Tennessee during the summer months. Total grazing days were calculated for each NWSG to determine the average cost/animal per grazing day. The average daily gain (ADG) was calculated for each NWSG to develop 3 harvested feed rations that would result in the same ADG over the same number of grazing day as each NWSG treatment. The average cost/animal per grazing day was lowest for SG ($0.48/animal/grazing d) and highest for BBIG+RC ($1.10/animal/grazing d). For both BBIG and SG, legumes increased the average cost/animal per grazing day because grazing days did not increase enough to account for the additional cost of the legumes. No difference was observed in ADG for heifers grazing BBIG (0.85 kg/d) and BBIG+RC (0.94 kg/d), and no difference was observed in ADG for heifers grazing SG (0.71 kg/d) and SG+RC (0.70 kg/d). However, the ADG for heifers grazing SG and SG+RC was lower than the ADG for heifers grazing either BBIG or BBIG+RC. The average cost/animal per grazing day was lower for all NWSG treatments than the average cost

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

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

2011-11-15

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

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

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

2011-01-01

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, ∼ 25 and ∼ 40 μg/dL, respectively, on PN10 and by PN30 all were ≤ 1 μg/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: ► Peak [BPb] in control, low-, moderate- and high-dose newborn mice with gestational lead exposure: ≤ 1, ≤ 10, 25 and 40 μg/dL ► Gestational lead exposure dose-dependently decreased the number of TH

Lactobacillus casei ssp.casei induced Th1 cytokine profile and natural killer cells activity in invasive ductal carcinoma bearing mice.

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Soltan Dallal, Mohammad Mehdi; Yazdi, Mohammad Hossein; Holakuyee, Marzieh; Hassan, Zuhair Mohammad; Abolhassani, Mohsen; Mahdavi, Mehdi

2012-06-01

Lactic acid bacteria which are used as probiotics have ability to modulate immune responses and modify immune mechanisms. It has also been indicated that some strains of this family can affect the immune responses against solid tumors. In the present work, we proposed to study the effects of oral administration of L.cacesi ssp casei on the NK cells cytotoxicity and also production of cytokines in spleen cells culture of BALB/c mice bearing invasive ductal carcinoma. 30 female In-bred BALB/c mice, were used and divided in two groups of test and control each containing 15 mice. Every day from 2 weeks before tumor transplantation 0.5 ml of PBS containing 2.7×108 CFU/ml of L.casei spp casei was orally administered to the test mice and it was followed 3 weeks after transplantation as well with 3 days interval between each week. Control mice received an equal volume of PBS in a same manner. Results showed that oral administration of L. casei significantly increased the production of IL-12 and IFN-γ (Psurvival was significantly prolonged in comparison to the controls. Our findings suggest that daily intake of L.casei can improve immune responses in mice bearing invasive ductal carcinoma, but further studies are needed to investigate the other involving mechanisms in this case.

Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity

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Moens Ugo

2007-11-01

Full Text Available Abstract Background The mitogen-activated protein kinases, MAPKs for short, constitute cascades of signalling pathways involved in the regulation of several cellular processes that include cell proliferation, differentiation and motility. They also intervene in neurological processes like fear conditioning and memory. Since little remains known about the MAPK-Activated Protein Kinase, MAPKAPK5, we constructed the first MAPKAPK knockin mouse model, using a constitutive active variant of MAPKAPK5 and analyzed the resulting mice for changes in anxiety-related behaviour. Methods We performed primary SHIRPA observations during background breeding into the C57BL/6 background and assessed the behaviour of the background-bred animals on the elevated plus maze and in the light-dark test. Our results were analyzed using Chi-square tests and homo- and heteroscedatic T-tests. Results Female transgenic mice displayed increased amounts of head dips and open arm time on the maze, compared to littermate controls. In addition, they also explored further into the open arm on the elevated plus maze and were less active in the closed arm compared to littermate controls. Male transgenic mice displayed no differences in anxiety, but their locomotor activity increased compared to non-transgenic littermates. Conclusion Our results revealed anxiety-related traits and locomotor differences between transgenic mice expressing constitutive active MAPKAPK5 and control littermates.

Phenotype selection reveals coevolution of muscle glycogen and protein and PTEN as a gate keeper for the accretion of muscle mass in adult female mice.

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Mandy Sawitzky

Full Text Available We have investigated molecular mechanisms for muscle mass accretion in a non-inbred mouse model (DU6P mice characterized by extreme muscle mass. This extreme muscle mass was developed during 138 generations of phenotype selection for high protein content. Due to the repeated trait selection a complex setting of different mechanisms was expected to be enriched during the selection experiment. In muscle from 29-week female DU6P mice we have identified robust increases of protein kinase B activation (AKT, Ser-473, up to 2-fold if compared to 11- and 54-week DU6P mice or controls. While a number of accepted effectors of AKT activation, including IGF-I, IGF-II, insulin/IGF-receptor, myostatin or integrin-linked kinase (ILK, were not correlated with this increase, phosphatase and tensin homologue deleted on chromosome 10 (PTEN was down-regulated in 29-week female DU6P mice. In addition, higher levels of PTEN phosphorylation were found identifying a second mechanism of PTEN inhibition. Inhibition of PTEN and activation of AKT correlated with specific activation of p70S6 kinase and ribosomal protein S6, reduced phosphorylation of eukaryotic initiation factor 2α (eIF2α and higher rates of protein synthesis in 29-week female DU6P mice. On the other hand, AKT activation also translated into specific inactivation of glycogen synthase kinase 3ß (GSK3ß and an increase of muscular glycogen. In muscles from 29-week female DU6P mice a significant increase of protein/DNA was identified, which was not due to a reduction of protein breakdown or to specific increases of translation initiation. Instead our data support the conclusion that a higher rate of protein translation is contributing to the higher muscle mass in mid-aged female DU6P mice. Our results further reveal coevolution of high protein and high glycogen content during the selection experiment and identify PTEN as gate keeper for muscle mass in mid-aged female DU6P mice.

GIMAP6 is required for T cell maintenance and efficient autophagy in mice.

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Pascall, John C; Webb, Louise M C; Eskelinen, Eeva-Liisa; Innocentin, Silvia; Attaf-Bouabdallah, Noudjoud; Butcher, Geoffrey W

2018-01-01

The GTPases of the immunity-associated proteins (GIMAP) GTPases are a family of proteins expressed strongly in the adaptive immune system. We have previously reported that in human cells one member of this family, GIMAP6, interacts with the ATG8 family member GABARAPL2, and is recruited to autophagosomes upon starvation, suggesting a role for GIMAP6 in the autophagic process. To study this possibility and the function of GIMAP6 in the immune system, we have established a mouse line in which the Gimap6 gene can be inactivated by Cre-mediated recombination. In mice bred to carry the CD2Cre transgene such that the Gimap6 gene was deleted within the T and B cell lineages there was a 50-70% reduction in peripheral CD4+ and CD8+ T cells. Analysis of splenocyte-derived proteins from these mice indicated increased levels of MAP1LC3B, particularly the lipidated LC3-II form, and S405-phosphorylation of SQSTM1. Electron microscopic measurements of Gimap6-/- CD4+ T cells indicated an increased mitochondrial/cytoplasmic volume ratio and increased numbers of autophagosomes. These results are consistent with autophagic disruption in the cells. However, Gimap6-/- T cells were largely normal in character, could be effectively activated in vitro and supported T cell-dependent antibody production. Treatment in vitro of CD4+ splenocytes from GIMAP6fl/flERT2Cre mice with 4-hydroxytamoxifen resulted in the disappearance of GIMAP6 within five days. In parallel, increased phosphorylation of SQSTM1 and TBK1 was observed. These results indicate a requirement for GIMAP6 in the maintenance of a normal peripheral adaptive immune system and a significant role for the protein in normal autophagic processes. Moreover, as GIMAP6 is expressed in a cell-selective manner, this indicates the potential existence of a cell-restricted mode of autophagic regulation.

Elemental analysis of biological tissues of Dmdmdx/J and C57BL/6J mice strains investigated by neutron activation analysis

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Sabrina Metairon; Zamboni, C.B.; Suzuki, M.F.; Bueno Junior, C.R.; Sant'Anna, O.A.

2013-01-01

In order to understand in more details the alterations that Duchenne muscular dystrophy disease may cause in biological tissues (blood, tibia, quadriceps and heart), correlations matrixes of the Dmd mdx /J dystrophic mice as well as C57BL/6J (control group) were generated. These mice were obtained from Jackson Laboratory (Maine, USA) and bred at IPEN (Dmd mdx /J), and at Centro de Estudos do Genoma Humano (C57BL/6J), both research centers at Sao Paulo city. Elements of clinical and nutritional relevance (Br, Ca, Cl, K, Mg, Na and S) were investigated by neutron activation analysis. These measurements were performed using the nuclear reactor IEA-R1 (3.5-4.5 MW, pool type) at IPEN. Comparisons between concentrations and correlations in these biological tissues, of these strains, showed that a Ca and Mg in blood are altered for the dystrophic mice. A significant change in the heart of dystrophic mice was also observed suggesting that a constant monitoring is required. Moreover, these results may help the researchers to evaluate the efficiency of new treatments and to compare the advantages of different treatment approaches before performing tests in patients with muscular dystrophy. (author)

Restoration of Lepr in β cells of Lepr null mice does not prevent hyperinsulinemia and hyperglycemia

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Anna M. D'souza

2017-06-01

Full Text Available Objective: The adipose-derived hormone leptin plays an important role in regulating body weight and glucose homeostasis. Leptin receptors are expressed in the central nervous system as well as peripheral tissues involved in regulating glucose homeostasis, including insulin-producing β cells of the pancreas. Previous studies assessing the role of leptin receptors in β cells used Cre-loxP to disrupt the leptin receptor gene (Lepr in β cells, but variable results were obtained. Furthermore, recombination of Lepr was observed in the hypothalamus or exocrine pancreas, in addition to the β cells, and Lepr in non-β cells may have compensated for the loss of Lepr in β cells, thus making it difficult to assess the direct effects of Lepr in β cells. To determine the significance of Lepr exclusively in β cells, we chose to selectively restore Lepr in β cells of Lepr null mice (LeprloxTB/loxTB. Materials and methods: We used a mouse model in which endogenous expression of Lepr was disrupted by a loxP-flanked transcription blocker (LeprloxTB/loxTB, but was restored by Cre recombinase knocked into the Ins1 gene, which is specifically expressed in β cells (Ins1Cre. We bred LeprloxTB/loxTB and Ins1Cre mice to generate LeprloxTB/loxTB and LeprloxTB/loxTB Ins1Cre mice, as well as Leprwt/wt and Leprwt/wt Ins1Cre littermate mice. Male and female mice were weighed weekly between 6 and 11 weeks of age and fasting blood glucose was measured during this time. Oral glucose was administered to mice aged 7–12 weeks to assess glucose tolerance and insulin secretion. Relative β and α cell area and islet size were also assessed by immunostaining and analysis of pancreas sections of 12–14 week old mice. Results: Male and female LeprloxTB/loxTB mice, lacking whole-body expression of Lepr, had a phenotype similar to db/db mice characterized by obesity, hyperinsulinemia, glucose intolerance, and impaired glucose stimulated insulin secretion. Despite restoring

Heat dissipation does not suppress an immune response in laboratory mice divergently selected for basal metabolic rate (BMR).

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Książek, Aneta; Konarzewski, Marek

2016-05-15

The capacity for heat dissipation is considered to be one of the most important constraints on rates of energy expenditure in mammals. To date, the significance of this constraint has been tested exclusively under peak metabolic demands, such as during lactation. Here, we used a different set of metabolic stressors, which do not induce maximum energy expenditures and yet are likely to expose the potential constraining effect of heat dissipation. We compared the physiological responses of mice divergently selected for high (H-BMR) and low basal metabolic rate (L-BMR) to simultaneous exposure to the keyhole limpet haemocyanin (KLH) antigen and high ambient temperature (Ta). At 34°C (and at 23°C, used as a control), KLH challenge resulted in a transient increase in core body temperature (Tb) in mice of both line types (by approximately 0.4°C). Warm exposure did not produce line-type-dependent differences in Tb (which was consistently higher by ca. 0.6°C in H-BMR mice across both Ta values), nor did it result in the suppression of antibody synthesis. These findings were also supported by the lack of between-line-type differences in the mass of the thymus, spleen or lymph nodes. Warm exposure induced the downsizing of heat-generating internal organs (small intestine, liver and kidneys) and an increase in intrascapular brown adipose tissue mass. However, these changes were similar in scope in both line types. Mounting a humoral immune response in selected mice was therefore not affected by ambient temperature. Thus, a combined metabolic challenge of high Ta and an immune response did not appreciably compromise the capacity to dissipate heat, even in the H-BMR mice. © 2016. Published by The Company of Biologists Ltd.

A selective cannabinoid CB2 agonist attenuates damage and improves memory retention following stroke in mice.

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Ronca, Richard D; Myers, Alyssa M; Ganea, Doina; Tuma, Ronald F; Walker, Ellen A; Ward, Sara Jane

2015-10-01

We have recently demonstrated that treatment with a cannabinoid CB2 agonist was protective in a mouse middle cerebral artery occlusion model of cerebral ischemia/reperfusion injury. The present study aimed to determine whether these protective effects of CB2 agonism would extend to a mouse photoinjury model of permanent ischemia and determine associated alterations in cognition and infarct size. Mice received three injections of the CB2 selective agonist O-1966 or vehicle 1h prior to and 2 and 5days following induction of stroke. Infarct size was assessed at 1, 3, or 7days post-injury and learning and memory effects of injury and O-1966 treatment were assessed on days 6 and 7 using a novel object recognition task and an operant acquisition and retention procedure. O-1966 treated mice had significantly smaller infarct volumes compared with vehicle treated mice. Photoinjury was also associated with a significant memory impairment on day 7 post-injury, and this deficit was reversed with O-1966 treatment. Surprisingly, sham-operated mice receiving O-1966 treatment showed a significant learning deficit in both the recognition and operant tasks compared with vehicle treated sham mice. We conclude that CB2 activation is protective against cognitive deficits and tissue damage following permanent ischemia, but may dysregulate glial or neuronal function of learning and memory circuits in the absence of injury and/or inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

High Fat High Sugar Diet Reduces Voluntary Wheel Running in Mice Independent of Sex Hormone Involvement

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Vellers, Heather L.; Letsinger, Ayland C.; Walker, Nicholas R.; Granados, Jorge Z.; Lightfoot, J. Timothy

2017-01-01

Introduction: Indirect results in humans suggest that chronic overfeeding decreases physical activity with few suggestions regarding what mechanism(s) may link overfeeding and decreased activity. The primary sex hormones are known regulators of activity and there are reports that chronic overfeeding alters sex hormone levels. Thepurpose of this study was to determine if chronic overfeeding altered wheel running through altered sex hormone levels. Materials and Methods: C57BL/6J mice were bred and the pups were weaned at 3-weeks of age and randomly assigned to either a control (CFD) or high fat/high sugar (HFHS) diet for 9–11 weeks depending on activity analysis. Nutritional intake, body composition, sex hormone levels, and 3-day and 2-week wheel-running activity were measured. Additionally, groups of HFHS animals were supplemented with testosterone (males) and 17β-estradiol (females) to determine if sex hormone augmentation altered diet-induced changes in activity. Results: 117 mice (56♂, 61♀) were analyzed. The HFHS mice consumed significantly more calories per day than CFD mice (male: p running-wheel distance in male (p = 0.05, 70 ± 28%) and female mice (p = 0.02, 57 ± 26%). In animals that received hormone supplementation, there was no significant effect on activity levels. Two-weeks of wheel access was not sufficient to alter HFHS-induced reductions in activity or increases in body fat. Conclusion: Chronic overfeeding reduces wheel running, but is independent of the primary sex hormones. PMID:28890701

Characters of tomato and pepper bred by space mutation in glasshouse

International Nuclear Information System (INIS)

Pei Xiaobo; Gu Xiaojun; Chen Chunhong; Li Shicheng

2004-01-01

Plant growth and yield of tomato and pepper bred by space mutation and materials carried by aero-craft 'Shenzhou' No.4 and its parent variety as control were studied in glasshouse. The results show that all varieties grew vigorously in glasshouse and the average fruit weight was about 221 g for tomato variety 641 and 648 and material HT10-3-2 and HT10-2. Accumulated yield for variety 648 was 2847.5 g, which was 9.9% higher than variety 641, indicating that they are suitable for glasshouse cultivation. Average fruit weight for pepper variety 616 was about 76 g, potential with accumulated yield of 440.9 g, indicating that it can be used for glasshouse cultivation. There was no significant difference between the Aero-craft carried materials and but the yield range change of among and its the carried materials 7.5%-8.0%

Differences in basal and stress-induced HPA regulation of wild house mice selected for high and low aggression

NARCIS (Netherlands)

Veenema, AH; Meijer, OC; de Kloet, ER; Koolhaas, JM; Bohus, BG; Meijer, Onno C.; Koolhaas, J M

Male wild house mice, selected for short (SAL) and long (LAL) attack latency, show distinctly different behavioral strategies in coping with environmental challenges. In this study, we tested the hypothesis that this difference in coping style is associated with a differential stress responsiveness

High-saturated fat-sucrose feeding affects lactation energetics in control mice and mice selectively bred for high wheel-running behavior

NARCIS (Netherlands)

Guidotti, Stefano; Jonas, Izabella; Schubert, Kristin A.; Garland, Theodore; Meijer, Harro A. J.; Scheurink, Anton J. W.; van Dijk, Gertjan

2013-01-01

Feeding a diet high in fat and sucrose (HFS) during pregnancy and lactation is known to increase susceptibility to develop metabolic derangements later in life. A trait for increased behavioral activity may oppose these effects, since this would drain energy from milk produced to be made available

Selection for high and low oxygen consumption-induced differences in maintenance energy requirements of mice.

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Darhan, Hongyu; Kikusato, Motoi; Toyomizu, Masaaki; Roh, Sang-Gun; Katoh, Kazuo; Sato, Masahiro; Suzuki, Keiichi

2017-07-01

Maintenance energy requirements (MER) of mice selected for high (H) or low (L) oxygen consumption (OC) were compared. Forty-four mice from H and L OC lines were weaned at 3 weeks and divided into four experimental groups: group A were sacrificed at 4 weeks; group B were fed ad libitum, and groups C and D were fed 2.8 and 2.4 g/day, respectively, from 4 to 8 weeks of age. Groups B-D were sacrificed at 8 weeks. Chemical components were estimated for all groups. MER was estimated using a model that partitioned metabolizable energy intake into that used for maintenance, and protein and fat deposition. The feed conversion ratio for the B group was significantly higher in the H than in the L line. Feed intake for metabolic energy content per metabolic body size was significantly also higher in the H line, whereas accumulated energy content per metabolic body size was significantly higher in the L line. MER of the H line was greater than that of the L line (P < 0.10). These results suggest that selection for H or L OC produced differences in chemical components, feed efficiency, and MER between the H and L lines. © 2016 Japanese Society of Animal Science.

Profiling trait anxiety: transcriptome analysis reveals cathepsin B (Ctsb as a novel candidate gene for emotionality in mice.

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Ludwig Czibere

Full Text Available Behavioral endophenotypes are determined by a multitude of counteracting but precisely balanced molecular and physiological mechanisms. In this study, we aim to identify potential novel molecular targets that contribute to the multigenic trait "anxiety". We used microarrays to investigate the gene expression profiles of different brain regions within the limbic system of mice which were selectively bred for either high (HAB or low (LAB anxiety-related behavior, and also show signs of comorbid depression-like behavior. We identified and confirmed sex-independent differences in the basal expression of 13 candidate genes, using tissue from the entire brain, including coronin 7 (Coro7, cathepsin B (Ctsb, muscleblind-like 1 (Mbnl1, metallothionein 1 (Mt1, solute carrier family 25 member 17 (Slc25a17, tribbles homolog 2 (Trib2, zinc finger protein 672 (Zfp672, syntaxin 3 (Stx3, ATP-binding cassette, sub-family A member 2 (Abca2, ectonucleotide pyrophosphatase/phosphodiesterase 5 (Enpp5, high mobility group nucleosomal binding domain 3 (Hmgn3 and pyruvate dehydrogenase beta (Pdhb. Additionally, we confirmed brain region-specific differences in the expression of synaptotagmin 4 (Syt4.Our identification of about 90 polymorphisms in Ctsb suggested that this gene might play a critical role in shaping our mouse model's behavioral endophenotypes. Indeed, the assessment of anxiety-related and depression-like behaviors of Ctsb knock-out mice revealed an increase in depression-like behavior in females. Altogether, our results suggest that Ctsb has significant effects on emotionality, irrespective of the tested mouse strain, making it a promising target for future pharmacotherapy.

Muscle-directed gene therapy for phenylketonuria (PKU): Development of transgenic mice with muscle-specific phenylalanine hydroxylase expression

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Harding, C.O.; Messing, A.; Wolff, J.A. [Univ. of Wisconsin, Madison, WI (United States)

1994-09-01

Phenylketonuria (PKU) is an attractive target for gene therapy because of shortcomings in current therapy including lifelong commitment to a difficult and expensive diet, persistent mild cognitive deficits in some children despite adequate dietary therapy, and maternal PKU syndrome. Phenylalanine hydroxylase (PAH) is normally expressed only in liver, but we propose to treat PKU by introducing the gene for PAH into muscle. In order to evaluate both the safety and efficacy of this approach, we have a developed a trangenic mouse which expresses PAH in both cardiac and skeletal muscle. The transgene includes promoter and enhancer sequences from the mouse muscle creatine kinase (MCK) gene fused to the mouse liver PAH cDNA. Mice which have inherited the transgene are healthy, active, and do not exhibit any signs of muscle weakness or wasting. Ectopic PAH expression in muscle is not detrimental to the health, neurologic function, or reproduction of the mice. Pah{sup enu2} hyperphenylalaninemic mice, a model of human PAH deficiency, bred to carry the transgene have substantial PAH expression in cardiac and skeletal muscle but none in liver. Muscle PAH expression alone does not complement the hyperphenylalaninemic phenotype of Pah{sup enu2} mice. However, administration of reduced tetrahydrobiopterin to transgenic Pah{sup enu2} mice is associated with a 25% mean decrease in serum phenylalanine levels. We predict that ectopic expression of PAH in muscle along with adequate muscle supplies of reduced biopterin cofactor will decrease hyperphenylalaninemia in PKU.

Mice selected for high versus low stress reactivity: a new animal model for affective disorders.

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Touma, Chadi; Bunck, Mirjam; Glasl, Lisa; Nussbaumer, Markus; Palme, Rupert; Stein, Hendrik; Wolferstätter, Michael; Zeh, Ramona; Zimbelmann, Marina; Holsboer, Florian; Landgraf, Rainer

2008-07-01

Affective disorders such as major depression are among the most prevalent and costly diseases of the central nervous system, but the underlying mechanisms are still poorly understood. In recent years, it has become evident that alterations of the stress hormone system, in particular dysfunctions (hyper- or hypo-activity) of the hypothalamic-pituitary-adrenal (HPA) axis, play a prominent role in the development of major depressive disorders. Therefore, we aimed to generate a new animal model comprising these neuroendocrine core symptoms in order to unravel parameters underlying increased or decreased stress reactivity. Starting from a population of outbred mice (parental generation: 100 males and 100 females of the CD-1 strain), two breeding lines were established according to the outcome of a 'stress reactivity test' (SRT), consisting of a 15-min restraint period and tail blood samplings immediately before and after exposure to the stressor. Mice showing a very high or a very low secretion of corticosterone in the SRT, i.e. animals expressing a hyper- or a hypo-reactivity of the HPA axis, were selected for the 'high reactivity' (HR) and the 'low reactivity' (LR) breeding line, respectively. Additionally, a third breeding line was established consisting of animals with an 'intermediate reactivity' (IR) in the SRT. Already in the first generation, i.e. animals derived from breeding pairs selected from the parental generation, significant differences in the reactivity of the HPA axis between HR, IR, and LR mice were observed. Moreover, these differences were found across all subsequent generations and could be increased by selective breeding, which indicates a genetic basis of the respective phenotype. Repeated testing of individuals in the SRT furthermore proved that the observed differences in stress responsiveness are present already early in life and can be regarded as a robust genetic predisposition. Tests investigating the animal's emotionality including anxiety

CONTRIBUTIONS TO KNOWLEDGE OF SOME MORPHOLOGICAL FEATURES IN YOUNG SOWS BRED IN FARMSTEADS ON CLUJ COUNTY INCIDENCE

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I. CORNOIU

2007-10-01

Full Text Available The present study tries to offer some information concerning the morphological stateof Bazna Breed female suina biological material bred and kept in farmsteads onCluj County incidence, near to enter to reproduce for the first time.Practically, after a biometric synthetic check, 37 young sows were phenotypicallyanalyzed, considered as acceptable to reproduction by the breeders.The obtained results were statistically processed and the formulated conclusionswant to be modest recommendations for suina breeders in general, and for Baznabreed in special.

Altered social behaviours in neurexin 1α knockout mice resemble core symptoms in neurodevelopmental disorders.

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Hannah Mary Grayton

Full Text Available BACKGROUND: Copy number variants have emerged as an important genomic cause of common, complex neurodevelopmental disorders. These usually change copy number of multiple genes, but deletions at 2p16.3, which have been associated with autism, schizophrenia and mental retardation, affect only the neurexin 1 gene, usually the alpha isoform. Previous analyses of neurexin 1α (Nrxn1α knockout (KO mouse as a model of these disorders have revealed impairments in synaptic transmission but failed to reveal defects in social behaviour, one of the core symptoms of autism. METHODS: We performed a detailed investigation of the behavioural effects of Nrxn1α deletion in mice bred onto a pure genetic background (C57BL/6J to gain a better understanding of its role in neurodevelopmental disorders. Wildtype, heterozygote and homozygote Nrxn1α KO male and female mice were tested in a battery of behavioural tests (n = 9-16 per genotype, per sex. RESULTS: In homozygous Nrxn1α KO mice, we observed altered social approach, reduced social investigation, and reduced locomotor activity in novel environments. In addition, male Nrxn1α KO mice demonstrated an increase in aggressive behaviours. CONCLUSIONS: These are the first experimental data that associate a deletion of Nrxn1α with alterations of social behaviour in mice. Since this represents one of the core symptom domains affected in autism spectrum disorders and schizophrenia in humans, our findings suggest that deletions within NRXN1 found in patients may be responsible for the impairments seen in social behaviours, and that the Nrxn1α KO mice are a useful model of human neurodevelopmental disorder.

Altered Social Behaviours in Neurexin 1α Knockout Mice Resemble Core Symptoms in Neurodevelopmental Disorders

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Grayton, Hannah Mary; Missler, Markus

2013-01-01

Background Copy number variants have emerged as an important genomic cause of common, complex neurodevelopmental disorders. These usually change copy number of multiple genes, but deletions at 2p16.3, which have been associated with autism, schizophrenia and mental retardation, affect only the neurexin 1 gene, usually the alpha isoform. Previous analyses of neurexin 1α (Nrxn1α) knockout (KO) mouse as a model of these disorders have revealed impairments in synaptic transmission but failed to reveal defects in social behaviour, one of the core symptoms of autism. Methods We performed a detailed investigation of the behavioural effects of Nrxn1α deletion in mice bred onto a pure genetic background (C57BL/6J) to gain a better understanding of its role in neurodevelopmental disorders. Wildtype, heterozygote and homozygote Nrxn1α KO male and female mice were tested in a battery of behavioural tests (n = 9–16 per genotype, per sex). Results In homozygous Nrxn1α KO mice, we observed altered social approach, reduced social investigation, and reduced locomotor activity in novel environments. In addition, male Nrxn1α KO mice demonstrated an increase in aggressive behaviours. Conclusions These are the first experimental data that associate a deletion of Nrxn1α with alterations of social behaviour in mice. Since this represents one of the core symptom domains affected in autism spectrum disorders and schizophrenia in humans, our findings suggest that deletions within NRXN1 found in patients may be responsible for the impairments seen in social behaviours, and that the Nrxn1α KO mice are a useful model of human neurodevelopmental disorder. PMID:23840597

Comparison of feed energy costs of maintenance, lean deposition, and fat deposition in three lines of mice selected for heat loss.

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Eggert, D L; Nielsen, M K

2006-02-01

Three replications of mouse selection populations for high heat loss (MH), low heat loss (ML), and a nonselected control (MC) were used to estimate the feed energy costs of maintenance and gain and to test whether selection had changed these costs. At 21 and 49 d of age, mice were weighed and subjected to dual x-ray densitometry measurement for prediction of body composition. At 21 d, mice were randomly assigned to an ad libitum, an 80% of ad libitum, or a 60% of ad libitum feeding group for 28-d collection of individual feed intake. Data were analyzed using 3 approaches. The first approach was an attempt to partition energy intake between costs for maintenance, fat deposition, and lean deposition for each replicate, sex, and line by multiple regression of feed intake on the sum of daily metabolic weight (kg(0.75)), fat gain, and lean gain. Approach II was a less restrictive attempt to partition energy intake between costs for maintenance and total gain for each replicate, sex, and line by multiple regression of feed intake on the sum of daily metabolic weight and total gain. Approach III used multiple regression on the entire data set with pooled regressions on fat and lean gains, and subclass regressions for maintenance. Contrasts were conducted to test the effect of selection (MH - ML) and asymmetry of selection [(MH + ML)/2 - MC] for the various energy costs. In approach I, there were no differences between lines for costs of maintenance, fat deposition, or protein deposition, but we question our ability to estimate these accurately. In approach II, selection changed both cost of maintenance (P = 0.03) and gain (P = 0.05); MH mice had greater per unit costs than ML mice for both. Asymmetry of the selection response was found in approach II for the cost of maintenance (P = 0.06). In approach III, the effect of selection (P maintenance cost, but asymmetry of selection (P > 0.17) was not evident. Sex effects were found for the cost of fat deposition (P = 0.02) in

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

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

2011-11-01

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, ~25 and ~40 μg/dL, respectively, on PN10 and by PN30 all were ≤ 1 μg/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. Copyright © 2011 Elsevier Inc. All rights reserved.

Dopamine D1 receptor modulation in nucleus accumbens lowers voluntary wheel running in rats bred to run high distances.

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Roberts, Michael D; Gilpin, Leigh; Parker, Kyle E; Childs, Thomas E; Will, Matthew J; Booth, Frank W

2012-02-01

Dopamine signaling in the nucleus accumbens (NAc) has been postulated to influence reward development towards drugs of abuse and exercise. Herein, we used generation 4-5 rats that were selectively bred to voluntary run high (HVR) versus low (LVR) distances in order to examine if dopamine-like 1 (D1) receptor modulation in the NAc differentially affects nightly voluntary wheel running between these lines. A subset of generation 5-6 HVR and LVR rats were also used to study the mRNA expression of key genes related to reward and addiction in the NAc (i.e., DRD1, DRD5, DRD2, Nr4a2, FosB, and BDNF). In a crossover fashion, a D1-like agonist SKF 82958 (2 μg per side) or D1-like full antagonist SCH 23390 (4 μg per side) was bilaterally injected into the NAc of HVR and LVR female Wistar rats prior to their high running nights. Notably, during hours 2-4 (between 2000 and 2300) of the dark cycle there was a significant decrement in running distances in the HVR rats treated with the D1 agonist (p=0.025) and antagonist (p=0.017) whereas the running distances in LVR rats were not affected. Interestingly, HVR and LVR rats possessed similar NAc concentrations of the studied mRNAs. These data suggest that: a) animals predisposed to run high distances on a nightly basis may quickly develop a rewarding response to exercise due to an optimal D1-like receptor signaling pathway in the NAc that can be perturbed by either activation or blocking, b) D1-like agonist or antagonist injections do not increase running distances in rats that are bred to run low nightly distances, and c) running differences between HVR and LVR animals are seemingly not due to the expression of the studied mRNAs. Given the societal prevalence of obesity and extraneous physical inactivity, future studies should be performed in order to further determine the culprit for the low running phenotype observed in LVR animals. Copyright © 2011. Published by Elsevier Inc.

HOME-GROWN AND ABROAD-BRED ENTREPRENEURS IN CHINA: A STUDY OF THE INFLUENCES OF EXTERNAL CONTEXT ON ENTREPRENEURIAL COMPETENCIES

OpenAIRE

THOMAS WING YAN MAN; THERESA LAU; K. F. CHAN

2008-01-01

As an attempt to explore the influence of external context on entrepreneurial competencies, we conducted a comparative analysis using a sample of 16 home-grown and abroad-bred entrepreneurs in China. Through a content analysis of the critical incidents during their business development, we found that both groups demonstrated a similar set of entrepreneurial competencies, with strategic, relationship, conceptual, organizing and opportunity competencies being the most predominant types. However...

Selective depletion of microglial progranulin in mice is not sufficient to cause neuronal ceroid lipofuscinosis or neuroinflammation.

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Petkau, Terri L; Kosior, Natalia; de Asis, Kathleen; Connolly, Colúm; Leavitt, Blair R

2017-11-17

Progranulin deficiency due to heterozygous null mutations in the GRN gene are a common cause of familial frontotemporal lobar degeneration (FTLD), while homozygous loss-of-function GRN mutations are thought to be a rare cause of neuronal ceroid lipofuscinosis (NCL). Aged progranulin-knockout (Grn-null) mice display highly exaggerated lipofuscinosis, microgliosis, and astrogliosis, as well as mild cell loss in specific brain regions. In the brain, progranulin is predominantly expressed in neurons and microglia, and previously, we demonstrated that neuronal-specific depletion of progranulin does not recapitulate the neuropathological phenotype of Grn-null mice. In this study, we evaluated whether selective depletion of progranulin expression in myeloid-lineage cells, including microglia, causes NCL-like neuropathology or neuroinflammation in mice. We generated mice with progranulin depleted in myeloid-lineage cells by crossing mice homozygous for a floxed progranulin allele to mice expressing Cre recombinase under control of the LyzM promotor (Lyz-cKO). Progranulin expression was reduced by approximately 50-70% in isolated microglia compared to WT levels. Lyz-cKO mice aged to 12 months did not display any increase in lipofuscin deposition, microgliosis, or astrogliosis in the four brain regions examined, though increases were observed for many of these measures in Grn-null animals. To evaluate the functional effect of reduced progranulin expression in isolated microglia, primary cultures were stimulated with controlled standard endotoxin and cytokine release was measured. While Grn-null microglia display a hyper-inflammatory phenotype, Lyz-cKO and WT microglia secreted similar levels of inflammatory cytokines. We conclude that progranulin expression from either microglia or neurons is sufficient to prevent the development of NCL-like neuropathology in mice. Furthermore, microglia that are deficient for progranulin expression but isolated from a progranulin

Hepatic tissue environment in NEMO-deficient mice critically regulates positive selection of donor cells after hepatocyte transplantation.

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Michaela Kaldenbach

Full Text Available BACKGROUND: Hepatocyte transplantation (HT is a promising alternative treatment strategy for end-stage liver diseases compared with orthotopic liver transplantation. A limitation for this approach is the low engraftment of donor cells. The deletion of the I-kappa B kinase-regulatory subunit IKKγ/NEMO in hepatocytes prevents nuclear factor (NF-kB activation and triggers spontaneous liver apoptosis, chronic hepatitis and the development of liver fibrosis and hepatocellular carcinoma. We hypothesized that NEMOΔhepa mice may therefore serve as an experimental model to study HT. METHODS: Pre-conditioned NEMOΔhepa mice were transplanted with donor-hepatocytes from wildtype (WT and mice deficient for the pro-apoptotic mediator Caspase-8 (Casp8Δhepa. RESULTS: Transplantation of isolated WT-hepatocytes into pre-conditioned NEMOΔhepa mice resulted in a 6-7 fold increase of donor cells 12 weeks after HT, while WT-recipients showed no liver repopulation. The use of apoptosis-resistant Casp8Δhepa-derived donor cells further enhanced the selection 3-fold after 12-weeks and up to 10-fold increase after 52 weeks compared with WT donors. While analysis of NEMOΔhepa mice revealed strong liver injury, HT-recipient NEMOΔhepa mice showed improved liver morphology and decrease in serum transaminases. Concomitant with these findings, the histological examination elicited an improved liver tissue architecture associated with significantly lower levels of apoptosis, decreased proliferation and a lesser amount of liver fibrogenesis. Altogether, our data clearly support the therapeutic benefit of the HT procedure into NEMOΔhepa mice. CONCLUSION: This study demonstrates the feasibility of the NEMOΔhepa mouse as an in vivo tool to study liver repopulation after HT. The improvement of the characteristic phenotype of chronic liver injury in NEMOΔhepa mice after HT suggests the therapeutic potential of HT in liver diseases with a chronic inflammatory phenotype and

Role of major histocompatibility complex class II in resistance of mice to naturally acquired infection with Syphacia obvelata

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Stewart, Patricia W.; Chapes, Stephen K.

2003-01-01

Genetics plays a substantial role in host resistance in many host-parasite interactions. We examined the prevalence of naturally acquired infection with Syphacia obvelata in a number of mouse strains housed in a non-barrier facility. These mice, which included cross-bred and congenic, inbred strains on various genetic backgrounds, differ in the loci for the immune function genes--major histocompatibility complex class II (MHCII), toll-like receptor 4 (Tlr4), and solute carrier family 11, member 1 (Slc11a1)--which allowed comparisons of the impact of these genes on resistance to pinworm infection. Male and female mice of various ages were sampled over an 18-month period; infection was determined by use of the cellophane tape test. Results indicated that mice that were MHCII+/+ had a significantly lower prevalence of infection than did mice that were MHCII-/-. Differences were not seen between male and female mice. Although MHCII+/+ mice had an age-associated decrease in infection prevalence, such decrease was not seen in MHCII-/- mice. In contrast, infection prevalence in mice with the normal Tlr4 gene (Tlr4(LPS-n/LPS-n)) gene did not differ significantly compared with that in mice that were homozygous for either the point mutation (Tlr4(LPS-d/LPS-d)) or deletion (Tlr4(LPS-del/LPS-del)) of that gene. Likewise, the presence (Sle11a1r/r) or absence (Slc11a1s/s) of functional alleles for Slc11a1 had no effect on the prevalence of infection with S. obvelata. In conclusion, presence of MHCII, but not Tlr4 or Slc11a1 significantly influences prevalence of naturally acquired infection with S. obvelata. These data justify further comprehensive analyses of the immune components that are involved in pinworm resistance.

Decreased Blastocyst Production in Mice Exposed to Increased Rack Noise

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Zamora, Bernadette M; Jiang, Meisheng; Wang, Ying; Chai, Minghua; Lawson, P Timothy; Lawson, Gregory W

2009-01-01

This study was conducted to investigate the possible effect of rack type on the blastocyst yield of mouse embryo donors. The first phase of the study consisted of housing some mice (group A) in a ventilated rack and others (group B) in a static rack in the same room for 3 d, followed by euthanasia for blastocyst collection and corticosterone assay. Parametric tests were used to compare groups. The number of blastocysts per donor was lower in group A (5.0 ± 1.4 blastocysts) than group B (13.1 ± 3.7 blastocysts). Mean noise was higher in the ventilated rack (80.4 dBC) than in the static rack (69.2 dBC). Serum corticosterone concentrations did not differ between groups. For the second phase of the study, a third group of mice (group C) was housed in a static rack without a ventilated rack in the same room. The noise level for group C was even lower (45.18 ± 2.91 dBC), and the blastocyst count per donor (16.4 ± 2.4) was higher than that of group B. The mean noise levels of empty ventilated and static racks differed significantly between groups for 10 different sound frequencies. Plotting mean blastocyst production against mean rack noise revealed a negative linear relationship with good strength of correlation. These results support the earlier observation that decreased blastocyst count occurs following housing of bred C57BL/6 donor mice in ventilated cages. PMID:19807968

Nucleus accumbens neuronal maturation differences in young rats bred for low versus high voluntary running behaviour

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Roberts, Michael D; Toedebusch, Ryan G; Wells, Kevin D; Company, Joseph M; Brown, Jacob D; Cruthirds, Clayton L; Heese, Alexander J; Zhu, Conan; Rottinghaus, George E; Childs, Thomas E; Booth, Frank W

2014-01-01

We compared the nucleus accumbens (NAc) transcriptomes of generation 8 (G8), 34-day-old rats selectively bred for low (LVR) versus high voluntary running (HVR) behaviours in rats that never ran (LVRnon-run and HVRnon-run), as well as in rats after 6 days of voluntary wheel running (LVRrun and HVRrun). In addition, the NAc transcriptome of wild-type Wistar rats was compared. The purpose of this transcriptomics approach was to generate testable hypotheses as to possible NAc features that may be contributing to running motivation differences between lines. Ingenuity Pathway Analysis and Gene Ontology analyses suggested that ‘cell cycle’-related transcripts and the running-induced plasticity of dopamine-related transcripts were lower in LVR versus HVR rats. From these data, a hypothesis was generated that LVR rats might have less NAc neuron maturation than HVR rats. Follow-up immunohistochemistry in G9–10 LVRnon-run rats suggested that the LVR line inherently possessed fewer mature medium spiny (Darpp-32-positive) neurons (P running wheel access in our G9–10 LVRs uniquely increased their Darpp-32-positive and Dcx-positive neuron densities. In summary, NAc cellularity differences and/or the lack of running-induced plasticity in dopamine signalling-related transcripts may contribute to low voluntary running motivation in LVR rats. PMID:24665095

Large scale expression changes of genes related to neuronal signaling and developmental processes found in lateral septum of postpartum outbred mice.

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Brian E Eisinger

Full Text Available Coordinated gene expression changes across the CNS are required to produce the mammalian maternal phenotype. Lateral septum (LS is a brain region critically involved with aspects of maternal care, and we recently examined gene expression of whole septum (LS and medial septum in selectively bred maternal mice. Here, we expand on the prior study by 1 conducting microarray analysis solely on LS in virgin and postpartum mice, 2 using outbred mice, and 3 evaluating the role of sensory input on gene expression changes. Large scale changes in genes related to neuronal signaling were identified, including four GABAA receptor subunits. Subunits α4 and δ were downregulated in maternal LS, likely reflecting a reduction in the extrasynaptic, neurosteroid-sensitive α4/δ containing receptor subtype. Conversely, subunits ε and θ were increased in maternal LS. Fifteen K+ channel related genes showed altered expression, as did dopamine receptors Drd1a and Drd2 (both downregulated, hypocretin receptor 1 (Hcrtr1, kappa opioid receptor 1 (Oprk1, and transient receptor potential channel 4 (Trpc4. Expression of a large number of genes linked to developmental processes or cell differentiation were also altered in postpartum LS, including chemokine (C-X-C motif ligand 12 (Cxcl12, fatty acid binding protein 7 (Fabp7, plasma membrane proteolipid (Pllp, and suppressor of cytokine signaling 2 (Socs2. Additional genes that are linked to anxiety, such as glutathione reductase (Gsr, exhibited altered expression. Pathway analysis also identified changes in genes related to cyclic nucleotide metabolism, chromatin structure, and the Ras gene family. The sensory presence of pups was found to contribute to the altered expression of a subset of genes across all categories. This study suggests that both large changes in neuronal signaling and the possible terminal differentiation of neuronal and/or glial cells play important roles in producing the maternal state.

Stress and radioresistance (genetic aspects)

International Nuclear Information System (INIS)

Lyubaschevsky, N.M.; Grigorkina, E.B.

1995-01-01

Inbred mice and randomly bred stock were exposed to long-term adrenaline and hypothermia stress effects for unification of their functional status, followed by acute total gamma irradiation by equal-effect doses (LD 50/30 ). The significant reduction of lethality distribution in inbred mice after combined stress and radiation effects was observed. The spread of lethality in random bred stock was increased as compared to the control group. The post-irradiation mortality in experimental animals differed only slightly from the values in the control groups. Conclusions are drawn about the principal meaning of genotype in radiosensitivity, about the role of an organism's functional status in determination of death date and about the possible epigenetic structuralisation of linear mice by radioresistance. (Author)

Pion contamination in the MICE muon beam

International Nuclear Information System (INIS)

Adams, D.; Barclay, P.; Bayliss, V.; Brashaw, T.W.; Alekou, A.; Apollonio, M.; Barber, G.; Asfandiyarov, R.; Blondel, A.; De Bari, A.; Bayes, R.; Bertoni, R.; Bonesini, M.; Blackmore, V.J.; Blot, S.; Bogomilov, M.; Booth, C.N.; Bowring, D.; Boyd, S.; Bravar, U.

2016-01-01

The international Muon Ionization Cooling Experiment (MICE) will perform a systematic investigation of ionization cooling with muon beams of momentum between 140 and 240 MeV/c at the Rutherford Appleton Laboratory ISIS facility. The measurement of ionization cooling in MICE relies on the selection of a pure sample of muons that traverse the experiment. To make this selection, the MICE Muon Beam is designed to deliver a beam of muons with less than ∼1% contamination. To make the final muon selection, MICE employs a particle-identification (PID) system upstream and downstream of the cooling cell. The PID system includes time-of-flight hodoscopes, threshold-Cherenkov counters and calorimetry. The upper limit for the pion contamination measured in this paper is f π  < 1.4% at 90% C.L., including systematic uncertainties. Therefore, the MICE Muon Beam is able to meet the stringent pion-contamination requirements of the study of ionization cooling

Pion contamination in the MICE muon beam

CERN Document Server

Bogomilov, M.; Vankova-Kirilova, G.; Bertoni, R.; Bonesini, M.; Chignoli, F.; Mazza, R.; Palladino, V.; de Bari, A.; Cecchet, G.; Capponi, M.; Iaciofano, A.; Orestano, D.; Pastore, F.; Tortora, L.; Kuno, Y.; Sakamoto, H.; Ishimoto, S.; Japan, Ibaraki; Filthaut, F.; Hansen, O.M.; Ramberger, S.; Vretenar, M.; Asfandiyarov, R.; Blondel, A.; Drielsma, F.; Karadzhov, Y.; Charnley, G.; Collomb, N.; Gallagher, A.; Grant, A.; Griffiths, S.; Hartnett, T.; Martlew, B.; Moss, A.; Muir, A.; Mullacrane, I.; Oates, A.; Owens, P.; Stokes, G.; Warburton, P.; White, C.; Adams, D.; Barclay, P.; Bayliss, V.; Bradshaw, T.W.; Courthold, M.; Francis, V.; Fry, L.; Hayler, T.; Hills, M.; Lintern, A.; Macwaters, C.; Nichols, A.; Preece, R.; Ricciardi, S.; Rogers, C.; Stanley, T.; Tarrant, J.; Watson, S.; Wilson, A.; Bayes, R.; Nugent, J.C.; Soler, F.J.P.; Cooke, P.; Gamet, R.; Alekou, A.; Apollonio, M.; Barber, G.; Colling, D.; Dobbs, A.; Dornan, P.; Hunt, C.; Lagrange, J-B.; Long, K.; Martyniak, J.; Middleton, S.; Pasternak, J.; Santos, E.; Savidge, T.; Uchida, M.A.; Blackmore, V.J.; Carlisle, T.; Cobb, J.H.; Lau, W.; Rayner, M.A.; Tunnell, C.D.; Booth, C.N.; Hodgson, P.; Langlands, J.; Nicholson, R.; Overton, E.; Robinson, M.; Smith, P.J.; Dick, A.; Ronald, K.; Speirs, D.; Whyte, C.G.; Young, A.; Boyd, S.; Franchini, P.; Greis, J.R.; Pidcott, C.; Taylor, I.; Gardener, R.; Kyberd, P.; Littlefield, M.; Nebrensky, J.J.; Bross, A.D.; Fitzpatrick, T.; Leonova, M.; Moretti, A.; Neuffer, D.; Popovic, M.; Rubinov, P.; Rucinski, R.; Roberts, T.J.; Bowring, D.; DeMello, A.; Gourlay, S.; Li, D.; Prestemon, S.; Virostek, S.; Zisman, M.; Drews, M.; Hanlet, P.; Kafka, G.; Kaplan, D.M.; Rajaram, D.; Snopok, P.; Torun, Y.; Winter, M.; Blot, S.; Kim, Y.K.; Bravar, U.; Onel, Y.; Cremaldi, L.M.; Hart, T.L.; Luo, T.; Sanders, D.A.; Summers, D.J.; Cline, D.; Yang, X.; Coney, L.; Hanson, G.G.; Heidt, C.

2016-01-01

The international Muon Ionization Cooling Experiment (MICE) will perform a systematic investigation of ionization cooling with muon beams of momentum between 140 and 240\\,MeV/c at the Rutherford Appleton Laboratory ISIS facility. The measurement of ionization cooling in MICE relies on the selection of a pure sample of muons that traverse the experiment. To make this selection, the MICE Muon Beam is designed to deliver a beam of muons with less than $\\sim$1\\% contamination. To make the final muon selection, MICE employs a particle-identification (PID) system upstream and downstream of the cooling cell. The PID system includes time-of-flight hodoscopes, threshold-Cherenkov counters and calorimetry. The upper limit for the pion contamination measured in this paper is $f_\\pi < 1.4\\%$ at 90\\% C.L., including systematic uncertainties. Therefore, the MICE Muon Beam is able to meet the stringent pion-contamination requirements of the study of ionization cooling.

Selection on Coding and Regulatory Variation Maintains Individuality in Major Urinary Protein Scent Marks in Wild Mice.

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Michael J Sheehan

2016-03-01

Full Text Available Recognition of individuals by scent is widespread across animal taxa. Though animals can often discriminate chemical blends based on many compounds, recent work shows that specific protein pheromones are necessary and sufficient for individual recognition via scent marks in mice. The genetic nature of individuality in scent marks (e.g. coding versus regulatory variation and the evolutionary processes that maintain diversity are poorly understood. The individual signatures in scent marks of house mice are the protein products of a group of highly similar paralogs in the major urinary protein (Mup gene family. Using the offspring of wild-caught mice, we examine individuality in the major urinary protein (MUP scent marks at the DNA, RNA and protein levels. We show that individuality arises through a combination of variation at amino acid coding sites and differential transcription of central Mup genes across individuals, and we identify eSNPs in promoters. There is no evidence of post-transcriptional processes influencing phenotypic diversity as transcripts accurately predict the relative abundance of proteins in urine samples. The match between transcripts and urine samples taken six months earlier also emphasizes that the proportional relationships across central MUP isoforms in urine is stable. Balancing selection maintains coding variants at moderate frequencies, though pheromone diversity appears limited by interactions with vomeronasal receptors. We find that differential transcription of the central Mup paralogs within and between individuals significantly increases the individuality of pheromone blends. Balancing selection on gene regulation allows for increased individuality via combinatorial diversity in a limited number of pheromones.

Classical genetic analyses of responses to nicotine and ethanol in crosses derived from long- and short-sleep mice.

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de Fiebre, C M; Collins, A C

1992-04-01

A classical (Mendelian) genetic analysis of responses to ethanol and nicotine was conducted in crosses derived from mouse lines which were selectively bred for differential duration of loss of the righting response (sleep-time) after ethanol. Dose-response curves for these mice, the long- and short-sleep mouse lines, as well as the derived F1, F2 and backcross (F1 x long-sleep and F1 x short-sleep) generations were generated for several measures of nicotine and ethanol sensitivity. Ethanol sensitivity was assessed using the sleep-time measure. Nicotine sensitivity was tested using a battery of behavioral and physiological tests which included measures of seizure activity, respiration rate, acoustic startle response, Y-maze activities (both crossing and rearing activities), heart rate and body temperature. The inheritance of sensitivities to both of these agents appears to be polygenic and inheritance can be explained primarily by additive genetic effects with some epistasis. Sensitivity to the ethanol sleep-time measure was genetically correlated with sensitivity to both nicotine-induced hypothermia and seizures; the correlation was greater between sleep-time and hypothermia. These data indicate that there is overlap in the genetic regulation of sensitivity to both ethanol and nicotine as measured by some, but not all, tests.

Immunological characteristics and response to lipopolysaccharide of mouse lines selectively bred with natural and acquired immunities.

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Narahara, Hiroki; Sakai, Eri; Katayama, Masafumi; Ohtomo, Yukiko; Yamamoto, Kanako; Takemoto, Miki; Aso, Hisashi; Ohwada, Shyuichi; Mohri, Yasuaki; Nishimori, Katsuhiko; Isogai, Emiko; Yamaguchi, Takahiro; Fukuda, Tomokazu

2012-05-01

Genetic improvement of resistance to infectious diseases is a challenging goal in animal breeding. Infection resistance involves multiple immunological characteristics, including natural and acquired immunity. In the present study, we developed an experimental model based on genetic selection, to improve immunological phenotypes. We selectively established three mouse lines based on phagocytic activity, antibody production and the combination of these two phenotypes. We analyzed the immunological characteristics of these lines using a lipopolysaccharide (LPS), which is one of the main components of Gram-negative bacteria. An intense immunological reaction was induced in each of the three mouse lines. Severe loss of body weight and liver damage were observed, and a high level of cytokine messenger RNA was detected in the liver tissue. The mouse line established using a combination of the two selection standards showed unique characteristics relative to the mouse lines selected on the basis of a single phenotype. Our results indicate that genetic selection and breeding is effective, even for immunological phenotypes with a relatively low heritability. Thus, it may be possible to improve resistance to infectious diseases by means of genetic selection. © 2011 The Authors. Animal Science Journal © 2011 Japanese Society of Animal Science.

Autosomal recessive congenital cataract in captive-bred vervet monkeys (Chlorocebus aethiops).

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Magwebu, Zandisiwe E; Abdul-Rasool, Sahar; Seier, Jürgen V; Chauke, Chesa G

2018-04-01

The aim of the study was to evaluate the genetic predisposition of congenital cataract in a colony of captive-bred vervet monkeys. Four congenital cataract genes: glucosaminyl (N-acetyl) transferase 2 (GCNT2), heat shock transcription factor 4 (HSF4), crystallin alpha A (CRYAA) and lens intrinsic membrane protein-2 (LIM2) were screened, sequenced and analysed for possible genetic variants in 36 monkeys. Gene expression was also evaluated in these genes. Fifteen sequence variants were identified in the coding regions of three genes (GCNT2, HSF4 and CRYAA). Of these variations, only three were missense mutations (M258V, V16I and S24N) and identified in the GCNT2 transcripts A, B and C, respectively, which resulted in a downregulated gene expression. Although the three missense mutations in GCNT2 have a benign effect, a possibility exists that the candidate genes (GCNT2, HSF4 and CRYAA) might harbour mutations that are responsible for total congenital cataract. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cocaine-induced locomotor activity in rats selectively bred for low and high voluntary running behavior.

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Brown, Jacob D; Green, Caroline L; Arthur, Ian M; Booth, Frank W; Miller, Dennis K

2015-02-01

The rewarding effects of physical activity and abused drugs are caused by stimulation of similar brain pathways. Low (LVR) and high (HVR) voluntary running lines were developed by selectively breeding Wistar rats on running distance performance on postnatal days 28-34. We hypothesized that LVR rats would be more sensitive to the locomotor-activating effects of cocaine than HVR rats due to their lower motivation for wheel running. We investigated how selection for LVR or HVR behavior affects inherited activity responses: (a) open field activity levels, (b) habituation to an open field environment, and (c) the locomotor response to cocaine. Open field activity was measured for 80 min on three successive days (days 1-3). Data from the first 20 min were analyzed to determine novelty-induced locomotor activity (day 1) and the habituation to the environment (days 1-3). On day 3, rats were acclimated to the chamber for 20 min and then received saline or cocaine (10, 20, or 30 mg/kg) injection. Dopamine transporter (DAT) protein in the nucleus accumbens was measured via Western blot. Selecting for low and high voluntary running behavior co-selects for differences in inherent (HVR > LVR) and cocaine-induced (LVR > HVR) locomotor activity levels. The differences in the selected behavioral measures do not appear to correlate with DAT protein levels. LVR and HVR rats are an intriguing physical activity model for studying the interactions between genes related to the motivation to run, to use drugs of abuse, and to exhibit locomotor activity.

Differential regulation of morphine antinociceptive effects by endogenous enkephalinergic system in the forebrain of mice

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Sun Wei-Zen

2008-09-01

Full Text Available Abstract Background Mice lacking the preproenkephalin (ppENK gene are hyperalgesic and show more anxiety and aggression than wild-type (WT mice. The marked behavioral changes in ppENK knock-out (KO mice appeared to occur in supraspinal response to painful stimuli. However the functional role of enkephalins in the supraspinal nociceptive processing and their underlying mechanism is not clear. The aim of present study was to compare supraspinal nociceptive and morphine antinociceptive responses between WT and ppENK KO mice. Results The genotypes of bred KO mice were confirmed by PCR. Met-enkephalin immunoreactive neurons were labeled in the caudate-putamen, intermediated part of lateral septum, lateral globus pallidus, intermediated part of lateral septum, hypothalamus, and amygdala of WT mice. Met-enkephalin immunoreactive neurons were not found in the same brain areas in KO mice. Tail withdrawal and von Frey test results did not differ between WT and KO mice. KO mice had shorter latency to start paw licking than WT mice in the hot plate test. The maximal percent effect of morphine treatments (5 mg/kg and 10 mg/kg, i.p. differed between WT and KO mice in hot plate test. The current source density (CSD profiles evoked by peripheral noxious stimuli in the primary somatosenstory cortex (S1 and anterior cingulate cortex (ACC were similar in WT and KO mice. After morphine injection, the amplitude of the laser-evoked sink currents was decreased in S1 while the amplitude of electrical-evoked sink currents was increased in the ACC. These differential morphine effects in S1 and ACC were enhanced in KO mice. Facilitation of synaptic currents in the ACC is mediated by GABA inhibitory interneurons in the local circuitry. Percent increases in opioid receptor binding in S1 and ACC were 5.1% and 5.8%, respectively. Conclusion The present results indicate that the endogenous enkephalin system is not involved in acute nociceptive transmission in the spinal cord

Enhanced fear expression in a psychopathological mouse model of trait anxiety: pharmacological interventions.

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Simone B Sartori

Full Text Available The propensity to develop an anxiety disorder is thought to be determined by genetic and environmental factors. Here we investigated the relationship between a genetic predisposition to trait anxiety and experience-based learned fear in a psychopathological mouse model. Male CD-1 mice selectively bred for either high (HAB, or normal (NAB anxiety-related behaviour on the elevated plus maze were subjected to classical fear conditioning. During conditioning both mouse lines showed increased fear responses as assessed by freezing behaviour. However, 24 h later, HAB mice displayed more pronounced conditioned responses to both a contextual or cued stimulus when compared with NAB mice. Interestingly, 6 h and already 1 h after fear conditioning, freezing levels were high in HAB mice but not in NAB mice. These results suggest that trait anxiety determines stronger fear memory and/or a weaker ability to inhibit fear responses in the HAB line. The enhanced fear response of HAB mice was attenuated by treatment with either the α(2,3,5-subunit selective benzodiazepine partial agonist L-838,417, corticosterone or the selective neurokinin-1 receptor antagonist L-822,429. Overall, the HAB mouse line may represent an interesting model (i for identifying biological factors underlying misguided conditioned fear responses and (ii for studying novel anxiolytic pharmacotherapies for patients with fear-associated disorders, including post-traumatic stress disorder and phobias.

Low concentrations of Rhodamine-6G selectively destroy tumor cells and improve survival of melanoma transplanted mice.

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Kutushov, M; Gorelik, O

2013-01-01

Rhodamine-6G is a fluorescent dye binding to mitochondria, thus reducing the intact mitochondria number and inhibiting mitochondrial metabolic activity. Resultantly, the respiratory chain functioning becomes blocked, the cell "suffocated" and eventually destroyed. Unlike normal cells, malignant cells demonstrate a priori reduced mitochondrial numbers and aberrant metabolism. Therefore, a turning point might exist, when Rhodamine-induced loss of active mitochondria would selectively destroy malignant, but spare normal cells. Various malignant vs. non-malignant cell lines were cultured with Rhodamine-6G at different concentrations. In addition, C57Bl mice were implanted with B16-F10 melanoma and treated with Rhodamine-6G at different dosage/time regimens. Viability and proliferation of cultured tumor cells were time and dose-dependently inhibited, up to 90%, by Rhodamine-6G, with profound histological signs of cell death. By contrast, inhibition of normal control cell proliferation hardly exceeded 15-17%. Melanoma-transplanted mice receiving Rhodamine-6G demonstrated prolonged survival, improved clinical parameters, inhibited tumor growth and metastases count, compared to their untreated counterparts. Twice-a-week 10-6M Rhodamine-6G regimen yielded the most prominent results. We conclude that malignant, but not normal, cells are selectively destroyed by low doses of Rhodamine-6G. In vivo, such treatment selectively suppresses tumor progression and dissemination, thus improving prognosis. We suggest that selective anti-tumor properties of Rhodamine-6G are based on unique physiologic differences in energy metabolism between malignant and normal cells. If found clinically relevant, low concentrations of Rhodamine-6G might be useful for replacing, or backing up, more aggressive nonselective chemotherapeutic compounds.

Direct and transgenerational effects of low doses of perinatal di-(2-ethylhexyl phthalate (DEHP on social behaviors in mice.

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Kayla M Quinnies

Full Text Available Di-(2-ethylhexyl phthalate (DEHP is an endocrine disrupting chemical commonly used as a plasticizer in medical equipment, food packaging, flooring, and children's toys. DEHP exposure during early development has been associated with adverse neurobehavioral outcomes in children. In animal models, early exposure to DEHP results in abnormal development of the reproductive system as well as altered behavior and neurodevelopment. Based on these data, we hypothesized that developmental exposure to DEHP would decrease social interactions and increase anxiety-like behaviors in mice in a dose-dependent manner, and that the effects would persist over generations. C57BL/6J mice consumed one of three DEHP doses (0, 5, 40, and 400 μg/kg body weight throughout pregnancy and during the first ten days of lactation. The two higher doses yielded detectable levels of DEHP metabolites in serum. Pairs of mice from control, low, and high DEHP doses were bred to create three dose lineages in the third generation (F3. Average anogenital index (AGI: anogenital distance/body weight was decreased in F1 males exposed to the low dose of DEHP and in F1 females exposed to the highest dose. In F1 mice, juvenile pairs from the two highest DEHP dose groups displayed fewer socially investigative behaviors and more exploratory behaviors as compared with control mice. The effect of DEHP on these behaviors was reversed in F3 mice as compared with F1 mice. F1 mice exposed to low and medium DEHP doses spent more time in the closed arms of the elevated plus maze than controls, indicating increased anxiety-like behavior. The generation-dependent effects on behavior and AGI suggest complex mechanisms by which DEHP directly impacts reproductive and neurobehavioral development and influences germline-inherited traits.

Pre-Exposure to Context Affects Learning Strategy Selection in Mice

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Tunur, Tumay; Dohanich, Gary P.; Schrader, Laura A.

2010-01-01

The multiple memory systems hypothesis proposes that different types of learning strategies are mediated by distinct neural systems in the brain. Male and female mice were tested on a water plus-maze task that could be solved by either a place or response strategy. One group of mice was pre-exposed to the same context as training and testing (PTC)…

Function of brain α2B-adrenergic receptor characterized with subtype-selective α2B antagonist and KO mice.

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Luhrs, Lauren; Manlapaz, Cynthia; Kedzie, Karen; Rao, Sandhya; Cabrera-Ghayouri, Sara; Donello, John; Gil, Daniel

2016-12-17

Noradrenergic signaling, through the α 2A and α 2C adrenergic receptors modulates the cognitive and behavioral symptoms of disorders such as schizophrenia, attention deficit hyperactivity disorder (ADHD), and addiction. However, it is unknown whether the α 2B receptor has any significant role in CNS function. The present study elucidates the potential role of the α 2B receptor in CNS function via the discovery and use of the first subtype-selective α 2B antagonist (AGN-209419), and behavioral analyses of α-receptor knockout (KO) mice. Using AGN-209419 as radioligand, α 2B receptor binding sites were identified within the olfactory bulb, cortex, thalamus, cerebellum, and striatum. Based on the observed expression patterns of α 2 subtypes in the brain, we compared α 2B KO, α 2A KO and α 2C KO mice behavioral phenotypes with their respective wild-type lines in anxiety (plus maze), compulsive (marble burying), and sensorimotor (prepulse inhibition) tasks. α 2B KO mice exhibited increased marble burying and α 2C KO mice exhibited an increased startle response to a pulse stimulus, but otherwise intact prepulse inhibition. To further explore compulsive behavior, we evaluated novelty-induced locomotor hyperactivity and found that α 2B KO and α 2C KO mice exhibited increased locomotion in the open field. Interestingly, when challenged with amphetamine, α 2C KO mice increased activity at lower doses relative to either α 2A KO or WT mice. However, α 2B KO mice exhibited stereotypy at doses of amphetamine that were only locomotor stimulatory to all other genotypes. Following co-administration of AGN-209419 with low-dose amphetamine in WT mice, stereotypy was observed, mimicking the α 2B KO phenotype. These findings suggest that the α 2B receptor is involved in CNS behaviors associated with sensorimotor gating and compulsivity, and may be therapeutically relevant for disorders such as schizophrenia, ADHD, post-traumatic stress disorder, addiction, and

Bidirectional enantioselective effects of the GABAB receptor agonist baclofen in two mouse models of excessive ethanol consumption.

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Kasten, Chelsea R; Blasingame, Shelby N; Boehm, Stephen L

2015-02-01

The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption. The first was a Drinking-in-the-Dark procedure that provides "binge-like" ethanol access to mice by restricting access to a 2-h period, 3 h into the dark cycle. The second was a two-bottle choice procedure that utilized selectively bred High Alcohol Preferring 1 (HAP1) mice to model chronic ethanol access. HAP1 mice are selectively bred to consume pharmacologically relevant amounts of ethanol in a 24-h two-bottle choice paradigm. The results showed that baclofen yields enantioselective effects on ethanol intake in both models, and that these effects are bidirectional. Total ethanol intake was decreased by R(+)-baclofen, while total intake was increased by S(-)-baclofen in the binge-like and chronic drinking models. Whereas overall binge-like saccharin intake was significantly reduced by R(+)-baclofen, chronic intake was not significantly altered. S(-)-baclofen did not significantly alter saccharin intake. Neither enantiomer significantly affected locomotion during binge-like reinforcer consumption. Collectively, these results demonstrate that baclofen produces enantioselective effects on ethanol consumption. More importantly, the modulation of consumption is bidirectional. The opposing enantioselective effects may explain some of the variance seen in published baclofen literature. Copyright © 2015 Elsevier Inc. All rights reserved.

Short term supplementation of dietary antioxidants selectively regulates the inflammatory responses during early cutaneous wound healing in diabetic mice

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Park Na-Young

2011-11-01

Full Text Available Abstract Background Diabetic foot ulcers are serious complications for diabetic patients, yet the precise mechanism that underlines the treatment of these diabetic complications remains unclear. We hypothesized that dietary antioxidant supplementation with vitamin C, combined either with vitamin E or with vitamin E and NAC, improves delayed wound healing through modulation of blood glucose levels, oxidative stress, and inflammatory response. Methods Diabetes was induced by administration of alloxan monohydrate. Mice were divided into 4 groups; CON (non-diabetic control mice fed AIN 93 G purified rodent diet, DM (diabetic mice fed AIN 93 G purified rodent diet, VCE (diabetic mice fed 0.5% vitamin C and 0.5% vitamin E supplemented diet, and Comb (diabetic mice fed 0.5% vitamin C, 0.5% vitamin E, and 2.5% NAC supplemented diet. After 10 days of dietary antioxidant supplementation, cutaneous full-thickness excisional wounds were performed, and the rate of wound closure was examined. TBARS as lipid peroxidation products and vitamin E levels were measured in the liver. Expression levels of oxidative stress and inflammatory response related proteins were measured in the cutaneous wound site. Results Dietary antioxidant supplementation improved blood glucose levels and wound closure rate and increased liver vitamin E, but not liver TBARS levels in the diabetic mice as compared to those of the CON. In addition, dietary antioxidant supplementation modulated the expression levels of pIκBα, HO-1, CuZnSOD, iNOS and COX-2 proteins in the diabetic mice. Conclusions These findings demonstrated that delayed wound healing is associated with an inflammatory response induced by hyperglycaemia, and suggests that dietary antioxidant supplementation may have beneficial effects on wound healing through selective modulation of blood glucose levels, oxidative stress, and inflammatory response.

A comparison of statistical methods for genomic selection in a mice population

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Neves Haroldo HR

2012-11-01

Full Text Available Abstract Background The availability of high-density panels of SNP markers has opened new perspectives for marker-assisted selection strategies, such that genotypes for these markers are used to predict the genetic merit of selection candidates. Because the number of markers is often much larger than the number of phenotypes, marker effect estimation is not a trivial task. The objective of this research was to compare the predictive performance of ten different statistical methods employed in genomic selection, by analyzing data from a heterogeneous stock mice population. Results For the five traits analyzed (W6W: weight at six weeks, WGS: growth slope, BL: body length, %CD8+: percentage of CD8+ cells, CD4+/ CD8+: ratio between CD4+ and CD8+ cells, within-family predictions were more accurate than across-family predictions, although this superiority in accuracy varied markedly across traits. For within-family prediction, two kernel methods, Reproducing Kernel Hilbert Spaces Regression (RKHS and Support Vector Regression (SVR, were the most accurate for W6W, while a polygenic model also had comparable performance. A form of ridge regression assuming that all markers contribute to the additive variance (RR_GBLUP figured among the most accurate for WGS and BL, while two variable selection methods ( LASSO and Random Forest, RF had the greatest predictive abilities for %CD8+ and CD4+/ CD8+. RF, RKHS, SVR and RR_GBLUP outperformed the remainder methods in terms of bias and inflation of predictions. Conclusions Methods with large conceptual differences reached very similar predictive abilities and a clear re-ranking of methods was observed in function of the trait analyzed. Variable selection methods were more accurate than the remainder in the case of %CD8+ and CD4+/CD8+ and these traits are likely to be influenced by a smaller number of QTL than the remainder. Judged by their overall performance across traits and computational requirements, RR

Selective Toll-Like Receptor 4 Antagonists Prevent Acute Blood-Brain Barrier Disruption After Subarachnoid Hemorrhage in Mice.

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Okada, Takeshi; Kawakita, Fumihiro; Nishikawa, Hirofumi; Nakano, Fumi; Liu, Lei; Suzuki, Hidenori

2018-05-31

There are no direct evidences showing the linkage between Toll-like receptor 4 (TLR4) and blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH). The purpose of this study was to examine if selective blockage of TLR4 prevents BBB disruption after SAH in mice and if the TLR4 signaling involves mitogen-activated protein kinases (MAPKs). One hundred and fifty-one C57BL/6 male mice underwent sham or endovascular perforation SAH operation, randomly followed by an intracerebroventricular infusion of vehicle or two dosages (117 or 585 ng) of a selective TLR4 antagonist IAXO-102 at 30 min post-operation. The effects were evaluated by survival rates, neurological scores, and brain water content at 24-72 h and immunoglobulin G immunostaining and Western blotting at 24 h post-SAH. IAXO-102 significantly prevented post-SAH neurological impairments, brain edema, and BBB disruption, resulting in improved survival rates. IAXO-102 also significantly suppressed post-SAH activation of a major isoform of MAPK p46 c-Jun N-terminal kinase (JNK) and matrix metalloproteinase-9 as well as periostin induction and preserved tight junction protein zona occludens-1. Another selective TLR4 antagonist TAK-242, which has a different binding site from IAXO-102, also showed similar effects to IAXO-102. This study first provided the evidence that TLR4 signaling is involved in post-SAH acute BBB disruption and that the signaling is mediated at least partly by JNK activation. TLR4-targeted therapy may be promising to reduce post-SAH morbidities and mortalities.

Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

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Kamimura, Hidetaka; Ito, Satoshi

2016-01-01

1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

Combinatorial RNA Interference Therapy Prevents Selection of Pre-existing HBV Variants in Human Liver Chimeric Mice

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Shih, Yao-Ming; Sun, Cheng-Pu; Chou, Hui-Hsien; Wu, Tzu-Hui; Chen, Chun-Chi; Wu, Ping-Yi; Enya Chen, Yu-Chen; Bissig, Karl-Dimiter; Tao, Mi-Hua

2015-01-01

Selection of escape mutants with mutations within the target sequence could abolish the antiviral RNA interference activity. Here, we investigated the impact of a pre-existing shRNA-resistant HBV variant on the efficacy of shRNA therapy. We previously identified a highly potent shRNA, S1, which, when delivered by an adeno-associated viral vector, effectively inhibits HBV replication in HBV transgenic mice. We applied the “PICKY” software to systemically screen the HBV genome, then used hydrodynamic transfection and HBV transgenic mice to identify additional six highly potent shRNAs. Human liver chimeric mice were infected with a mixture of wild-type and T472C HBV, a S1-resistant HBV variant, and then treated with a single or combined shRNAs. The presence of T472C mutant compromised the therapeutic efficacy of S1 and resulted in replacement of serum wild-type HBV by T472C HBV. In contrast, combinatorial therapy using S1 and P28, one of six potent shRNAs, markedly reduced titers for both wild-type and T472C HBV. Interestingly, treatment with P28 alone led to the emergence of escape mutants with mutations in the P28 target region. Our results demonstrate that combinatorial RNAi therapy can minimize the escape of resistant viral mutants in chronic HBV patients. PMID:26482836

Adaptive response of spermatogenic cell apoptosis selectively induced by low dose X-ray irradiation in mice

International Nuclear Information System (INIS)

Liu Guangwei; Dong Lihua; Liu Yang; Lv Zhe; Liu Shuchun; Gong Shouliang

2003-01-01

Objective: The adaptive response of spermatogenic cell apoptosis induced by whole-body X-ray irradiation at low doses was studied in mice. Methods: Kunming male mice were irradiated with an inductive dose (D1:75 mGy) and/or a challenging dose (D2:1.0, 2.0 or 3.0 Gy). Different kinds of spermatogenic cells were separated using density gradient centrifugation and their apoptotic percentages were analysed using flow cytometry (FCM). Results: When the mice were irradiated with D1 6 h before irradiation with D2, the apoptotic percentages of the spermatogonia and spermatocytes declined rapidly as compared with those in the groups irradiated with D2 only, and those of spermatids and spermatozoa showed no significant changes. When the interval times between D1 and D2 was 3, 6, 12 or 24 h, the apoptotic percentages in spermatogonia and spermatocytes reduced early, significantly and continued for a longer duration after smaller D2(1.0 and 2.0 Gy) irradiation, while the apoptotic percentages did not change after larger D2(3.0 Gy) irradiation. Conclusion: The adaptive response of apoptosis in spermatogonia and spermatocytes could be selectively induced by low dose X-ray irradiation. The adaptive response could be closely related to the D2 dose and interval time between D1 and D2

Metabolic and behavioral responses to high-fat feeding in mice selectively bred for high wheel-running activity

NARCIS (Netherlands)

Vaanholt, L. M.; Jonas, I.; Doornbos, M.; Schubert, K. A.; Nyakas, C.; Garland, T.; Visser, G. H.; van Dijk, G.; Garland Jr., T.

2008-01-01

Objective: Increased dietary fat intake is a precipitating factor for the development of obesity and associated metabolic disturbances. Physically active individuals generally have a reduced risk of developing these unhealthy states, but the underlying mechanisms are poorly understood. In the

Use of vinegar and oreganón Plectranthus amboinicus (Lour. Spreng infusion for “Acriollados” bred broilers (Gallus gallus domesticus

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Carlos Chiriboga Chuchuca

2016-07-01

Full Text Available This research was conducted at the Farm Santa Inés, belonging to the Technical University of Machala, using 160 bred broilers (Gallus gallus domesticus , stayed the same as trying to meet the highest standards of management and health, however to cause challenges no vaccines or antibiotic treatment within the farm. The aim was to determine the efficacy of vinegar and infusion of oreganón Plectranthus amboinicus in acriollados bred broilers. The research lasted 42 days, 16 were randomized groups of 10 chickens each, considering 4 treatments (T1 = vinegar, T2 = vinegar + oreganón infusion, T3 = oreganón infusion, T4 = control with 4 replicates each. Balanced administered free of antibiotics, food consumption data and daily treated water were performed, the weights of the birds weekly; stool samples were collected at the start, middle and end of the assay. In conclusion, the field variables did not obtain statistically significant differences in treatment, but in the Microbiology, the T1, T2 and T3 showed efficiencies decrease when compared to T4, but T3 at the end of the research differed from the T1, T2, and T4. Assuming oreganón Plectranthus amboinicus infusion induces a reduction in the number of CFU in both Total Flora and coliforms.

A murine model of falciparum-malaria by in vivo selection of competent strains in non-myelodepleted mice engrafted with human erythrocytes.

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Iñigo Angulo-Barturen

Full Text Available To counter the global threat caused by Plasmodium falciparum malaria, new drugs and vaccines are urgently needed. However, there are no practical animal models because P. falciparum infects human erythrocytes almost exclusively. Here we describe a reliable falciparum murine model of malaria by generating strains of P. falciparum in vivo that can infect immunodeficient mice engrafted with human erythrocytes. We infected NOD(scid/beta2m-/- mice engrafted with human erythrocytes with P. falciparum obtained from in vitro cultures. After apparent clearance, we obtained isolates of P. falciparum able to grow in peripheral blood of engrafted NOD(scid/beta2m-/- mice. Of the isolates obtained, we expanded in vivo and established the isolate Pf3D7(0087/N9 as a reference strain for model development. Pf3D7(0087/N9 caused productive persistent infections in 100% of engrafted mice infected intravenously. The infection caused a relative anemia due to selective elimination of human erythrocytes by a mechanism dependent on parasite density in peripheral blood. Using this model, we implemented and validated a reproducible assay of antimalarial activity useful for drug discovery. Thus, our results demonstrate that P. falciparum contains clones able to grow reproducibly in mice engrafted with human erythrocytes without the use of myeloablative methods.

Effect of calorie restriction on spontaneous physical activity and body mass in mice divergently selected for basal metabolic rate (BMR).

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Brzęk, Paweł; Gębczyński, Andrzej K; Książek, Aneta; Konarzewski, Marek

2016-07-01

Spontaneous physical activity (SPA) represents an important component of daily energy expenditures in animals and humans. Intra-specific variation in SPA may be related to the susceptibility to metabolic disease or obesity. In particular, reduced SPA under conditions of limited food availability may conserve energy and prevent loss of body and fat mass ('thrifty genotype hypothesis'). However, both SPA and its changes during food restriction show wide inter-individual variations. We studied the effect of 30% caloric restriction (CR) on SPA in laboratory mice divergently selected for high (H-BMR) and low (L-BMR) basal metabolic rate. Selection increased SPA in the H-BMR line but did not change it in the L-BMR mice. This effect reflected changes in SPA intensity but not SPA duration. CR increased SPA intensity more strongly in the L-BMR line than in the H-BMR line and significantly modified the temporal variation of SPA. However, the initial between-line differences in SPA were not affected by CR. Loss of body mass during CR did not differ between both lines. Our results show that the H-BMR mice can maintain their genetically determined high SPA under conditions of reduced food intake without sacrificing their body mass. We hypothesize that this pattern may reflect the higher flexibility in the energy budget in the H-BMR line, as we showed previously that mice from this line reduced their BMR during CR. These energy savings may allow for the maintenance of elevated SPA in spite of reduced food intake. We conclude that the effect of CR on SPA is in large part determined by the initial level of BMR, whose variation may account for the lack of universal pattern of behavioural responses to CR. Copyright © 2016 Elsevier Inc. All rights reserved.

Intrathymic selection of NK1.1+α/β T cell antigen receptor (TCR)+ cells in transgenic mice bearing TCR specific for chicken ovalbumin and restricted to I-Ad

OpenAIRE

Iwabuchi, Chikako; Iwabuchi, Kazuya; Nakagawa, Ken-ichi; Takayanagi, Toshiaki; Nishihori, Hiroki; Tone, Saori; Ogasawara, Kazumasa; Good, Robert A.; Onoé, Kazunori

1998-01-01

Generation and negative selection of NK1.1+α/β T cell receptor (TCR)+ thymocytes were analyzed using TCR-transgenic (B10.D2 × DO10)F1 and (C57BL/6 × DO10)F1 mice and Rag-1−/−/DO10 mice, which had been established by breeding and backcrossing between Rag-1−/− and DO10 mice. Almost all T cells from these mice were shown to bear Vα13/Vβ8.2 that is specific for chicken ovalbumin (cOVA) and restricted to I-Ad. A normal proportion of the NK1.1+ Vα13/Vβ8.2+ thymocytes was generated in these mice. Ho...

High Fat High Sugar Diet Reduces Voluntary Wheel Running in Mice Independent of Sex Hormone Involvement

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Heather L. Vellers

2017-08-01

Full Text Available Introduction: Indirect results in humans suggest that chronic overfeeding decreases physical activity with few suggestions regarding what mechanism(s may link overfeeding and decreased activity. The primary sex hormones are known regulators of activity and there are reports that chronic overfeeding alters sex hormone levels. Thepurpose of this study was to determine if chronic overfeeding altered wheel running through altered sex hormone levels.Materials and Methods: C57BL/6J mice were bred and the pups were weaned at 3-weeks of age and randomly assigned to either a control (CFD or high fat/high sugar (HFHS diet for 9–11 weeks depending on activity analysis. Nutritional intake, body composition, sex hormone levels, and 3-day and 2-week wheel-running activity were measured. Additionally, groups of HFHS animals were supplemented with testosterone (males and 17β-estradiol (females to determine if sex hormone augmentation altered diet-induced changes in activity.Results: 117 mice (56♂, 61♀ were analyzed. The HFHS mice consumed significantly more calories per day than CFD mice (male: p < 0.0001; female: p < 0.0001 and had significantly higher body fat (male: p < 0.0001; female: p < 0.0001. The HFHS diet did not reduce sex hormone levels, but did significantly reduce acute running-wheel distance in male (p = 0.05, 70 ± 28% and female mice (p = 0.02, 57 ± 26%. In animals that received hormone supplementation, there was no significant effect on activity levels. Two-weeks of wheel access was not sufficient to alter HFHS-induced reductions in activity or increases in body fat.Conclusion: Chronic overfeeding reduces wheel running, but is independent of the primary sex hormones.

Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior.

Science.gov (United States)

Schaufler, Jörg; Ronovsky, Marianne; Savalli, Giorgia; Cabatic, Maureen; Sartori, Simone B; Singewald, Nicolas; Pollak, Daniela D

2016-01-01

Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs - also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated. The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB). The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal Cry2 expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while Per2 and Per3 mRNA levels were higher in HAB mice under fluoxetine treatment. The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed.

Antibody responses in pregnancy-induced transmammary transmission of Ancylostoma caninum hookworm larvae.

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Arasu, P; Heller, A

1999-09-20

Third stage larvae of the Ancylostoma caninum hookworm nematode have the capacity to infect a dog, abort the normal maturation pathway to become blood-feeding intestinal worms, and instead distribute throughout the body in a developmentally arrested state that is relatively resilient to most chemotherapeutic agents. During pregnancy, a percentage of the arrested larvae reactivate and transmit via the mammary glands to infect the nursing puppies with resulting iron-deficiency anemia and potential mortality. To determine if the suppression of parasite-specific antibody responses during pregnancy facilitates the reactivation and transmammary transfer of hookworm larvae, a murine model of A. caninum infection was used to compare the infected versus uninfected animals that were either bred or not bred. Initial comparisons of genetically divergent BALB/c versus C57BL/6 mice showed that both the strains mounted strong Th2 biased IgG1 and IgE antibody responses to A. caninum infection. Using the BALB/c strain for the breeding analyses, it was confirmed that larval transfer to the mouse pups only occurred during the post-partum lactational period. In the dams, levels of total and antigen-specific IgG1 and total IgE were highly correlated with parasite burden. During most phases of pregnancy and lactation, infected dams had lower total IgG1, IgG2a and IgE levels as compared to unbred mice at comparable times post-infection; this downward modulation of antibody responses supports the established dogma of a generalized immunosuppression associated with pregnancy. However, at parturition and post-partum lactation, antigen-specific IgG1 levels measured at 1:5000 serum dilutions were comparable between bred and unbred mice, and antigen-specific IgG2a levels at 1:100 serum dilutions were also not significantly different except for a marginal reduction in the bred mice at the lactational timepoint. The comparable anti-A. caninum IgG1 levels between bred and unbred mice, and low

Selective WGA uptake in the hippocampus from the locus coeruleus of DBH-WGA transgenic mice

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Susan G eWalling

2012-05-01

Full Text Available We generated transgenic mice in which a transsynaptic tracer, wheat germ agglutinin (WGA, was specifically expressed in the locus coeruleus neurons under the control of the dopamine-β-hydroxylase gene promoter. WGA protein was produced in more than 95% of the tyrosine hydroxylase-positive locus coeruleus neurons sampled. Transynaptic transfer of WGA was most evident in CA3 neurons of the hippocampus, but appeared absent in CA1 neurons. Faint but significant WGA immunoreactivity was observed surrounding the nuclei of dentate granule cells. Putative hilar mossy cells, identified by the presence of calretinin in the ventral hippocampus, appeared uniformly positive for transynaptically transferred WGA protein. GAD67-positive interneurons in the hilar and CA3 regions tended to be WGA-positive, although a subset of them did not show WGA co-localization. The same mixed WGA uptake profile was apparent when examining co-localization with parvalbumin. The selective uptake of WGA by dentate granule cells, mossy cells and CA3 pyramidal neurons is consistent with evidence for a large proportion of conventional synapses adjacent to locus coeruleus axonal varicosities in these regions. The lack of WGA uptake in the CA1 region and its relatively sparse innervation by dopamine-β-hydroxylase-positive fibers suggest that a majority of the tyrosine hydroxylase-positive classical synapses revealed by electron microscopy in that region may be producing dopamine. The overall pattern of WGA uptake in these transgenic mice suggests a selective role for the granule cell-mossy cell-CA3 network in processing novelty or the salient environmental contingency changes signaled by locus coeruleus activity.

Phenotypic flexibility of traits related to energy acquisition in mice divergently selected for basal metabolic rate (BMR).

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Ksiazek, Aneta; Czerniecki, Jan; Konarzewski, Marek

2009-03-01

Theoretical considerations suggest that one of the main factors determining phenotypic flexibility of the digestive system is the size (mass) of internal organs. To test this, we used mice from two lines selected for high and low levels of basal metabolic rate (BMR). Mice with higher BMRs also have larger internal organs and higher daily food consumption (C) under non-stressful conditions. We exposed animals from both lines to a sudden cold exposure by transferring them (without prior acclimation) from an ambient temperature of 23 degrees C to 5 degrees C. Cold exposure elicited a twofold increase in C and a 25% reduction of apparent digestive efficiency. For the same body mass-corrected C, small intestine, kidneys, heart and liver of cold-exposed low-BMR mice were smaller than those of the high-BMR line. Therefore, the internal organs of low-BMR animals were burdened with substantially higher metabolic loads (defined as C or digestible food intake per total mass of a particular organ). The mass-specific activity of citrate synthase (CS) in the liver and kidneys (but not heart) was also lower in the low-BMR mice. The magnitude of phenotypic flexibility of internal organ size and CS activity was strictly proportional to the organ mass (in the case of kidneys and liver, also mass-specific CS activity) prior to an increased energy demand. Thus, phenotypic flexibility had additive rather than multiplicative dynamics. Our results also suggest that variation in BMR positively correlates with the magnitude of an immediate spare capacity that fuels the initial response of internal organs to a sudden metabolic stress.

Graft-versus-leukemia, donor selection for adoptive immunotherapy in mice

International Nuclear Information System (INIS)

LeFeber, W.P.; Truitt, R.L.; Rose, W.C.; Bortin, M.M.

1977-01-01

The optimal donor for adoptive immunotherapy would exhibit great antitumor reactivity and no antihost reactivity. Immunocompetent cells from 11 strains of mice were tested in vivo for their reactivity against a long-passage AKR acute lymphoblastic leukemia and against immunosuppressed nonleukemic AKR mice. Donor mice were syngeneic, unprimed H-2 compatible, primed H-2 compatible, congenic, or H-2 incompatible with AKR. Bioassays were used to evaluate the relative graft-vs.-leukemia (GvL) reactivity and the relative graft-vs.-host (GvH) reactivity of transplanted bone marrow and lymph-node cells from the panel of donors. No significant GvL reactivity was found when cells from syngeneic, unprimed H-2 compatible, or congenic donors were tested. H-2 compatible donors that were immunized with γ-irradiated AKR leukemic spleen cells showed modest GvL reactivity, but associated with the immunization was a disproportionate increase in acute and delayed GvH mortality. Among the H-2 mismatched donors, mice of the SJL strain appeared to most closely approach the ideal because of least intense GvH reactivity and maximal GvL reactivity. As measured in these experiments there was no correlation between the severity of GvH disease and the efficacy of the GvL reaction; GvL reactivity in unprimed donors was always associated with H-2 incompatibility; disparity between donor and recipient at H-2 did not guarantee an effective GvL reaction; and the increase in GvL reactivity obtained by immunizing H-2 compatible donors was overshadowed by the increase in GvH disease

Resveratrol Attenuates Exercise-Induced Adaptive Responses in Rats Selectively Bred for Low Running Performance

OpenAIRE

Hart, Nikolett; Sarga, Linda; Csende, Zsolt; Koch, Lauren G.; Britton, Steven L.; Davies, Kelvin J.A.; Radak, Zsolt

2013-01-01

Low capacity runner (LCR) rats have been developed by divergent artificial selection for treadmill endurance capacity to explore an aerobic biology-disease connection. The beneficial effects of resveratrol supplementation have been demonstrated in endurance running. In this study it was examined whether 12 weeks of treadmill exercise training and/or resveratrol can retrieve the low running performance of the LCR and impact mitochondrial biogenesis and quality control. Resveratrol regressed ru...

Nutritional Potential of Selected Insect Species Reared on the Island of Sumatra.

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Adámková, Anna; Mlček, Jiří; Kouřimská, Lenka; Borkovcová, Marie; Bušina, Tomáš; Adámek, Martin; Bednářová, Martina; Krajsa, Jan

2017-05-12

Inhabitants of the Indonesian island of Sumatra are faced with the problem of insufficient food supplies and the consequent risk of undernourishment and health issues. Edible insects as a traditional and readily available food source could be part of the solution. The nutritional value of insects depends on many factors, e.g., species, developmental stage, sex, diet, and climatic conditions. However, edible insects bred in Sumatra for human consumption have never before been assessed with regard to their nutritional value. Our study involved analyses of crude protein, chitin, fat and selected fatty acid contents of giant mealworm larvae ( Zophobas morio ), larvae of the common mealworm ( Tenebrio molitor) and nymphs of the field cricket ( Gryllus assimilis ). Crude protein content in the samples ranged from 46% to 56%. Highest (35%) and lowest (31%) amounts of fat were recorded in giant mealworm larvae and larvae of the common mealworm, respectively. Chitin amounts ranged from 6% to 13%. Based on these values, which are comparable to those known from other food insects reared in different regions of the world, the edible species bred in Sumatra could become food sources with a potential to help stave off hunger and undernourishment.

Enhanced glucose tolerance in pancreatic-derived factor (PANDER knockout C57BL/6 mice

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Shari L. Moak

2014-11-01

Full Text Available Pancreatic-derived factor (PANDER; also known as FAM3B is a uniquely structured protein strongly expressed within and secreted from the endocrine pancreas. PANDER has been hypothesized to regulate fasting and fed glucose homeostasis, hepatic lipogenesis and insulin signaling, and to serve a potential role in the onset or progression of type 2 diabetes (T2D. Despite having potentially pivotal pleiotropic roles in glycemic regulation and T2D, there has been limited generation of stable animal models for the investigation of PANDER function, and there are no models on well-established genetic murine backgrounds for T2D. Our aim was to generate an enhanced murine model to further elucidate the biological function of PANDER. Therefore, a pure-bred PANDER knockout C57BL/6 (PANKO-C57 model was created and phenotypically characterized with respect to glycemic regulation and hepatic insulin signaling. The PANKO-C57 model exhibited an enhanced metabolic phenotype, particularly with regard to enhanced glucose tolerance. Male PANKO-C57 mice displayed decreased fasting plasma insulin and C-peptide levels, whereas leptin levels were increased as compared with matched C57BL/6J wild-type mice. Despite similar peripheral insulin sensitivity between both groups, hepatic insulin signaling was significantly increased during fasting conditions, as demonstrated by increased phosphorylation of hepatic PKB/Akt and AMPK, along with mature SREBP-1 expression. Insulin stimulation of PANKO-C57 mice resulted in increased hepatic triglyceride and glycogen content as compared with wild-type C57BL/6 mice. In summary, the PANKO-C57 mouse represents a suitable model for the investigation of PANDER in multiple metabolic states and provides an additional tool to elucidate the biological function and potential role in T2D.

Cancer resistance of SR/CR mice in the genetic knockout backgrounds of leukocyte effector mechanisms: determinations for functional requirements.

Science.gov (United States)

Sanders, Anne M; Stehle, John R; Blanks, Michael J; Riedlinger, Gregory; Kim-Shapiro, Jung W; Monjazeb, Arta M; Adams, Jonathan M; Willingham, Mark C; Cui, Zheng

2010-03-31

Spontaneous Regression/Complete Resistant (SR/CR) mice are a colony of cancer-resistant mice that can detect and rapidly destroy malignant cells with innate cellular immunity, predominately mediated by granulocytes. Our previous studies suggest that several effector mechanisms, such as perforin, granzymes, or complements, may be involved in the killing of cancer cells. However, none of these effector mechanisms is known as critical for granulocytes. Additionally, it is unclear which effector mechanisms are required for the cancer killing activity of specific leukocyte populations and the survival of SR/CR mice against the challenges of lethal cancer cells. We hypothesized that if any of these effector mechanisms was required for the resistance to cancer cells, its functional knockout in SR/CR mice should render them sensitive to cancer challenges. This was tested by cross breeding SR/CR mice into the individual genetic knockout backgrounds of perforin (Prf-/-), superoxide (Cybb-/), or inducible nitric oxide (Nos2-/). SR/CR mice were bred into individual Prf-/-, Cybb-/-, or Nos2-/- genetic backgrounds and then challenged with sarcoma 180 (S180). Their overall survival was compared to controls. The cancer killing efficiency of purified populations of macrophages and neutrophils from these immunodeficient mice was also examined. When these genetically engineered mice were challenged with cancer cells, the knockout backgrounds of Prf-/-, Cybb-/-, or Nos2-/- did not completely abolish the SR/CR cancer resistant phenotype. However, the Nos2-/- background did appear to weaken the resistance. Incidentally, it was also observed that the male mice in these immunocompromised backgrounds tended to be less cancer-resistant than SR/CR controls. Despite the previously known roles of perforin, superoxide or nitric oxide in the effector mechanisms of innate immune responses, these effector mechanisms were not required for cancer-resistance in SR/CR mice. The resistance was

The selective A-type K+ current blocker Tx3-1 isolated from the Phoneutria nigriventer venom enhances memory of naïve and Aβ(25-35)-treated mice.

Science.gov (United States)

Gomes, Guilherme M; Dalmolin, Gerusa D; Cordeiro, Marta do Nascimento; Gomez, Marcus V; Ferreira, Juliano; Rubin, Maribel A

2013-12-15

Potassium channels regulate many neuronal functions, including neuronal excitability and synaptic plasticity, contributing, by these means, to mnemonic processes. In particular, A-type K(+) currents (IA) play a key role in hippocampal synaptic plasticity. Therefore, we evaluated the effect of the peptidic toxin Tx3-1, a selective blocker of IA currents, extracted from the venom of the spider Phoneutria nigriventer, on memory of mice. Administration of Tx3-1 (i.c.v., 300 pmol/site) enhanced both short- and long-term memory consolidation of mice tested in the novel object recognition task. In comparison, 4-aminopyridine (4-AP; i.c.v., 30-300 pmol/site), a non-selective K(+) channel blocker did not alter long-term memory and caused toxic side effects such as circling, freezing and tonic-clonic seizures. Moreover, Tx3-1 (i.c.v., 10-100 pmol/site) restored memory of Aβ25-35-injected mice, and exhibited a higher potency to improve memory of Aβ25-35-injected mice when compared to control group. These results show the effect of the selective blocker of IA currents Tx3-1 in both short- and long-term memory retention and in memory impairment caused by Aβ25-35, reinforcing the role of IA in physiological and pathological memory processes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Selection of Breeding Stock among Australian Purebred Dog Breeders, with Particular Emphasis on the Dam

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Veronika Czerwinski

2016-11-01

Full Text Available Every year, thousands of purebred domestic dogs are bred by registered dog breeders. Yet, little is known about the rearing environment of these dogs, or the attitudes and priorities surrounding breeding practices of these dog breeders. The objective of this study was to explore some of the factors that dog breeders consider important for stock selection, with a particular emphasis on issues relating to the dam. Two-hundred and seventy-four Australian purebred dog breeders, covering 91 breeds across all Australian National Kennel Club breed groups, completed an online survey relating to breeding practices. Most breeders surveyed (76% reported specialising in one breed of dog, the median number of dogs and bitches per breeder was two and three respectively, and most breeders bred two litters or less a year. We identified four components, relating to the dam, that were considered important to breeders. These were defined as Maternal Care, Offspring Potential, Dam Temperament, and Dam Genetics and Health. Overall, differences were observed in attitudes and beliefs across these components, showing that there is variation according to breed/breed groups. In particular, the importance of Maternal Care varied according to dog breed group. Breeders of brachycephalic breeds tended to differ the most in relation to Offspring Potential and Dam Genetics and Health. The number of breeding dogs/bitches influenced breeding priority, especially in relation to Dam Temperament, however no effect was found relating to the number of puppies bred each year. Only 24% of breeders used their own sire for breeding. The finding that some breeders did not test for diseases relevant to their breed, such as hip dysplasia in Labrador Retrievers and German Shepherds, provides important information on the need to educate some breeders, and also buyers of purebred puppies, that screening for significant diseases should occur. Further research into the selection of breeding dams

Physiological and production response of dairy goats bred in a tropical climate

Science.gov (United States)

de Souza, Priscila Teixeira; Salles, Maria Gorete Flores; da Costa, Antônio Nélson Lima; Carneiro, Hilton Alexandre Vidal; de Souza, Leonardo Peres; Rondina, Davide; de Araújo, Airton Alencar

2014-09-01

The aim of this work was to determine the adaptability of Saanen and ½Saanen × ½Anglo-Nubian (½S½AN) goats bred in tropical climates. The study included 30 goats, 15 Saanen and 15 ½S½AN. The data was collected during the rainy and dry seasons. During the whole experimental period, the environment variables were recorded, as well as rectal temperature (RT), superficial temperature (ST), respiratory rate (RR) and heart rate (HR) and milk production (MP). The adaptability coefficient (AC) was calculated for both genotypes. The averages were evaluated by ANOVA at 5 % probability. There was a genotype and period of year effect, as well as the interaction genotype × period of year. Pearson's simple correlation analysis was then carried out between milk production and physiological and environment variables. There was a statistical difference ( p goats, regardless of the season. MP was greater in the dry season ( p goats. Under the conditions of the present study, it is concluded that the goats were influenced by climatic factors, where the rainy period was more likely to cause thermal stress in the animals.

Selection of VSH-derived “Pol-line” honey bees and evaluation of their Varroa-resistance characteristics

OpenAIRE

Danka , Robert G.; Harris , Jeffery W.; Dodds , Garrett E.

2016-01-01

International audience; AbstractHoney bees with Varroa sensitive hygiene (VSH) have good resistance to Varroa destructor. We bred “Pol-line” bees by outcrossing VSH queens to US commercial stocks from 2008 to 2014 and then selecting colonies with low mite infestations. Beginning in 2011, field performance of colonies with outcrossed Pol-line queens was compared to colonies with outcrossed VSH queens. Mite infestations after one season were comparable in colonies of the two bee types. Queens f...

Performance of Genomic Selection in Mice

OpenAIRE

Legarra, Andrés; Robert-Granié, Christèle; Manfredi, Eduardo; Elsen, Jean-Michel

2008-01-01

Selection plans in plant and animal breeding are driven by genetic evaluation. Recent developments suggest using massive genetic marker information, known as “genomic selection.” There is little evidence of its performance, though. We empirically compared three strategies for selection: (1) use of pedigree and phenotypic information, (2) use of genomewide markers and phenotypic information, and (3) the combination of both. We analyzed four traits from a heterogeneous mouse population (http://...

Monitoring reproductive performance of cross-bred dairy cattle on smallholder farms in Malaysia

International Nuclear Information System (INIS)

Wahab, S.; Jainudeen, M.R.; Azizuddin, K.

1990-01-01

The paper reports on the reproductive performance of smallholder dairy cross-bred cattle in Malaysia, as monitored by milk progesterone radioimmunoassay and rectal palpation. Infertility was identified as the major problem faced by the smallholder farmers. The results show that there is a strong and significant association between suckling and delayed post-partum ovarian activity. The longer calving intervals in smallholder dairy herds compared with those in institutional herds are due to inactive ovaries rather than failure to detect oestrus. The use of a progesterone releasing intravaginal device (PRID) for treatment of anoestrus resulted in 93% of cows cycling, with a conception rate of 46% to insemination at the induced oestrus. Cows that suckled their calves had significantly longer calving intervals. The mean body score for cattle on smallholder herds was 3.8 -+ 1.1, and fertile cows had significantly higher scores than infertile cows. There was strong evidence to suggest that increased body scores corresponded to shorter intervals between calving and resumption of sexual activity, calving and conception, and successive calvings. (author). 12 refs, 4 tabs

Generation of a new bioluminescent model for visualisation of mammary tumour development in transgenic mice

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Zagozdzon Agnieszka M

2012-05-01

Full Text Available Abstract Background Numerous transgenic models have been generated to study breast cancer. However, despite many advantages, traditional transgenic models for breast cancer are also burdened with difficulties in early detection and longitudinal observation of transgene-induced tumours, which in most cases are randomly located and occur at various time points. Methods such as palpation followed by mechanical measurement of the tumours are of limited value in transgenic models. There is a crucial need for making these previously generated models suitable for modern methods of tumour visualisation and monitoring, e.g. by bioluminescence-based techniques. This approach was successfully used in the current study. Results A new mouse strain (MMTV-Luc2 mice expressing Luc2 luciferase primarily in mammary tissue in females, with low-level background expression in internal organs, was generated and bred to homozygosity. After these mice were intercrossed with MMTV-PyVT mice, all double transgenic females developed mammary tumours by the age of 10 weeks, the localisation and progression of which could be effectively monitored using the luminescence-based in vivo imaging. Luminescence-based readout allowed for early visualisation of the locally overgrown mammary tissue and for longitudinal evaluation of local progression of the tumours. When sampled ex vivo at the age of 10 weeks, all tumours derived from MMTV-Luc2PyVT females displayed robust bioluminescent signal. Conclusions We have created a novel transgenic strain for visualisation and longitudinal monitoring of mammary tumour development in transgenic mice as an addition and/or a new and more advanced alternative to manual methods. Generation of this mouse strain is vital for making many of the existing mammary tumour transgenic models applicable for in vivo imaging techniques.

Generation of a new bioluminescent model for visualisation of mammary tumour development in transgenic mice

LENUS (Irish Health Repository)

Zagozdzon, Agnieszka M

2012-05-30

AbstractBackgroundNumerous transgenic models have been generated to study breast cancer. However, despite many advantages, traditional transgenic models for breast cancer are also burdened with difficulties in early detection and longitudinal observation of transgene-induced tumours, which in most cases are randomly located and occur at various time points. Methods such as palpation followed by mechanical measurement of the tumours are of limited value in transgenic models. There is a crucial need for making these previously generated models suitable for modern methods of tumour visualisation and monitoring, e.g. by bioluminescence-based techniques. This approach was successfully used in the current study.ResultsA new mouse strain (MMTV-Luc2 mice) expressing Luc2 luciferase primarily in mammary tissue in females, with low-level background expression in internal organs, was generated and bred to homozygosity. After these mice were intercrossed with MMTV-PyVT mice, all double transgenic females developed mammary tumours by the age of 10 weeks, the localisation and progression of which could be effectively monitored using the luminescence-based in vivo imaging. Luminescence-based readout allowed for early visualisation of the locally overgrown mammary tissue and for longitudinal evaluation of local progression of the tumours. When sampled ex vivo at the age of 10 weeks, all tumours derived from MMTV-Luc2PyVT females displayed robust bioluminescent signal.ConclusionsWe have created a novel transgenic strain for visualisation and longitudinal monitoring of mammary tumour development in transgenic mice as an addition and\\/or a new and more advanced alternative to manual methods. Generation of this mouse strain is vital for making many of the existing mammary tumour transgenic models applicable for in vivo imaging techniques.

Linear and Poisson models for genetic evaluation of tick resistance in cross-bred Hereford x Nellore cattle.

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Ayres, D R; Pereira, R J; Boligon, A A; Silva, F F; Schenkel, F S; Roso, V M; Albuquerque, L G

2013-12-01

Cattle resistance to ticks is measured by the number of ticks infesting the animal. The model used for the genetic analysis of cattle resistance to ticks frequently requires logarithmic transformation of the observations. The objective of this study was to evaluate the predictive ability and goodness of fit of different models for the analysis of this trait in cross-bred Hereford x Nellore cattle. Three models were tested: a linear model using logarithmic transformation of the observations (MLOG); a linear model without transformation of the observations (MLIN); and a generalized linear Poisson model with residual term (MPOI). All models included the classificatory effects of contemporary group and genetic group and the covariates age of animal at the time of recording and individual heterozygosis, as well as additive genetic effects as random effects. Heritability estimates were 0.08 ± 0.02, 0.10 ± 0.02 and 0.14 ± 0.04 for MLIN, MLOG and MPOI models, respectively. The model fit quality, verified by deviance information criterion (DIC) and residual mean square, indicated fit superiority of MPOI model. The predictive ability of the models was compared by validation test in independent sample. The MPOI model was slightly superior in terms of goodness of fit and predictive ability, whereas the correlations between observed and predicted tick counts were practically the same for all models. A higher rank correlation between breeding values was observed between models MLOG and MPOI. Poisson model can be used for the selection of tick-resistant animals. © 2013 Blackwell Verlag GmbH.

Social rank-associated stress vulnerability predisposes individuals to cocaine attraction.

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Yanovich, Chen; Kirby, Michael L; Michaelevski, Izhak; Yadid, Gal; Pinhasov, Albert

2018-01-29

Studies of personality have suggested that dissimilarities in ability to cope with stressful situations results in differing tendency to develop addictive behaviors. The present study used selectively bred stress-resilient, socially-dominant (Dom) and stress-vulnerable, socially-submissive (Sub) mice to investigate the interaction between environmental stress and inbred predisposition to develop addictive behavior to cocaine. In a Conditioned Place Preference (CPP) paradigm using cocaine, Sub mice displayed an aversion to drug, whereas Dom mice displayed drug attraction. Following a 4-week regimen of Chronic Mild Stress (CMS), Sub mice in CPP displayed a marked increase (>400%) in cocaine attraction, whereas Dom mice did not differ in attraction from their non-stressed state. Examination of hippocampal gene expression revealed in Sub mice, exposure to external stimuli, stress or cocaine, increased CRH expression (>100%), which was evoked in Dom mice only by cocaine exposure. Further, stress-induced decreases in DRD1 (>60%) and DRD2 (>50%) expression in Sub mice differed markedly from a complete lack of change in Dom mice. From our findings, we propose that social stratification dictates vulnerability to stress-induced attraction that may lead to addiction via differential regulation of hippocampal response to dopaminergic input, which in turn may influence differing tendency to develop addictive behaviors.

Female genotype influences the behavioral performance of mice selected for reproductive traits.

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Weisker, S M; Barkley, M

1991-10-01

The behavioral performance of mice that differ in regularity of the estrous cycle and litter size was studied after female exposure to a male of the same or a different strain. Emotional reactivity was measured using the pole, straightaway and open field tests. Factor interpretations of emotionality included motor discharge, autonomic imbalance and acrophobia. Mice characterized by regular estrous cycles and large litters (line E) were more explorative and emotionally reactive with respect to motor discharge and autonomic imbalance. In contrast, mice with less regular estrous cycles and small litter size (line CN-) were more acrophobic. These strain differences in behavioral performance were influenced by the genotype of the female rather than the cohabitating male.

Voluntary Running Aids to Maintain High Body Temperature in Rats Bred for High Aerobic Capacity

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Karvinen, Sira M.; Silvennoinen, Mika; Ma, Hongqiang; Törmäkangas, Timo; Rantalainen, Timo; Rinnankoski-Tuikka, Rita; Lensu, Sanna; Koch, Lauren G.; Britton, Steven L.; Kainulainen, Heikki

2016-01-01

The production of heat, i.e., thermogenesis, is a significant component of the metabolic rate, which in turn affects weight gain and health. Thermogenesis is linked to physical activity (PA) level. However, it is not known whether intrinsic exercise capacity, aging, and long-term voluntary running affect core body temperature. Here we use rat models selectively bred to differ in maximal treadmill endurance running capacity (Low capacity runners, LCR and High capacity Runners, HCR), that as adults are divergent for aerobic exercise capacity, aging, and metabolic disease risk to study the connection between PA and body temperature. Ten high capacity runner (HCR) and ten low capacity runner (LCR) female rats were studied between 9 and 21 months of age. Rectal body temperature of HCR and LCR rats was measured before and after 1-year voluntary running/control intervention to explore the effects of aging and PA. Also, we determined whether injected glucose and spontaneous activity affect the body temperature differently between LCR and HCR rats at 9 vs. 21 months of age. HCRs had on average 1.3°C higher body temperature than LCRs (p temperature level of HCRs to similar levels with LCRs. The opportunity to run voluntarily had a significant impact on the body temperature of HCRs (p temperature at a similar level as when at younger age. Compared to LCRs, HCRs were spontaneously more active, had higher relative gastrocnemius muscle mass and higher UCP2, PGC-1α, cyt c, and OXPHOS levels in the skeletal muscle (p temperature of LCRs. However, glucose injection resulted in a lowering of the body temperature of LCRs (p temperature compared to rats born with low exercise capacity and disease risk. Voluntary running allowed HCRs to maintain high body temperature during aging, which suggests that high PA level was crucial in maintaining the high body temperature of HCRs. PMID:27504097

Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice.

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Lan, Zi-Jian; Krause, M S; Redding, S D; Li, X; Wu, G Z; Zhou, H X; Bohler, H C; Ko, C; Cooney, A J; Zhou, Junmei; Lei, Z M

2017-03-15

Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicle accumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Pten deficient theca cells were potentiated. The phosphorylation of Foxo1 was increased, while the binding of Foxo1 to forkhead response elements in the Lhcgr promoter was reduced in tPtenMT theca cells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in theca cells might be mediated by reducing the inhibitory effect of Foxo1 on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in theca cells may be involved in certain types of PCOS pathogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

Discrimination of tomatoes bred by spaceflight mutagenesis using visible/near infrared spectroscopy and chemometrics

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Shao, Yongni; Xie, Chuanqi; Jiang, Linjun; Shi, Jiahui; Zhu, Jiajin; He, Yong

2015-04-01

Visible/near infrared spectroscopy (Vis/NIR) based on sensitive wavelengths (SWs) and chemometrics was proposed to discriminate different tomatoes bred by spaceflight mutagenesis from their leafs or fruits (green or mature). The tomato breeds were mutant M1, M2 and their parent. Partial least squares (PLS) analysis and least squares-support vector machine (LS-SVM) were implemented for calibration models. PLS analysis was implemented for calibration models with different wavebands including the visible region (400-700 nm) and the near infrared region (700-1000 nm). The best PLS models were achieved in the visible region for the leaf and green fruit samples and in the near infrared region for the mature fruit samples. Furthermore, different latent variables (4-8 LVs for leafs, 5-9 LVs for green fruits, and 4-9 LVs for mature fruits) were used as inputs of LS-SVM to develop the LV-LS-SVM models with the grid search technique and radial basis function (RBF) kernel. The optimal LV-LS-SVM models were achieved with six LVs for the leaf samples, seven LVs for green fruits, and six LVs for mature fruits, respectively, and they outperformed the PLS models. Moreover, independent component analysis (ICA) was executed to select several SWs based on loading weights. The optimal LS-SVM model was achieved with SWs of 550-560 nm, 562-574 nm, 670-680 nm and 705-715 nm for the leaf samples; 548-556 nm, 559-564 nm, 678-685 nm and 962-974 nm for the green fruit samples; and 712-718 nm, 720-729 nm, 968-978 nm and 820-830 nm for the mature fruit samples. All of them had better performance than PLS and LV-LS-SVM, with the parameters of correlation coefficient (rp), root mean square error of prediction (RMSEP) and bias of 0.9792, 0.2632 and 0.0901 based on leaf discrimination, 0.9837, 0.2783 and 0.1758 based on green fruit discrimination, 0.9804, 0.2215 and -0.0035 based on mature fruit discrimination, respectively. The overall results indicated that ICA was an effective way for the

Rhythmicity in mice selected for extremes in stress reactivity: behavioural, endocrine and sleep changes resembling endophenotypes of major depression.

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Chadi Touma

Full Text Available Dysregulation of the hypothalamic-pituitary-adrenal (HPA axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD. Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called 'stress reactivity' (SR mouse model consists of three separate breeding lines selected for either high (HR, intermediate (IR, or low (LR corticosterone increase in response to stressors.In order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period, resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice.Thus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new

Metabolic risk factors in mice divergently selected for BMR fed high fat and high carb diets.

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Sadowska, Julita; Gębczyński, Andrzej K; Konarzewski, Marek

2017-01-01

Factors affecting contribution of spontaneous physical activity (SPA; activity associated with everyday tasks) to energy balance of humans are not well understood, as it is not clear whether low activity is related to dietary habits, precedes obesity or is a result of thereof. In particular, human studies on SPA and basal metabolic rates (BMR, accounting for >50% of human energy budget) and their associations with diet composition, metabolic thrift and obesity are equivocal. To clarify these ambiguities we used a unique animal model-mice selected for divergent BMR rates (the H-BMR and L-BMR line type) presenting a 50% between-line type difference in the primary selected trait. Males of each line type were divided into three groups and fed either a high fat, high carb or a control diet. They then spent 4 months in individual cages under conditions emulating human "sedentary lifestyle", with SPA followed every month and measurements of metabolic risk indicators (body fat mass %, blood lipid profile, fasting blood glucose levels and oxidative damage in the livers, kidneys and hearts) taken at the end of study. Mice with genetically determined high BMR assimilated more energy and had higher SPA irrespective of type of diet. H-BMR individuals were characterized by lower dry body fat mass %, better lipid profile and lower fasting blood glucose levels, but higher oxidative damage in the livers and hearts. Genetically determined high BMR may be a protective factor against diet-induced obesity and most of the metabolic syndrome indicators. Elevated spontaneous activity is correlated with high BMR, and constitutes an important factor affecting individual capability to sustain energy balance even under energy dense diets.

Transgenic Parasites Stably Expressing Full-Length Plasmodium falciparum Circumsporozoite Protein as a Model for Vaccine Down-Selection in Mice Using Sterile Protection as an Endpoint

Science.gov (United States)

Porter, Michael D.; Nicki, Jennifer; Pool, Christopher D.; DeBot, Margot; Illam, Ratish M.; Brando, Clara; Bozick, Brooke; De La Vega, Patricia; Angra, Divya; Spaccapelo, Roberta; Crisanti, Andrea; Murphy, Jittawadee R.; Bennett, Jason W.; Schwenk, Robert J.; Ockenhouse, Christian F.

2013-01-01

Circumsporozoite protein (CSP) of Plasmodium falciparum is a protective human malaria vaccine candidate. There is an urgent need for models that can rapidly down-select novel CSP-based vaccine candidates. In the present study, the mouse-mosquito transmission cycle of a transgenic Plasmodium berghei malaria parasite stably expressing a functional full-length P. falciparum CSP was optimized to consistently produce infective sporozoites for protection studies. A minimal sporozoite challenge dose was established, and protection was defined as the absence of blood-stage parasites 14 days after intravenous challenge. The specificity of protection was confirmed by vaccinating mice with multiple CSP constructs of differing lengths and compositions. Constructs that induced high NANP repeat-specific antibody titers in enzyme-linked immunosorbent assays were protective, and the degree of protection was dependent on the antigen dose. There was a positive correlation between antibody avidity and protection. The antibodies in the protected mice recognized the native CSP on the parasites and showed sporozoite invasion inhibitory activity. Passive transfer of anti-CSP antibodies into naive mice also induced protection. Thus, we have demonstrated the utility of a mouse efficacy model to down-select human CSP-based vaccine formulations. PMID:23536694

An animal model of differential genetic risk for methamphetamine intake

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Tamara ePhillips

2015-09-01

Full Text Available The question of whether genetic factors contribute to risk for methamphetamine (MA use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA-induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1 agonist, and a non-functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the

SEROLOGICAL EVIDENCE OF EXPOSURE TO Anaplasma phagocytophilum IN HORSES FROM THE RIO DE JANEIRO STATE MOUNTED POLICE BRED IN THE URBAN ZONE

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Marcia Farias Rolim

2015-07-01

Full Text Available Anaplasma phagocytophilum is an emergent hemoparasite in regions where ticks are regularly found. In order to investigate the rate of anti-A. phagocytophilum antibody in horses of the Mounted Police of Rio de Janeiro state and therefore the presence of this agent, 41 horses from the Cavalry Squadron (CS and 50 from the Regiment of Mounted Police (RMP were selected. For the serologic diagnosis the Indirect Fluorescent Antibody test was performed. In the present work, among 91 equine sera samples anti-A. phagocytophilum antibodies, with titer ≥ 1:80, were detected in 11 animals (12%, being five (5% from males and six (7% females, with no statistical difference. The adult animals with ages varying between five and 14 years presented the highest rate of positive reaction, although antibodies were detected in animals of all ages. We did not observe statistic differences in relation to the presence of anti-A. phagocytophilum antibodies among the animals bred in the CS and RMP. The presence of anti-A.phagocytophilim antibodies in horses of the Mounted Police with no clinical signs is indicative that the parasite is present in the enzootic form among the horses of the urban area. The circulation of the parasite among the animals is not dependent of the presence of tick infestations.

Improvement of neuromuscular synaptic phenotypes without enhanced survival and motor function in severe spinal muscular atrophy mice selectively rescued in motor neurons.

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Ximena Paez-Colasante

Full Text Available In the inherited childhood neuromuscular disease spinal muscular atrophy (SMA, lower motor neuron death and severe muscle weakness result from the reduction of the ubiquitously expressed protein survival of motor neuron (SMN. Although SMA mice recapitulate many features of the human disease, it has remained unclear if their short lifespan and motor weakness are primarily due to cell-autonomous defects in motor neurons. Using Hb9(Cre as a driver, we selectively raised SMN expression in motor neurons in conditional SMAΔ7 mice. Unlike a previous study that used choline acetyltransferase (ChAT(Cre+ as a driver on the same mice, and another report that used Hb9(Cre as a driver on a different line of conditional SMA mice, we found no improvement in survival, weight, motor behavior and presynaptic neurofilament accumulation. However, like in ChAT(Cre+ mice, we detected rescue of endplate size and mitigation of neuromuscular junction (NMJ denervation status. The rescue of endplate size occurred in the absence of an increase in myofiber size, suggesting endplate size is determined by the motor neuron in these animals. Real time-PCR showed that the expression of spinal cord SMN transcript was sharply reduced in Hb9(Cre+ SMA mice relative to ChAT(Cre+ SMA mice. This suggests that our lack of overall phenotypic improvement is most likely due to an unexpectedly poor recombination efficiency driven by Hb9(Cre . Nonetheless, the low levels of SMN were sufficient to rescue two NMJ structural parameters indicating that these motor neuron cell autonomous phenotypes are very sensitive to changes in motoneuronal SMN levels. Our results directly suggest that even those therapeutic interventions with very modest effects in raising SMN in motor neurons may provide mitigation of neuromuscular phenotypes in SMA patients.

Mice null for the deubiquitinase USP18 spontaneously develop leiomyosarcomas

International Nuclear Information System (INIS)

Chinyengetere, Fadzai; Sekula, David J.; Lu, Yun; Giustini, Andrew J.; Sanglikar, Aarti; Kawakami, Masanori; Ma, Tian; Burkett, Sandra S.; Eisenberg, Burton L.; Wells, Wendy A.; Hoopes, Paul J.; Demicco, Elizabeth G.; Lazar, Alexander J; Torres, Keila E.; Memoli, Vincent; Freemantle, Sarah J.; Dmitrovsky, Ethan

2015-01-01

USP18 (ubiquitin-specific protease 18) removes ubiquitin-like modifier interferon stimulated gene 15 (ISG15) from conjugated proteins. USP18 null mice in a FVB/N background develop tumors as early as 2 months of age. These tumors are leiomyosarcomas and thus represent a new murine model for this disease. Heterozygous USP18 +/− FVB/N mice were bred to generate wild-type, heterozygous and homozygous cohorts. Tumors were characterized immunohistochemically and two cell lines were derived from independent tumors. Cell lines were karyotyped and their responses to restoration of USP18 activity assessed. Drug testing and tumorigenic assays were also performed. USP18 immunohistochemical staining in a large series of human leiomyosacomas was examined. USP18 −/− FVB/N mice spontaneously develop tumors predominantly on the back of the neck with most tumors evident between 6–12 months (80 % penetrance). Immunohistochemical characterization of the tumors confirmed they were leiomyosarcomas, which originate from smooth muscle. Restoration of USP18 activity in sarcoma-derived cell lines did not reduce anchorage dependent or independent growth or xenograft tumor formation demonstrating that these cells no longer require USP18 suppression for tumorigenesis. Karyotyping revealed that both tumor-derived cell lines were aneuploid with extra copies of chromosomes 3 and 15. Chromosome 15 contains the Myc locus and MYC is also amplified in human leiomyosarcomas. MYC protein levels were elevated in both murine leiomyosarcoma cell lines. Stabilized P53 protein was detected in a subset of these murine tumors, another feature of human leiomyosarcomas. Immunohistochemical analyses of USP18 in human leiomyosarcomas revealed a range of staining intensities with the highest USP18 expression in normal vascular smooth muscle. USP18 tissue array analysis of primary leiomyosarcomas from 89 patients with a clinical database revealed cases with reduced USP18 levels had a significantly

Cytokeratin 19 promoter directs the expression of Cre recombinase in various epithelia of transgenic mice.

Science.gov (United States)

Zhao, Gui-Feng; Zhao, Shuang; Liu, Jia-Jie; Wu, Ji-Cheng; He, Hao-Yu; Ding, Xiao-Qing; Yu, Xue-Wen; Huang, Ke-Qiang; Li, Zhi-Jie; Zheng, Hua-Chuan

2017-03-14

Cytokeratin 19 (K19) is expressed in various differentiated cells, including gastric, intestinal and bronchial epithelial cells, and liver duct cells. Here, we generated a transgenic mouse line, K19-Cre, in which the expression of Cre recombinase was controlled by the promoter of K19. To test the tissue distribution and excision activity of Cre recombinase, K19-Cre transgenic mice were bred with Rosa26 reporter strain and a mouse strain that carries PTEN conditional alleles (PTENLoxp/Loxp). At mRNA level, Cre was strongly expressed in the stomach, lung and intestine, while in stomach, lung, and liver at protein level. The immunoreactivity to Cre was strongly observed the cytoplasm of gastric, bronchial and intestinal epithelial cells. Cre activity was detectable in gastric, bronchial and intestinal epithelial cells, according to LacZ staining. In K19-Cre/PTEN Loxp/Loxp mice, PTEN was abrogated in stomach, intestine, lung, liver and breast, the former two of which were verified by in situ PCR. There appeared breast cancer with PTEN loss. These data suggest that K19 promoter may be a useful tool to study the pathophysiological functions of cytokeratin 19-positive cells, especially gastrointestinal epithelial cells. Cell specificity of neoplasia is not completely attributable to the cell-specific expression of oncogenes and cell-specific loss of tumor suppressor genes.

Imaging studies of the hindlimbs of pacas (Cuniculus paca) bred in captivity.

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Araújo, F A P; Rahal, S C; Doiche, D P; Machado, M R F; Vulcano, L C; Teixeira, C R; El-Warrak, A O

2010-01-01

To evaluate the hindlimbs of pacas bred in captivity using radiographic and computed tomography (CT) studies. Nine mature pacas (Cuniculus paca) 5.9-8.2 kg in body weight. Radiographical aspects of the bones of the hindlimbs were evaluated, and the Norberg angle and inclination angle were measured for each hindlimb. Anteversion angle were measured in CT examination. The bone anatomy of the hindlimb of the paca was similar to that of the guinea pig, apart from two lunulae and a single fabella (lateral) which were observed. The Norberg angle had mean value of 130.56º ± 3.81 without any significant difference between testers. Inclination angles ranged from 142.44º ± 4.82 to 145.44º ± 4.09 by Hauptman's method, and from 144.94º ± 3.13 to 148.22º ± 3.25 by Montavon's method, for right and left hindlimbs respectively. Average values for the anteversion angles measured with CT ranged from 28.56º ± 5.56 to 32.91º ± 2.62. The data may be used in future studies comparing the paca to other rodent species. In addition, the paca could be used as an animal model in orthopaedic research.

76 FR 76741 - Government-Owned Inventions; Availability for Licensing

Science.gov (United States)

2011-12-08

... conditional knockout mutation can be cross-bred using, for example, Cre-expressing mice to generate tissue... anisotropy in yeast cells using double- pulsed field gradient MR. NMR Biomed. 2011 July 22. E-pub ahead of...

Captive-bred neotropical birds diagnosed with Cryptosporidium Avian genotype III.

Science.gov (United States)

Silva Novaes, Ricardo; Pires, Marcus Sandes; Sudré, Adriana Pittella; Bergamo do Bomfim, Teresa Cristina

2018-02-01

Currently, there are only three valid species of Cryptosporidium infecting avian hosts, namely, Cryptosporidium meleagridis, Cryptosporidium baileyi, Cryptosporidium galli and Cryptosporidium avium in addition to 12 genotypes of unknown species status. The objectives of this study were to microscopically diagnose the presence of Cryptosporidium in birds from a commercial aviary located in Rio de Janeiro, Brazil; genotypically characterize species and/or genotypes of genus Cryptosporidum; and conduct sequencing and phylogenetic analyses to compare the obtained DNA sequences with those deposited in GenBank. A total of 85 fecal samples were collected from wild captive-bred birds: 48 of family Psittacidae and 37 of family Ramphastidae. Initially, a search for the presence of Cryptosporidium sp. oocysts was conducted using the centrifugal-flotation in saturated sugar solution technique, after that, the collected samples were analyzed microscopically. Cryptosporidium infections were only detected in 24.32% of samples belonging to the family Ramphastidae. DNA was extracted from positive samples and molecular diagnostics was applied targeting the 18S rRNA gene, followed by sequencing and phylogenetic analysis. The Cryptosporidium Avian genotype III was diagnosed in this study more closely related to the gastric species. This is the first record of Cryptosporidium Avian genotype III in order Piciformes and family Ramphastidae, where three host species (Ramphastus toco, Ramphastus tucanus, and Pteroglossus bailloni) were positive for the etiologic agent. Based on the molecular data obtained, these wild birds raised in captivity do not represent a source of human cryptosporidiosis, considering that Cryptosporidium Avian genotype III does not constitute a zoonosis. Copyright © 2017. Published by Elsevier B.V.

Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice.

Science.gov (United States)

Zhang, Yong; Liu, Hong; Li, Wei; Zhang, Zhengang; Shang, Xuejun; Zhang, David; Li, Yuhong; Zhang, Shiyang; Liu, Junpin; Hess, Rex A; Pazour, Gregory J; Zhang, Zhibing

2017-12-01

Intraflagellar transport (IFT) is an evolutionarily conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. In mice, mutations in IFT proteins have been shown to cause several ciliopathies including retinal degeneration, polycystic kidney disease, and hearing loss. However, little is known about its role in the formation of the sperm tail, which has the longest flagella of mammalian cells. IFT27 is a component of IFT-B complex and binds to IFT25 directly. In mice, IFT27 is highly expressed in the testis. To investigate the role of IFT27 in male germ cells, the floxed Ift27 mice were bred with Stra8-iCre mice so that the Ift27 gene was disrupted in spermatocytes/spermatids. The Ift27: Stra8-iCre mutant mice did not show any gross abnormalities, and all of the mutant mice survived to adulthood. There was no difference between testis weight/body weight between controls and mutant mice. All adult homozygous mutant males examined were completely infertile. Histological examination of the testes revealed abnormally developed germ cells during the spermiogenesis phase. The epididymides contained round bodies of cytoplasm. Sperm number was significantly reduced compared to the controls and only about 2% of them remained significantly reduced motility. Examination of epididymal sperm by light microscopy and SEM revealed multiple morphological abnormalities including round heads, short and bent tails, abnormal thickness of sperm tails in some areas, and swollen tail tips in some sperm. TEM examination of epididymal sperm showed that most sperm lost the "9+2″ axoneme structure, and the mitochondria sheath, fibrous sheath, and outer dense fibers were also disorganized. Some sperm flagella also lost cell membrane. Levels of IFT25 and IFT81 were significantly reduced in the testis of the conditional Ift27 knockout mice, and levels of IFT20, IFT74, and IFT140 were not changed. Sperm lipid rafts, which were disrupted in the

Intraflagellar Transporter Protein (IFT27), an IFT25 binding partner, Is Essential For Male Fertility and Spermiogenesis In Mice

Science.gov (United States)

Zhang, Yong; Liu, Hong; Li, Wei; Zhang, Zhengang; Shang, Xuejun; Zhang, David; Li, Yuhong; Zhang, Shiyang; Liu, Junpin; Hess, Rex A; Pazour, Gregory J; Zhang, Zhibing

2017-01-01

Intraflagellar transport (IFT) is an evolutionarily conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. In mice, mutations in IFT proteins have been shown to cause several ciliopathies including retinal degeneration, polycystic kidney disease, and hearing loss. However, little is known about its role in the formation of the sperm tail, which has the longest flagella of mammalian cells. IFT27 is a component of IFT-B complex and binds to IFT25 directly. In mice, IFT27 is highly expressed in the testis. To investigate the role of IFT27 in male germ cells, the floxed Ift27 mice were bred with Stra8-iCre mice so that the Ift27 gene was disrupted in spermatocytes/spermatids. The Ift27:Stra8-iCre mutant mice did not show any gross abnormalities, and all of the mutant mice survive to adulthood. There was no difference between testis weight/body weight between controls and mutant mice. All adult homozygous mutant males examined were completely infertile. Histological examination of the testes revealed abnormally developed germ cells during the spermiogenesis phase. The epididymis contained round bodies of cytoplasm. Sperm number was significantly reduced compared to the controls and only about 2% of them remained significantly reduced motility. Examination of epididymal sperm by light microscopy and SEM revealed multiple morphological abnormalities including round heads, short and bent tails, abnormal thickness of sperm tails in some areas, and swollen tail tips in some sperm. TEM examination of epididymal sperm showed that most sperm lost the “9+2” axoneme structure, and the mitochondria sheath, fibrous sheath, and outer dense fibers were also disorganized. Some sperm flagella also lost cell membrane. Levels of IFT25 and IFT81 were significantly reduced in the testis of the conditional Ift27 knockout mice, and levels of IFT20, IFT74, and IFT140 were not changed. Sperm lipid rafts, which were disrupted in the conditional

Mutation analysis of GLDC, AMT and GCSH in cataract captive-bred vervet monkeys (Chlorocebus aethiops).

Science.gov (United States)

Chauke, Chesa G; Magwebu, Zandisiwe E; Sharma, Jyoti R; Arieff, Zainunisha; Seier, Jürgen V

2016-08-01

Non-ketotic hyperglycinaemia (NKH) is an autosomal recessive inborn error of glycine metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. This study describes the first screening of NKH in cataract captive-bred vervet monkeys (Chlorocebus aethiops). Glycine dehydrogenase (GLDC), aminomethyltransferase (AMT) and glycine cleavage system H protein (GCSH) were prioritized. Mutation analysis of the complete coding sequence of GLDC and AMT revealed six novel single-base substitutions, of which three were non-synonymous missense and three were silent nucleotide changes. Although deleterious effects of the three amino acid substitutions were not evaluated, one substitution of GLDC gene (S44R) could be disease-causing because of its drastic amino acid change, affecting amino acids conserved in different primate species. This study confirms the diagnosis of NKH for the first time in vervet monkeys with cataracts. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

BA321, a novel carborane analog that binds to androgen and estrogen receptors, acts as a new selective androgen receptor modulator of bone in male mice

International Nuclear Information System (INIS)

Watanabe, Kenta; Hirata, Michiko; Tominari, Tsukasa; Matsumoto, Chiho; Endo, Yasuyuki; Murphy, Gillian; Nagase, Hideaki

2016-01-01

Carboranes are a class of carbon-containing polyhedral boron cluster compounds with globular geometry and hydrophobic surface that interact with hormone receptors such as estrogen receptor (ER) and androgen receptor (AR). We have synthesized BA321, a novel carborane compound, which binds to AR. We found here that it also binds to ERs, ERα and ERβ. In orchidectomized (ORX) mice, femoral bone mass was markedly reduced due to androgen deficiency and BA321 restored bone loss in the male, whilst the decreased weight of seminal vesicle in ORX mice was not recovered by administration of BA321. In female mice, BA321 acts as a pure estrogen agonist, and restored both the loss of bone mass and uterine atrophy due to estrogen deficiency in ovariectomized (OVX) mice. In bone tissues, the trabecular bone loss occurred in both ORX and OVX mice, and BA321 completely restored the trabecular bone loss in both sexes. Cortical bone loss occurred in ORX mice but not in OVX mice, and BA321 clearly restored cortical bone loss due to androgen deficiency in ORX mice. Therefore, BA321 is a novel selective androgen receptor modulator (SARM) that may offer a new therapy option for osteoporosis in the male. - Highlights: • A novel carborane compound BA321 binds to both AR and ERs, ERα and ERβ. • BA321 restores bone loss in orchidectomized mice without effects on sex organ. • BA321 acts as an estrogen agonist in bone and uterus in ovariectomized mice. • BA321 may be a new SARM to prevent the loss of musculoskeletal mass in elder men.

BA321, a novel carborane analog that binds to androgen and estrogen receptors, acts as a new selective androgen receptor modulator of bone in male mice

Energy Technology Data Exchange (ETDEWEB)

Watanabe, Kenta [Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Cooperative Major in Advanced Health Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Hirata, Michiko [Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Tominari, Tsukasa [Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Matsumoto, Chiho [Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Endo, Yasuyuki [Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsushima, Aoba-ku, Sendai, 981-8558 (Japan); Murphy, Gillian [Department of Oncology, University of Cambridge, Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, Cambridge, CB2 0RE (United Kingdom); Nagase, Hideaki [Institute of Global Innovation Research, Tokyo University of Agriculture and Technology, 2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan); Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7FY (United Kingdom); and others

2016-09-09

Carboranes are a class of carbon-containing polyhedral boron cluster compounds with globular geometry and hydrophobic surface that interact with hormone receptors such as estrogen receptor (ER) and androgen receptor (AR). We have synthesized BA321, a novel carborane compound, which binds to AR. We found here that it also binds to ERs, ERα and ERβ. In orchidectomized (ORX) mice, femoral bone mass was markedly reduced due to androgen deficiency and BA321 restored bone loss in the male, whilst the decreased weight of seminal vesicle in ORX mice was not recovered by administration of BA321. In female mice, BA321 acts as a pure estrogen agonist, and restored both the loss of bone mass and uterine atrophy due to estrogen deficiency in ovariectomized (OVX) mice. In bone tissues, the trabecular bone loss occurred in both ORX and OVX mice, and BA321 completely restored the trabecular bone loss in both sexes. Cortical bone loss occurred in ORX mice but not in OVX mice, and BA321 clearly restored cortical bone loss due to androgen deficiency in ORX mice. Therefore, BA321 is a novel selective androgen receptor modulator (SARM) that may offer a new therapy option for osteoporosis in the male. - Highlights: • A novel carborane compound BA321 binds to both AR and ERs, ERα and ERβ. • BA321 restores bone loss in orchidectomized mice without effects on sex organ. • BA321 acts as an estrogen agonist in bone and uterus in ovariectomized mice. • BA321 may be a new SARM to prevent the loss of musculoskeletal mass in elder men.

Environmental enrichment ameliorates depressive-like symptoms in young rats bred for learned helplessness.

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Richter, S Helene; Zeuch, Benjamin; Riva, Marco A; Gass, Peter; Vollmayr, Barbara

2013-09-01

The incidence of major depression is known to be influenced by both genetic and environmental factors. In the current study, we therefore set out to investigate depressive-like behavior and its modification by environmental enrichment using rats bred for 'learned helplessness'. 45 males of congenitally helpless (cLH, n=22) and non-helpless (cNLH, n=23) rats of two different generations were used to systematically investigate differential effects of environmental enrichment on learned helpless behavior, anhedonic-like behavior (sweetened condensed milk consumption) and spontaneous behavior in the home cage. While enrichment was found to reduce learned helpless behavior in 14 weeks old, but not 28 weeks old cLH rats, it did not affect the consumption of sweetened condensed milk. Regarding the home cage behavior, no consistent changes between rats of different strains, housing conditions, and ages were observed. We could thus demonstrate that a genetic predisposition for learned helplessness may interact with environmental conditions in mediating some, but not all depressive-like symptoms in congenitally learned helpless rats. However, future efforts are needed to isolate the differential benefits of environmental factors in mediating the different depression-related symptoms. Copyright © 2013 Elsevier B.V. All rights reserved.

Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice

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Smith, Kiersten S.; Engin, Elif; Meloni, Edward G.; Rudolph, Uwe

2012-01-01

GABAA receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABAA receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABAA receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABAA receptors are necessary for BZs to exert their effects on conditioned fear responses.. Our findings illustrate both an overlap and a divergence between the GABAA receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABAA receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABAA receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored. PMID:22465203

Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice

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Nguyen, Hai T; Guiard, Bruno P; Bacq, Alexandre; David, Denis J; David, Indira; Quesseveur, Gaël; Gautron, Sophie; Sanchez, Connie; Gardier, Alain M

2013-01-01

BACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT]ext and [NA]ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT−/−) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]ext and/or [NA]ext affected the antidepressant-like activity of escitalopram. KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]ext and [NA]ext. As expected, escitalopram failed to increase cortical [5-HT]ext in SERT−/− mice, whereas its neurochemical effects on [NA]ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA]extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET). PMID:22233336

Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice.

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Armando, Ines; Asico, Laureano D; Wang, Xiaoyan; Jones, John E; Serrão, Maria Paula; Cuevas, Santiago; Grandy, David K; Soares-da-Silva, Patricio; Jose, Pedro A

2018-04-13

Abnormalities of the D 2 R gene (DRD2) play a role in the pathogenesis of human essential hypertension; variants of the DRD2 have been reported to be associated with hypertension. Disruption of Drd2 (D 2 -/- ) in mice increases blood pressure. The hypertension of D 2 -/- mice has been related, in part, to increased sympathetic activity, renal oxidative stress, and renal endothelin B receptor (ETBR) expression. We tested in D 2 -/- mice the effect of etamicastat, a reversible peripheral inhibitor of dopamine-β-hydroxylase that reduces the biosynthesis of norepinephrine from dopamine and decreases sympathetic nerve activity. Blood pressure was measured in anesthetized D 2 -/- mice treated with etamicastat by gavage, (10 mg/kg), conscious D 2 -/- mice, and D 2 +/+ littermates, and mice with the D 2 R selectively silenced in the kidney, treated with etamicastat in the drinking water (10 mg/kg per day). Tissue and urinary catecholamines and renal expression of selected G protein-coupled receptors, enzymes related to the production of reactive oxygen species, and sodium transporters were also measured. Etamicastat decreased blood pressure both in anesthetized and conscious D 2 -/- mice and mice with renal-selective silencing of D 2 R to levels similar or close to those measured in D 2 +/+ littermates. Etamicastat decreased cardiac and renal norepinephrine and increased cardiac and urinary dopamine levels in D 2 -/- mice. It also normalized the increased renal protein expressions of ETBR, NADPH oxidase isoenzymes, and urinary 8-isoprostane, as well as renal NHE3 and NCC, and increased the renal expression of D 1 R but not D 5 R in D 2 -/- mice. In conclusion, etamicastat is effective in normalizing the increased blood pressure and some of the abnormal renal biochemical alterations of D 2 -/- mice.

Estimation of breeding values using selected pedigree records.

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Morton, Richard; Howarth, Jordan M

2005-06-01

Fish bred in tanks or ponds cannot be easily tagged individually. The parentage of any individual may be determined by DNA fingerprinting, but is sufficiently expensive that large numbers cannot be so finger-printed. The measurement of the objective trait can be made on a much larger sample relatively cheaply. This article deals with experimental designs for selecting individuals to be finger-printed and for the estimation of the individual and family breeding values. The general setup provides estimates for both genetic effects regarded as fixed or random and for fixed effects due to known regressors. The family effects can be well estimated when even very small numbers are finger-printed, provided that they are the individuals with the most extreme phenotypes.

Maternal exposure to Western diet affects adult body composition and voluntary wheel running in a genotype-specific manner in mice.

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Hiramatsu, Layla; Kay, Jarren C; Thompson, Zoe; Singleton, Jennifer M; Claghorn, Gerald C; Albuquerque, Ralph L; Ho, Brittany; Ho, Brett; Sanchez, Gabriela; Garland, Theodore

2017-10-01

Some human diseases, including obesity, Type II diabetes, and numerous cancers, are thought to be influenced by environments experienced in early life, including in utero. Maternal diet during the perinatal period may be especially important for adult offspring energy balance, potentially affecting both body composition and physical activity. This effect may be mediated by the genetic background of individuals, including, for example, potential "protective" mechanisms for individuals with inherently high levels of physical activity or high basal metabolic rates. To examine some of the genetic and environmental factors that influence adult activity levels, we used an ongoing selection experiment with 4 replicate lines of mice bred for high voluntary wheel running (HR) and 4 replicate, non-selected control lines (C). Dams (half HR and half C) were fed a "Western" diet (WD, high in fat and sucrose) or a standard diet (SD) from 2weeks prior to mating until their pups could feed on solid food (14days of age). We analyzed dam and litter characteristics from birth to weaning, and offspring mass and physical activity into adulthood. One male offspring from each litter received additional metabolic and behavioral tests. Maternal WD caused pups to eat solid food significantly earlier for C litters, but not for HR litters (interaction of maternal environment and genotype). With dam mass as a covariate, mean pup mass was increased by maternal WD but litter size was unaffected. HR dams had larger litters and tended to have smaller pups than C dams. Home-cage activity of juvenile focal males was increased by maternal WD. Juvenile lean mass, fat mass, and fat percent were also increased by maternal WD, but food consumption (with body mass as a covariate) was unaffected (measured only for focal males). Behavior in an elevated plus maze, often used to indicate anxiety, was unaffected by maternal WD. Maximal aerobic capacity (VO 2 max) was also unaffected by maternal WD, but HR had

Long-term improvements in sensory inhibition with gestational choline supplementation linked to α7 nicotinic receptors through studies in Chrna7 null mutation mice.

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Stevens, Karen E; Choo, Kevin S; Stitzel, Jerry A; Marks, Michael J; Adams, Catherine E

2014-03-13

Perinatal choline supplementation has produced several benefits in rodent models, from improved learning and memory to protection from the behavioral effects of fetal alcohol exposure. We have shown that supplemented choline through gestation and lactation produces long-term improvement in deficient sensory inhibition in DBA/2 mice which models a similar deficit in schizophrenia patients. The present study extends that research by feeding normal or supplemented choline diets to DBA/2 mice carrying the null mutation for the α7 nicotinic receptor gene (Chrna7). DBA/2 mice heterozygotic for Chrna7 were bred together. Dams were placed on supplemented (5 gm/kg diet) or normal (1.1 gm/kg diet) choline at mating and remained on the specific diet until offspring weaning. Thereafter, offspring were fed standard rodent chow. Adult offspring were assessed for sensory inhibition. Brains were obtained to ascertain hippocampal α7 nicotinic receptor levels. Choline-supplemented mice heterozygotic or null-mutant for Chrna7 failed to show improvement in sensory inhibition. Only wildtype choline-supplemented mice showed improvement with the effect solely through a decrease in test amplitude. This supports the hypothesis that gestational-choline supplementation is acting through the α7 nicotinic receptor to improve sensory inhibition. Although there was a significant gene-dose-related change in hippocampal α7 receptor numbers, binding studies did not reveal any choline-dose-related change in binding in any hippocampal region, the interaction being driven by a significant genotype main effect (wildtype>heterozygote>null mutant). These data parallel a human study wherein the offspring of pregnant women receiving choline supplementation during gestation, showed better sensory inhibition than offspring of women on placebo. Published by Elsevier B.V.

Antinociceptive action of DBO 17 and DBO 11 in mice: two 3,8 diazabicyclo (3.2.1.) octane derivates with selective mu opioid receptor affinity.

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Fadda, P; Barlocco, D; Tronci, S; Cignarella, G; Fratta, W

1997-11-01

Two 3,8 diazabicyclo (3.2.1.) octane derivates, namely DBO 17 and DBO 11, were studied for the opioid-like activity. In the rat brain membrane preparation binding studies, DBO 17 and DBO 11 showed a high affinity and selectivity for the mu opioid receptor (Ki's: 5.1 and 25 nM, respectively). DBO 17 and DBO 11 inhibited the nociceptive response in the hot-plate test of mice with ED50 values of 0.16 mg/kg and 0.44 mg/kg, respectively. The antinociceptive action of both DBO 17 and DBO 11 was blocked by naloxone. Tolerance to the antinociceptive action of DBO 17 and DBO 11 was present after 13 and 7 days of repeated treatment, respectively. Both DBO 17 and DBO 11 were ineffective in morphine-tolerant mice and vice versa. Chronic treatments (three times daily for seven consecutive days) of DBO 17 and DBO 11 induced a naloxone-precipitated withdrawal syndrome in DBO 17 treated mice similar to that in morphine treated mice, whereas in DBO 11 treated mice abstinence signs were virtually absent. These results indicate an interesting pharmacological profile that suggests these compounds as possible new candidates for the clinical treatment of pain.

Genetical polymorphism of acc synthase and ACC oxidase in Apple selections bred in Čačak

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Marić Slađana

2005-01-01

Full Text Available The work on breeding new apple cultivars, of improved quality and longer storage life has been going on for a long time at the Fruit and Grape Research Centre in Čačak. As a result nine promising apple selections, that show the range of fruit storage capability (J/l/7, J/l/20, J/2/12, J/2/14, J/ll/31, J/54/53/59, J/60/7/63, Šumatovka 1 O.P. and Šumatovka 2 O.P., were singled out. Fruit ripening is genetically programmed, complex physiological process with the important role of plant hormone ethylene. Allelic polymorphism of the genes encoding ACC synthase and ACC oxidase, enzymes on ethylene biosynthetic pathway, was studied in promising apple selections and compared to their storage life. Polymorphism was detected by the polymerase chain reaction (PCR method and restriction analysis with 6 restriction enzymes. Two alleles of the gene encoding ACC synthase (ACS1-1 and ACS1-2, three alleles of the ACC oxidase gene (a, b and n were identified and a positive test for early seedling selection, the fruits of which will be characterized by long storage life, was indicated.

IKKε knockout prevents high fat diet induced arterial atherosclerosis and NF-κB signaling in mice.

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Changchun Cao

Full Text Available AIMS: Atherosclerosis is a public health concern affecting many worldwide, but its pathogenesis remains unclear. In this study we investigated the role of IKKε during the formation of atherosclerosis and its molecular mechanism in the mouse aortic vessel wall. METHODS AND RESULTS: C57BL/6 wild-type or IKKε knockout mice bred into the ApoE knockout genetic background were divided into 4 groups: (1 wild-type (WT, (2 ApoE knockout (AK, (3 IKKε knockout (IK, (4 or both ApoE and IKKε knockout (DK. Each group of mice were fed with a high fat diet (HFD for 12 weeks from 8 weeks of age. Immunohistochemistry and Western blotting analysis demonstrated obvious increases in the expression of IKKε in the AK group compared with the WT group, especially in the intima. Serum lipid levels were significantly higher in the AK and DK groups than in the other two groups. Staining with hematoxylin-eosin and Oil Red, as well as scanning electron microscopy revealed less severe atherosclerotic lesions in the DK group than in the AK group. Immunofluorescence and Western blot analysis demonstrated obvious increases in the expression of NF-κB pathway components and downstream factors in the AK group, especially in the intima, while these increases were blocked in the DK group. CONCLUSION: The knockout of IKKε prevented significant atherosclerosis lesions in the mouse aorta from in both wild-type and ApoE knockout mice fed a HFD, suggesting that IKKε may play a vital role in HFD-induced atherosclerosis and would be an important target for the treatment of atherosclerosis.

Perinatal programming of depressive-like behavior by inflammation in adult offspring mice whose mothers were fed polluted eels: Gender selective effects.

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Soualeh, Nidhal; Dridi, Imen; Eppe, Gauthier; Némos, Christophe; Soulimani, Rachid; Bouayed, Jaouad

2017-07-01

Several lines of evidence indicate that early-life inflammation may predispose to mental illness, including depression, in later-life. We investigated the impact of perinatal exposure to polluted eels on neonatal, postnatal, and adult brain inflammation, and on the resignation behavior of male and female adult offspring mice. The effects of maternal standard diet (laboratory food) were compared to the same diet enriched with low, intermediate, or highly polluted eels. Brain inflammatory markers including cytokines were assessed in offspring mice on the day of birth (i.e., on the postnatal day-PND 1), upon weaning (PND 21) and at adulthood (PND 100). Plasma myeloperoxidase and corticosterone levels were evaluated at PND 100. Immobility behavior of offspring was assessed in adulthood (i.e., at PNDs 95-100), using the tail suspension and forced swimming tests. Chronic brain inflammation was found in male and female offspring mice compared to controls, as assessed at PNDs 1, 21, and 100. The level of myeloperoxidase was found to be significantly higher in both adult males and females vs. control offspring. However, high corticosterone levels were only found in male offspring mice that were perinatally exposed to eels, suggesting a gender-selective dysregulation of the adult hypothalamic-pituitaryadrenal (HPA) axis. Gender-specific differences were also detected in adulthood in regard to offspring resignation behavior. Thus, compared to controls, males, but not females, whose mothers were fed eels during pregnancy and lactation exhibited a depressive-like behavior in adult age in both behavioral models of depression. Depressive symptoms were more pronounced in male mice perinatally exposed to either intermediate or highly polluted eels than those exposed to only lowly polluted eels. Our results indicate that early-life inflammatory insult is a plausible causative factor that induces the depressive phenotype exhibited by male adult offspring mice, most likely through a

Gut Microbiota and a Selectively Bred Taste Phenotype: A Novel Model of Microbiome-Behavior Relationships.

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Lyte, Mark; Fodor, Anthony A; Chapman, Clinton D; Martin, Gary G; Perez-Chanona, Ernesto; Jobin, Christian; Dess, Nancy K

2016-06-01

The microbiota-gut-brain axis is increasingly implicated in obesity, anxiety, stress, and other health-related processes. Researchers have proposed that gut microbiota may influence dietary habits, and pathways through the microbiota-gut-brain axis make such a relationship feasible; however, few data bear on the hypothesis. As a first step in the development of a model system, the gut microbiome was examined in rat lines selectively outbred on a taste phenotype with biobehavioral profiles that have diverged with respect to energy regulation, anxiety, and stress. Occidental low and high-saccharin-consuming rats were assessed for body mass and chow, water, and saccharin intake; littermate controls had shared cages with rats in the experimental group but were not assessed. Cecum and colon microbial communities were profiled using Illumina 16S rRNA sequencing and multivariate analysis of microbial diversity and composition. The saccharin phenotype was confirmed (low-saccharin-consuming rats, 0.7Δ% [0.9Δ%]; high-saccharin-consuming rats, 28.1Δ% [3.6Δ%]). Regardless of saccharin exposure, gut microbiota differed between lines in terms of overall community similarity and taxa at lower phylogenetic levels. Specifically, 16 genera in three phyla distinguished the lines at a 10% false discovery rate. The study demonstrates for the first time that rodent lines created through selective pressure on taste and differing on functionally related correlates host different microbial communities. Whether the microbiota are causally related to the taste phenotype or its correlates remains to be determined. These findings encourage further inquiry on the relationship of the microbiome to taste, dietary habits, emotion, and health.

Embryonic effects transmitted by male mice irradiated with 512 MeV/u 56Fe nuclei

International Nuclear Information System (INIS)

Wiley, L.M.; Van Beek, M.E.A.B.; Raabe, O.G.

1994-01-01

High-energy, high-charge nuclei may contribute substantially to the yearly equivalent dose in space flight from galactic cosmic radiation (GCR) at solar minimum. The largest single heavy-ion component is 56 Fe. We used the mouse embryo chimera assay to test 512 MeV/u 56 Fe nuclei for effects on the rate of proliferation of embryonic cells transmitted by sperm from irradiated mice. Male CD1 mice were acutely irradiated with 0.01, 0.05, or 0.1 Gy (LET, 184 keV/μm; fluence, 3.5 x 10 4 -3.3 x 10 5 nuclei/cm 2 ; average dose rate, 0.02 Gy/min) at the Lawrence Berkeley Laboratory BEVATRON/BEVALAC Facility in Berkeley, CA. Irradiated males were bred weekly for 7 weeks to nonirradiated females and their four-cell embryos were paired with control embryos, forming aggregation chimeras. After 30-35 h of culture, chimeras were dissociated to obtain open-quotes proliferation ratiosclose quotes (number of cells contributed by the embryo from the irradiated male/total number of cells in the chimera). Significant dose-dependent decreases in proliferation ratios were obtained across all three dose groups for postirradiation week 2 (P 56 Fe nuclei. However, up to 47% of sperm during postirradiation weeks 1 and 2 transmitted proliferation ratios that were at or below one standard deviation from control mean proliferation ratios. 26 refs., 4 figs., 10 tabs

Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice.

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Leonora E Long

Full Text Available The cannabis constituent cannabidiol (CBD possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT received vehicle or CBD (1, 50 or 100 mg/kg i.p. for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg also selectively increased GABA(A receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes.

Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety.

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Cohen, Joshua L; Glover, Matthew E; Pugh, Phyllis C; Fant, Andrew D; Simmons, Rebecca K; Akil, Huda; Kerman, Ilan A; Clinton, Sarah M

2015-01-01

The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high versus low behavioral response to novelty and found that high-reactive (bred high-responder, bHR) rats displayed greater risk-taking, impulsivity and aggression relative to low-reactive (bred low-responder, bLR) rats, which showed high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable, but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior to the brain development and emotional behavior of bLR offspring. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine the effects on the following: (1) developmental gene expression in the hippocampus and amygdala and (2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain's developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations. © 2015 S. Karger AG, Basel.

Estimation of Genetic Variance Components Including Mutation and Epistasis using Bayesian Approach in a Selection Experiment on Body Weight in Mice

DEFF Research Database (Denmark)

Widyas, Nuzul; Jensen, Just; Nielsen, Vivi Hunnicke

Selection experiment was performed for weight gain in 13 generations of outbred mice. A total of 18 lines were included in the experiment. Nine lines were allotted to each of the two treatment diets (19.3 and 5.1 % protein). Within each diet three lines were selected upwards, three lines were...... selected downwards and three lines were kept as controls. Bayesian statistical methods are used to estimate the genetic variance components. Mixed model analysis is modified including mutation effect following the methods by Wray (1990). DIC was used to compare the model. Models including mutation effect...... have better fit compared to the model with only additive effect. Mutation as direct effect contributes 3.18% of the total phenotypic variance. While in the model with interactions between additive and mutation, it contributes 1.43% as direct effect and 1.36% as interaction effect of the total variance...

Chronic Voluntary Ethanol Consumption Induces Favorable Ceramide Profiles in Selectively Bred Alcohol-Preferring (P Rats.

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Jessica Godfrey

Full Text Available Heavy alcohol consumption has detrimental neurologic effects, inducing widespread neuronal loss in both fetuses and adults. One proposed mechanism of ethanol-induced cell loss with sufficient exposure is an elevation in concentrations of bioactive lipids that mediate apoptosis, including the membrane sphingolipid metabolites ceramide and sphingosine. While these naturally-occurring lipids serve as important modulators of normal neuronal development, elevated levels resulting from various extracellular insults have been implicated in pathological apoptosis of neurons and oligodendrocytes in several neuroinflammatory and neurodegenerative disorders. Prior work has shown that acute administration of ethanol to developing mice increases levels of ceramide in multiple brain regions, hypothesized to be a mediator of fetal alcohol-induced neuronal loss. Elevated ceramide levels have also been implicated in ethanol-mediated neurodegeneration in adult animals and humans. Here, we determined the effect of chronic voluntary ethanol consumption on lipid profiles in brain and peripheral tissues from adult alcohol-preferring (P rats to further examine alterations in lipid composition as a potential contributor to ethanol-induced cellular damage. P rats were exposed for 13 weeks to a 20% ethanol intermittent-access drinking paradigm (45 ethanol sessions total or were given access only to water (control. Following the final session, tissues were collected for subsequent chromatographic analysis of lipid content and enzymatic gene expression. Contrary to expectations, ethanol-exposed rats displayed substantial reductions in concentrations of ceramides in forebrain and heart relative to non-exposed controls, and modest but significant decreases in liver cholesterol. qRT-PCR analysis showed a reduction in the expression of sphingolipid delta(4-desaturase (Degs2, an enzyme involved in de novo ceramide synthesis. These findings indicate that ethanol intake levels

Investigation of the role of non-selective calcium channel blocker (flunarizine) on cerebral ischemic-reperfusion associated cognitive dysfunction in aged mice.

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Gulati, Puja; Muthuraman, Arunachalam; Kaur, Parneet

2015-04-01

The present study was designed to investigate the role of flunarizine (a non-selective calcium channel blocker) on cerebral ischemic-reperfusion associated cognitive dysfunction in aged mice. Bilateral carotid artery occlusion of 12min followed by reperfusion for 24h was given to induce cerebral injury in male Swiss mice. The assessment of learning & memory was performed by Morris water maze test; motor in-coordination was evaluated by rota rod, lateral push and inclined beam walking tests; cerebral infarct size was quantified by triphenyltetrazolium chloride staining. In addition, reduced glutathione (GSH), total calcium and acetylcholinesterase (AChE) activity were also estimated in aged brain tissue. Donepezil treated group served as a positive control in this study. Ischemia reperfusion (I/R) injury produced significant increase in cerebral infarct size. A significant loss of memory along with impairment of motor performance was also noted. Further, I/R injury also produced significant increase in levels of total calcium, AChE activity and decrease in GSH levels. Pretreatment of flunarizine significantly attenuated I/R induced infarct size, behavioral and biochemical changes. Hence, it may be concluded that, a non-selective calcium channel blocker can be useful in I/R associated cognitive dysfunction due to its anti-oxidant, anti-infarct and modulatory actions of neurotransmitters & calcium channels. Copyright © 2015 Elsevier Inc. All rights reserved.

Activity-dependent formation of a vesicular inhibitory amino acid transporter gradient in the superior olivary complex of NMRI mice.

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Ebbers, Lena; Weber, Maren; Nothwang, Hans Gerd

2017-10-26

In the mammalian superior olivary complex (SOC), synaptic inhibition contributes to the processing of binaural sound cues important for sound localization. Previous analyses demonstrated a tonotopic gradient for postsynaptic proteins mediating inhibitory neurotransmission in the lateral superior olive (LSO), a major nucleus of the SOC. To probe, whether a presynaptic molecular gradient exists as well, we investigated immunoreactivity against the vesicular inhibitory amino acid transporter (VIAAT) in the mouse auditory brainstem. Immunoreactivity against VIAAT revealed a gradient in the LSO and the superior paraolivary nucleus (SPN) of NMRI mice, with high expression in the lateral, low frequency processing limb and low expression in the medial, high frequency processing limb of both nuclei. This orientation is opposite to the previously reported gradient of glycine receptors in the LSO. Other nuclei of the SOC showed a uniform distribution of VIAAT-immunoreactivity. No gradient was observed for the glycine transporter GlyT2 and the neuronal protein NeuN. Formation of the VIAAT gradient was developmentally regulated and occurred around hearing-onset between postnatal days 8 and 16. Congenital deaf Claudin14 -/- mice bred on an NMRI background showed a uniform VIAAT-immunoreactivity in the LSO, whereas cochlear ablation in NMRI mice after hearing-onset did not affect the gradient. Additional analysis of C57Bl6/J, 129/SvJ and CBA/J mice revealed a strain-specific formation of the gradient. Our results identify an activity-regulated gradient of VIAAT in the SOC of NRMI mice. Its absence in other mouse strains adds a novel layer of strain-specific features in the auditory system, i.e. tonotopic organization of molecular gradients. This calls for caution when comparing data from different mouse strains frequently used in studies involving transgenic animals. The presence of strain-specific differences offers the possibility of genetic mapping to identify molecular

QTL analysis of dietary obesity in C57BL/6byj X 129P3/J F2 mice: diet- and sex-dependent effects.

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Lin, Cailu; Theodorides, Maria L; McDaniel, Amanda H; Tordoff, Michael G; Zhang, Qinmin; Li, Xia; Bosak, Natalia; Bachmanov, Alexander A; Reed, Danielle R

2013-01-01

Obesity is a heritable trait caused by complex interactions between genes and environment, including diet. Gene-by-diet interactions are difficult to study in humans because the human diet is hard to control. Here, we used mice to study dietary obesity genes, by four methods. First, we bred 213 F2 mice from strains that are susceptible [C57BL/6ByJ (B6)] or resistant [129P3/J (129)] to dietary obesity. Percent body fat was assessed after mice ate low-energy diet and again after the same mice ate high-energy diet for 8 weeks. Linkage analyses identified QTLs associated with dietary obesity. Three methods were used to filter candidate genes within the QTL regions: (a) association mapping was conducted using >40 strains; (b) differential gene expression and (c) comparison of genomic DNA sequence, using two strains closely related to the progenitor strains from Experiment 1. The QTL effects depended on whether the mice were male or female or which diet they were recently fed. After feeding a low-energy diet, percent body fat was linked to chr 7 (LOD=3.42). After feeding a high-energy diet, percent body fat was linked to chr 9 (Obq5; LOD=3.88), chr 12 (Obq34; LOD=3.88), and chr 17 (LOD=4.56). The Chr 7 and 12 QTLs were sex dependent and all QTL were diet-dependent. The combination of filtering methods highlighted seven candidate genes within the QTL locus boundaries: Crx, Dmpk, Ahr, Mrpl28, Glo1, Tubb5, and Mut. However, these filtering methods have limitations so gene identification will require alternative strategies, such as the construction of congenics with very small donor regions.

Incensole acetate reduces depressive-like behavior and modulates hippocampal BDNF and CRF expression of submissive animals.

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Moussaieff, Arieh; Gross, Moshe; Nesher, Elimelech; Tikhonov, Tatiana; Yadid, Gal; Pinhasov, Albert

2012-12-01

Incensole acetate (IA), a constituent of Boswellia resin ('frankincense'), was previously demonstrated to exhibit an antidepressive-like effect in the Forced Swim Test (FST) in mice following single dose administration (50 mg/kg). Here, we show that acute administration of considerably lower dose (10 mg/kg) IA to selectively bred mice, showing prominent submissive behavior, exerted significant antidepressant-like effects in the FST. Furthermore, chronic administration of 1 or 5 mg/kg per day of IA for three consecutive weeks dose- and time-dependently reduced the submissiveness of the mice in the Dominant-Submissive Relationship test, developed to screen the chronic effect of antidepressants. This behavioral effect was concomitant to reduced serum corticosterone levels, dose-dependent down-regulation of corticotropin releasing factor and up-regulation of brain derived neurotrophic factor transcripts IV and VI expression in the hippocampus. These data suggest that IA modulates the hypothalamic-pituitary-adrenal (HPA) axis and influences hippocampal gene expression, leading to beneficial behavioral effects supporting its potential as a novel treatment of depressive-like disorders.

Lyapunov, singular and bred vectors in a multi-scale system: an empirical exploration of vectors related to instabilities

International Nuclear Information System (INIS)

Norwood, Adrienne; Kalnay, Eugenia; Ide, Kayo; Yang, Shu-Chih; Wolfe, Christopher

2013-01-01

imitating the tropical El Niño–Southern Oscillation. The bred vectors are able to separate the fast and slow modes of growth through appropriate selection of the breeding perturbation size and rescaling interval. The Lyapunov vectors are able to successfully separate the fast ‘extratropical atmosphere’, but are unable to completely decouple the ‘tropical atmosphere’ from the ‘ocean’. This leads to ‘coupled’ Lyapunov vectors that are mainly useful in the (slow) ‘ocean’ system, but are still affected by changes in the (fast) ‘tropical’ system. The singular vectors are excellent in capturing the fast modes, but are unable to capture the slow modes of growth. The dissimilar behavior of the three types of vectors leads to a degradation in the similarities of the subspaces they inhabit and affects their relative ability of representing the coupled modes. This article is part of a special issue of Journal of Physics A: Mathematical and Theoretical devoted to ‘Lyapunov analysis: from dynamical systems theory to applications’. (paper)

Antimalarial activity of selected Ethiopian medicinal plants in mice

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Eshetu M. Bobasa

2018-02-01

Full Text Available Context: Parasites are the leading killers in subtropical areas of which malaria took the lion share from protozoan diseases. Measuring the impact of antimalarial drug resistance is difficult, and the impact may not be recognized until it is severe, especially in high transmission areas. Aims: To evaluate the in vivo antimalarial activities of hydroalcoholic extracts of the roots of Piper capense and Adhatoda schimperiana, against Plasmodium berghei in mice. Methods: Four-day suppressive and curative test animal models were used to explore the antimalarial activities of the plants. 200, 400, and 600 mg/kg of each plant extract was administered to check the activities versus vehicle administered mice. Mean survival time and level of parasitemia were the major variables employed to compare the efficacy vs. negative control. Results: In both models the 400 and 600 mg/kg doses of Adhatoda schimperiana and the 600 mg/kg dose Piper capense. showed significant parasitemia suppression and increased in mean survival time at p≤0.05. The middle dose of Piper capense had a border line inhibition where the extracts were considered active when parasitemia was reduced by ≥ 30%. Conclusions: The hydroalcoholic extracts of the roots of Adhatoda schimperiana and Piper capense possess moderate antimalarial activities, which prove its traditional claims. Thus, further studies should be done to isolate the active constituents for future use in the modern drug discovery.

Selective amotivation deficits following chronic psychosocial stress in mice.

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Tsai Cabal, Alejandro; Ioanas, Horea-Ioan; Seifritz, Erich; Saab, Bechara J

2017-01-15

Amotivation is a major symptom of several psychiatric disorders. However, which specific motivations are most affected in various illnesses is not well understood. In major depressive disorder (MDD), anecdotal evidence suggests the motivation to explore may be especially affected, but direct evidence from either patients or animal models is lacking. To investigate the potential for, and nature of, exploratory drive deficits in MDD, we subjected mice to a chronic social defeat (CSD) manipulation that gives rise to a MDD-like behavioural ensemble, and performed a behavioural battery to examine bodyweight homeostasis, ambulation, anxiety, exploratory behaviour motivated by either novelty or fear, and short-term memory. Consistent with previous reports, we found a disruption of bodyweight homeostasis and reduced ambulation following CSD treatment, but we found no evidence for anxiogenic effects or impairments in short-term memory. Surprisingly, we also observed profoundly delayed and diminished exploration of novel, safe space following CSD, while exploration motivated by fear remained intact. These results extend our knowledge of the behavioural phenotypes in mice resulting from CSD by homing in on specific motivational drives. In MDD patients, reduced exploration could compound disease symptomatology by preventing engagement in what could be rewarding exploration experiences, and targeting deficits in the motivation to explore may represent a novel avenue for treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

MEAT PERFORMANCE OF THE CZECH SPOTTED CATTLE BULLS BRED IN MOUNTAIN REGION

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J. VOŘÍŠKOVÁ

2008-10-01

Full Text Available Chosen indicators of meat performance of 98 bulls of Czech Spotted cattle bred in elevation above 720 m above sea-level in the mountain region of Šumava are presented in the article. The fattening was realized in a barn with a deep litter. The feed ration consisted of haylage throughout the year. The bulls were divided into three groups according to their genotype - C100, C75-85R (CxR and C75-85A (CxA. The highest live weight at slaughter was achieved in the group C100 with 650 kg with the average age of 726 days and the weight of the carcasses of 363.8 kg. On the other hand, the worst results were achieved in the group CxA. For comparison a group of 14 bulls of the Holstein breed was created (H100, which was fattened in the same conditions. The bulls achieved their highest live weight before slaughter (664.6 kg, but at the highest age (743 days. Statistically significant differences were proven in the meat performance after individual fathers – the best results were documented with the offspring of the bull BO-837. After the separation of the set of bulls according to live weight at the end of fattening, the highest results were achieved by the group above 700 kg. The best class using the SEUROP method was achieved by the group with slaughtering live weight between 650 kg and 700 kg.

Selective inhibition of phosphodiesterase 5 enhances glutamatergic synaptic plasticity and memory in mice.

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Uthayathas, Subramaniam; Parameshwaran, Kodeeswaran; Karuppagounder, Senthilkumar S; Ahuja, Manuj; Dhanasekaran, Muralikrishnan; Suppiramaniam, Vishnu

2013-11-01

Phosphodiesterases (PDEs) belong to a family of proteins that control metabolism of cyclic nucleotides. Targeting PDE5, for enhancing cellular function, is one of the therapeutic strategies for male erectile dysfunction. We have investigated whether in vivo inhibition of PDE5, which is expressed in several brain regions, will enhance memory and synaptic transmission in the hippocampus of healthy mice. We have found that acute administration of sildenafil, a specific PDE5 inhibitor, enhanced hippocampus-dependent memory tasks. To elucidate the underlying mechanism in the memory enhancement, effects of sildenafil on long-term potentiation (LTP) were measured. The level of LTP was significantly elevated, with concomitant increases in basal synaptic transmission, in mice treated with sildenafil (1 mg/kg/day) for 15 days compared to control mice. These results suggest that moderate PDE5 inhibition enhances memory by increasing synaptic plasticity and transmission in the hippocampus. Copyright © 2013 Wiley Periodicals, Inc.

Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice.

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Buckman, Laura B; Thompson, Misty M; Lippert, Rachel N; Blackwell, Timothy S; Yull, Fiona E; Ellacott, Kate L J

2015-01-01

Introduction of a high-fat diet to mice results in a period of voracious feeding, known as hyperphagia, before homeostatic mechanisms prevail to restore energy intake to an isocaloric level. Acute high-fat diet hyperphagia induces astrocyte activation in the rodent hypothalamus, suggesting a potential role of these cells in the homeostatic response to the diet. The objective of this study was to determine physiologic role of astrocytes in the acute homeostatic response to high-fat feeding. We bred a transgenic mouse model with doxycycline-inducible inhibition of NFkappaB (NFκB) signaling in astrocytes to determine the effect of loss of NFκB-mediated astrocyte activation on acute high-fat hyperphagia. ELISA was used to measure the levels of markers of astrocyte activation, glial-fibrillary acidic protein (GFAP) and S100B, in the medial basal hypothalamus. Inhibition of NFκB signaling in astrocytes prevented acute high-fat diet-induced astrocyte activation and resulted in a 15% increase in caloric intake (P fat feeding.

Aerosols transmit prions to immunocompetent and immunodeficient mice.

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Johannes Haybaeck

Full Text Available Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrP(C, efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrP(C selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrP(Sc and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories.

Selective and membrane-permeable small molecule inhibitors of nicotinamide N-methyltransferase reverse high fat diet-induced obesity in mice.

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Neelakantan, Harshini; Vance, Virginia; Wetzel, Michael D; Wang, Hua-Yu Leo; McHardy, Stanton F; Finnerty, Celeste C; Hommel, Jonathan D; Watowich, Stanley J

2018-01-01

There is a critical need for new mechanism-of-action drugs that reduce the burden of obesity and associated chronic metabolic comorbidities. A potentially novel target to treat obesity and type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in cellular metabolism and energy homeostasis. To validate NNMT as an anti-obesity drug target, we investigated the permeability, selectivity, mechanistic, and physiological properties of a series of small molecule NNMT inhibitors. Membrane permeability of NNMT inhibitors was characterized using parallel artificial membrane permeability and Caco-2 cell assays. Selectivity was tested against structurally-related methyltransferases and nicotinamide adenine dinucleotide (NAD + ) salvage pathway enzymes. Effects of NNMT inhibitors on lipogenesis and intracellular levels of metabolites, including NNMT reaction product 1-methylnicotianamide (1-MNA) were evaluated in cultured adipocytes. Effects of a potent NNMT inhibitor on obesity measures and plasma lipid were assessed in diet-induced obese mice fed a high-fat diet. Methylquinolinium scaffolds with primary amine substitutions displayed high permeability from passive and active transport across membranes. Importantly, methylquinolinium analogues displayed high selectivity, not inhibiting related SAM-dependent methyltransferases or enzymes in the NAD + salvage pathway. NNMT inhibitors reduced intracellular 1-MNA, increased intracellular NAD + and S-(5'-adenosyl)-l-methionine (SAM), and suppressed lipogenesis in adipocytes. Treatment of diet-induced obese mice systemically with a potent NNMT inhibitor significantly reduced body weight and white adipose mass, decreased adipocyte size, and lowered plasma total cholesterol levels. Notably, administration of NNMT inhibitors did not impact total food intake nor produce any observable adverse effects. These results support development of small molecule NNMT inhibitors as therapeutics to

Effect of oral administration of lactobacillus acidophilus on the immune responses and survival of BALB/c mice bearing human breast cancer

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Soltan Dallal MM

2010-02-01

Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: In according to immunomodulatory effect of probiotics and effect of these bacteria on the effectiveness of immune responses, at the present work we proposed the evaluation of oral administration of L.acidophilus on the immune statues in BALB/c mice bearing breast cancer."n"nMethods: A total of 30 In-bred BALB/c mices aged from six to eight weeks weighting 25-30g were randomly enrolled in our study, in two groups each consist of 15 mices. The L.acidophilus ATCC4356 strain used in this study was inoculated in MRS broth and cultivated for a day at 37°C under anaerobic conditions, collected by centrifugation and resuspend in Phosphate Buffer Saline (PBS. After preparation of proper amount of these suspensions it was orally administered to the mice with a gastric feeding, Control mices received an equal volume of PBS in duration of study."n"nResults: Results showed the increase in production of IFnγ (p<0.005, and decrease in production of Th2 cytokines such as IL4 (p=0.347 in the L.acidophilus administered mice in comparison to control group of mice. In addition the proliferation of immune cells in probiotic group was significantly higher than controls, and most importantly probiotic administered mice showed

Migration Of Ancylostoma caninum Larvae Into Lungs Of Mice Fed ...

African Journals Online (AJOL)

Two randomly selected groups of Swiss Albino Wistar mice were therefore infected with 1000 infective larvae of Ancylostoma caninum/mouse. Test mice received 250mg Allium sativum/kg body weight daily ... KEY WORDS: Allium sativum, lungs, Ancylostoma caninum. Global Journal of Pure and Applied Sciences Vol.11(2) ...

Two types of T helper cells in mice: Differences in cellular immune functions and cytokine secretion - selective reduction of one type after total lymphoid irradiation

International Nuclear Information System (INIS)

Bass, H.Z.

1989-01-01

As observed from a large panel of mouse T helper clones, there are at least two subsets of CD4 + T cells that both differ in function and demonstrate distinct patterns of cytokine secretion after antigen or mitogen stimulation. Th1 cells synthesize IL-2, INF-γ and lymphotoxin. They produce a DTH reaction in the footpads of naive mice. In addition, Th1 cells are required for the generation of CTL, and they appear to augment IgG2a antibody production. In contrast, by secreting IL-4, IL-5, and IL-6, Th2 cells play an essential role in humoral immunity. TLI consists of high dose, fractionated irradiation delivered selectively to the major lymphoid tissues. Four to six weeks after TLI, the CD4 + cells of the treated mice (counted as a percentage of the total spleen lymphocytes) recover to the similar levels as those in normal BALB/c mice. These CD4 + cells can help normal syngeneic B cells to produce a vigorous antibody response to TNP-KLH in adoptive cell transfer experiments, but the same cells are inactive in the MLR, and they fail to transfer DTH in TNP-KLH primed syngeneic BALB/c mice

Chronic inhibition of dopamine β-hydroxylase facilitates behavioral responses to cocaine in mice.

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Meriem Gaval-Cruz

Full Text Available The anti-alcoholism medication, disulfiram (Antabuse, decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH, the enzyme that converts dopamine (DA to norepinephrine (NE in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh -/- mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/- and Dbh -/- mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh -/- mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/- mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/- mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh -/- mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor enhance qualitatively different cocaine-induced behaviors.

Chronic Inhibition of Dopamine β-Hydroxylase Facilitates Behavioral Responses to Cocaine in Mice

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Gaval-Cruz, Meriem; Liles, Larry Cameron; Iuvone, Paul Michael; Weinshenker, David

2012-01-01

The anti-alcoholism medication, disulfiram (Antabuse), decreases cocaine use in humans regardless of concurrent alcohol consumption and facilitates cocaine sensitization in rats, but the functional targets are unknown. Disulfiram inhibits dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. The goal of this study was to test the effects of chronic genetic or pharmacological DBH inhibition on behavioral responses to cocaine using DBH knockout (Dbh −/−) mice, disulfiram, and the selective DBH inhibitor, nepicastat. Locomotor activity was measured in control (Dbh +/−) and Dbh −/− mice during a 5 day regimen of saline+saline, disulfiram+saline, nepicastat+saline, saline+cocaine, disulfiram+cocaine, or nepicastat+cocaine. After a 10 day withdrawal period, all groups were administered cocaine, and locomotor activity and stereotypy were measured. Drug-naïve Dbh −/− mice were hypersensitive to cocaine-induced locomotion and resembled cocaine-sensitized Dbh +/− mice. Chronic disulfiram administration facilitated cocaine-induced locomotion in some mice and induced stereotypy in others during the development of sensitization, while cocaine-induced stereotypy was evident in all nepicastat-treated mice. Cocaine-induced stereotypy was profoundly increased in the disulfiram+cocaine, nepicastat+cocaine, and nepicastat+saline groups upon cocaine challenge after withdrawal in Dbh +/− mice. Disulfiram or nepicastat treatment had no effect on behavioral responses to cocaine in Dbh −/− mice. These results demonstrate that chronic DBH inhibition facilitates behavioral responses to cocaine, although different methods of inhibition (genetic vs. non-selective inhibitor vs. selective inhibitor) enhance qualitatively different cocaine-induced behaviors. PMID:23209785

Body Temperature Measurements for Metabolic Phenotyping in Mice

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Meyer, Carola W.; Ootsuka, Youichirou; Romanovsky, Andrej A.

2017-01-01

Endothermic organisms rely on tightly balanced energy budgets to maintain a regulated body temperature and body mass. Metabolic phenotyping of mice, therefore, often includes the recording of body temperature. Thermometry in mice is conducted at various sites, using various devices and measurement practices, ranging from single-time probing to continuous temperature imaging. Whilst there is broad agreement that body temperature data is of value, procedural considerations of body temperature measurements in the context of metabolic phenotyping are missing. Here, we provide an overview of the various methods currently available for gathering body temperature data from mice. We explore the scope and limitations of thermometry in mice, with the hope of assisting researchers in the selection of appropriate approaches, and conditions, for comprehensive mouse phenotypic analyses. PMID:28824441

Mapping of a gene responsible for dermatitis in NOA (Naruto Research Institute Otsuka Atrichia) mice, an animal model of allergic dermatitis.

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Natori, K; Tamari, M; Watanabe, O; Onouchi, Y; Shiomoto, Y; Kubo, S; Nakamura, Y

1999-01-01

The NOA (Naruto Research Institute Otsuka Atrichia) mouse is an animal model of allergic or atopic dermatitis, a condition characterized by ulcerative skin lesions with accumulation of mast cells and increased serum IgE. These features of the murine disease closely resemble human atopy and atopic disorders. We performed linkage analysis in NOA back-cross progeny, as a step toward identifying and isolating a gene responsible for the NOA phenotype. We crossed NOA mice with five other murine strains (C57BL/6J, IQI, C3H/HeJ, DBA/2J, and BALB/cByJ) and then bred back-cross animals. Using microsatellite markers, we scanned the entire genomes of 559 N2 offspring from the five parental strains. Linkage analysis revealed a significant association between ulcerative skin lesions and markers on murine chromosome 14. Statistical analysis indicated that the critical region was assigned to the vicinity of D14Mit236 and D14Mit160.

Somatostatin receptor 1 and 5 double knockout mice mimic neurochemical changes of Huntington's disease transgenic mice.

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Padmesh S Rajput

Full Text Available Selective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD. However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5.To delineate subtype selective biological responses we have here investigated changes in SSTR1 and 5 double knockout mice brain and compared with HD transgenic mouse model (R6/2. Our study revealed significant loss of dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32 and comparable changes in SST, N-methyl-D-aspartic acid receptors subtypes, calbindin and brain nitric oxide synthase expression as well as in key signaling proteins including calpain, phospho-extracellular-signal-regulated kinases1/2, synapsin-IIa, protein kinase C-α and calcineurin in SSTR1/5(-/- and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice.This is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntington's disease.

Effect of Jiangzhi tablet on gastrointestinal propulsive function in mice

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Wang, Xiangrong; Geng, Xiuli; Zhao, Jingsheng; Fan, Lili; Zhang, Zhengchen

2018-04-01

This paper aims to study the effect of lipid-lowering tablets on gastric emptying and small intestinal propulsion in mice. Mice were randomly divided into control group, Digestant Pill group, Jiangzhi tablet group, middle dose and small dose, the mice gastric emptying phenolsulfonphthalein, gastric residual rate of phenol red indicator to evaluate the gastric emptying rate, residual rate of detection in mouse stomach; small intestine propulsion and selection of carbon ink as the experimental index. Effects were observed to promote the function of normal mice gastric emptying and intestine. The gastric emptying and small intestinal motor function of normal mice were all promoted by each administration group, and the effect was most obvious in small dose group. The effect of reducing blood lipid on gastrointestinal motility of mice ware obviously enhanced.

The cellular cancer resistance of the SR/CR mouse

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Koch, Janne; Hau, Jann; Jensen, Henrik Elvang

2012-01-01

The SR/CR mouse phenotype, first described in 1999 in BALB/c and later bred into C57BL/6 mice, is resistant to cancer formation following high doses of cancer cells administered intraperitoneally. The tumor cell targeting and destruction mechanisms have not been identified. By fluorescence-activa...... controls. Importantly, this differentially regulated immune response of SR/CR mice could not be found in response to challenge with the lymphoma cell line EL-4....

Do Superoxide Dismutase (SOD) and Catalase (CAT) protect Cells from DNA Damage Induced by Active Arsenicals?

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Superoxide dismutase (SOD) catalyzes the conversion of superoxide to hydrogen peroxide, which can be converted to water and oxygen through the action of catalase. Heterozygous mice of strain B6: 129S7-SodltmlLeb/J were obtained from Jackson Laboratories and bred to produce offspr...

International Journal of Basic, Applied and Innovative Research ...

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Uwaifoh

2012-12-31

Dec 31, 2012 ... This study therefore, evaluates the effect of Chloroquine on pain in mice. MATERIALS AND METHODS. Experimental animal/ groups: The animals were bred in the animal house, department Pharmacology, University. Calabar. The animals were kept in the animal house of department of Human Physiology ...

Effect of reproductive tract scoring on reproductive efficiency in beef heifers bred by timed insemination and natural service versus only natural service.

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Gutierrez, K; Kasimanickam, R; Tibary, A; Gay, J M; Kastelic, J P; Hall, J B; Whittier, W D

2014-04-15

in both groups became pregnant earlier in the breeding season compared with heifers with lower RTS (log-rank statistics: P < 0.0001). Heifers in the AI-NS group become pregnant at a faster rate compared with those in the NSO group (P < 0.01). The BS-PR for heifers with RTS 5 was different between AI-NS and NSO groups (P < 0.0001). In conclusion, the RTS influenced both the number of beef heifers that became pregnant during the breeding season and the time at which they become pregnant. Furthermore, irrespective of RTS, heifers bred by NSO required more time to become pregnant than their counterparts in herds that used timed AI. The application of RTS system is reliant on the use of synchronization protocol. The application of RTS for selection may plausibly remove precocious females with lower RTS. On the contrary, application of RTS would help select heifers that will become pregnant earlier in breeding season. Copyright © 2014 Elsevier Inc. All rights reserved.

Skewed X-inactivation in cloned mice

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Senda, Sho; Wakayama, Teruhiko; Yamazaki, Yukiko; Ohgane, Jun; Hattori, Naka; Tanaka, Satoshi; Yanagimachi, Ryuzo; Shiota, Kunio

2004-01-01

In female mammals, dosage compensation for X-linked genes is accomplished by inactivation of one of two X chromosomes. The X-inactivation ratio (a percentage of the cells with inactivated maternal X chromosomes in the whole cells) is skewed as a consequence of various genetic mutations, and has been observed in a number of X-linked disorders. We previously reported that phenotypically normal full-term cloned mouse fetuses had loci with inappropriate DNA methylation. Thus, cloned mice are excellent models to study abnormal epigenetic events in mammalian development. In the present study, we analyzed X-inactivation ratios in adult female cloned mice (B6C3F1). Kidneys of eight naturally produced controls and 11 cloned mice were analyzed. Although variations in X-inactivation ratio among the mice were observed in both groups, the distributions were significantly different (Ansary-Bradley test, P < 0.01). In particular, 2 of 11 cloned mice showed skewed X-inactivation ratios (19.2% and 86.8%). Similarly, in intestine, 1 of 10 cloned mice had a skewed ratio (75.7%). Skewed X-inactivation was observed to various degrees in different tissues of different individuals, suggesting that skewed X-inactivation in cloned mice is the result of secondary cell selection in combination with stochastic distortion of primary choice. The present study is the first demonstration that skewed X-inactivation occurs in cloned animals. This finding is important for understanding both nuclear transfer technology and etiology of X-linked disorders

Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons.

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Barik, Jacques; Marti, Fabio; Morel, Carole; Fernandez, Sebastian P; Lanteri, Christophe; Godeheu, Gérard; Tassin, Jean-Pol; Mombereau, Cédric; Faure, Philippe; Tronche, François

2013-01-18

Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system. We bred mice with selective inactivation of the gene encoding the glucocorticoid receptor (GR) along the DA pathway, and exposed them to repeated aggressions. GR in dopaminoceptive but not DA-releasing neurons specifically promoted social aversion as well as dopaminergic neurochemical and electrophysiological neuroadaptations. Anxiety and fear memories remained unaffected. Acute inhibition of the activity of DA-releasing neurons fully restored social interaction in socially defeated wild-type mice. Our data suggest a GR-dependent neuronal dichotomy for the regulation of emotional and social behaviors, and clearly implicate GR as a link between stress resiliency and dopaminergic tone.

Pregnancy in obese mice protects selectively against visceral adiposity and is associated with increased adipocyte estrogen signalling.

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Silvia M A Pedroni

Full Text Available Maternal obesity is linked with increased adverse pregnancy outcomes for both mother and child. The metabolic impact of excessive fat within the context of pregnancy is not fully understood. We used a mouse model of high fat (HF feeding to induce maternal obesity to identify adipose tissue-mediated mechanisms driving metabolic dysfunction in pregnant and non-pregnant obese mice. As expected, chronic HF-feeding for 12 weeks preceding pregnancy increased peripheral (subcutaneous and visceral (mesenteric fat mass. However, unexpectedly at late gestation (E18.5 HF-fed mice exhibited a remarkable normalization of visceral but not peripheral adiposity, with a 53% reduction in non-pregnant visceral fat mass expressed as a proportion of body weight (P<0.001. In contrast, in control animals, pregnancy had no effect on visceral fat mass proportion. Obesity exaggerated glucose intolerance at mid-pregnancy (E14.5. However by E18.5, there were no differences, in glucose tolerance between obese and control mice. Transcriptomic analysis of visceral fat from HF-fed dams at E18.5 revealed reduced expression of genes involved in de novo lipogenesis (diacylglycerol O-acyltransferase 2--Dgat2 and inflammation (chemokine C-C motif ligand 20--Ccl2 and upregulation of estrogen receptor α (ERα compared to HF non pregnant. Attenuation of adipose inflammation was functionally confirmed by a 45% reduction of CD11b+CD11c+ adipose tissue macrophages (expressed as a proportion of all stromal vascular fraction cells in HF pregnant compared to HF non pregnant animals (P<0.001. An ERα selective agonist suppressed both de novo lipogenesis and expression of lipogenic genes in adipocytes in vitro. These data show that, in a HF model of maternal obesity, late gestation is associated with amelioration of visceral fat hypertrophy, inflammation and glucose intolerance, and suggest that these effects are mediated in part by elevated visceral adipocyte ERα signaling.

Mu-opioid receptor inhibition decreases voluntary wheel running in a dopamine-dependent manner in rats bred for high voluntary running.

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Ruegsegger, Gregory N; Brown, Jacob D; Kovarik, M Cathleen; Miller, Dennis K; Booth, Frank W

2016-12-17

The mesolimbic dopamine and opioid systems are postulated to influence the central control of physical activity motivation. We utilized selectively bred rats for high (HVR) or low (LVR) voluntary running behavior to examine (1) inherent differences in mu-opioid receptor (Oprm1) expression and function in the nucleus accumbens (NAc), (2) if dopamine-related mRNAs, wheel-running, and food intake are differently influenced by intraperitoneal (i.p.) naltrexone injection in HVR and LVR rats, and (3) if dopamine is required for naltrexone-induced changes in running and feeding behavior in HVR rats. Oprm1 mRNA and protein expression were greater in the NAc of HVR rats, and application of the Oprm1 agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) to dissociated NAc neurons produced greater depolarizing responses in neurons from HVR versus LVR rats. Naltrexone injection dose-dependently decreased wheel running and food intake in HVR, but not LVR, rats. Naltrexone (20mg/kg) decreased tyrosine hydroxylase mRNA in the ventral tegmental area and Fos and Drd5 mRNA in NAc shell of HVR, but not LVR, rats. Additionally, lesion of dopaminergic neurons in the NAc with 6-hydroxydopamine (6-OHDA) ablated the decrease in running, but not food intake, in HVR rats following i.p. naltrexone administration. Collectively, these data suggest the higher levels of running observed in HVR rats, compared to LVR rats, are mediated, in part, by increased mesolimbic opioidergic signaling that requires downstream dopaminergic activity to influence voluntary running, but not food intake. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Preserved dopaminergic homeostasis and dopamine-related behaviour in hemizygous TH-Cre mice.

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Runegaard, Annika H; Jensen, Kathrine L; Fitzpatrick, Ciarán M; Dencker, Ditte; Weikop, Pia; Gether, Ulrik; Rickhag, Mattias

2017-01-01

Cre-driver mouse lines have been extensively used as genetic tools to target and manipulate genetically defined neuronal populations by expression of Cre recombinase under selected gene promoters. This approach has greatly advanced neuroscience but interpretations are hampered by the fact that most Cre-driver lines have not been thoroughly characterized. Thus, a phenotypic characterization is of major importance to reveal potential aberrant phenotypes prior to implementation and usage to selectively inactivate or induce transgene expression. Here, we present a biochemical and behavioural assessment of the dopaminergic system in hemizygous tyrosine hydroxylase (TH)-Cre mice in comparison to wild-type (WT) controls. Our data show that TH-Cre mice display preserved dopaminergic homeostasis with unaltered levels of TH and dopamine as well as unaffected dopamine turnover in striatum. TH-Cre mice also show preserved dopamine transporter expression and function supporting sustained dopaminergic transmission. In addition, TH-Cre mice demonstrate normal responses in basic behavioural paradigms related to dopaminergic signalling including locomotor activity, reward preference and anxiolytic behaviour. Our results suggest that TH-Cre mice represent a valid tool to study the dopamine system, though careful characterization must always be performed to prevent false interpretations following Cre-dependent transgene expression and manipulation of selected neuronal pathways. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Metabolic responses to high-fat diets rich in n-3 or n-6 long-chain polyunsaturated fatty acids in mice selected for either high body weight or leanness explain different health outcomes

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Nuernberg Karin

2011-08-01

Full Text Available Abstract Background Increasing evidence suggests that diets high in polyunsaturated fatty acids (PUFA confer health benefits by improving insulin sensitivity and lipid metabolism in liver, muscle and adipose tissue. Methods The present study investigates metabolic responses in two different lines of mice either selected for high body weight (DU6 leading to rapid obesity development, or selected for high treadmill performance (DUhTP leading to a lean phenotype. At 29 days of age the mice were fed standard chow (7.2% fat, 25.7% protein, or a high-fat diet rich in n-3 PUFA (n-3 HFD, 27.7% fat, 19% protein or a high-fat diet rich in n-6 PUFA (n-6 HFD, 27.7% fat, 18.6% protein for 8 weeks. The aim of the study was to determine the effect of these PUFA-rich high-fat diets on the fatty acid profile and on the protein expression of key components of insulin signalling pathways. Results Plasma concentrations of leptin and insulin were higher in DU6 in comparison with DUhTP mice. The high-fat diets stimulated a strong increase in leptin levels and body fat only in DU6 mice. Muscle and liver fatty acid composition were clearly changed by dietary lipid composition. In both lines of mice n-3 HFD feeding significantly reduced the hepatic insulin receptor β protein concentration which may explain decreased insulin action in liver. In contrast, protein kinase C ζ expression increased strongly in abdominal fat of n-3 HFD fed DUhTP mice, indicating enhanced insulin sensitivity in adipose tissue. Conclusions A diet high in n-3 PUFA may facilitate a shift from fuel deposition in liver to fuel storage as fat in adipose tissue in mice. Tissue specific changes in insulin sensitivity may describe, at least in part, the health improving properties of dietary n-3 PUFA. However, important genotype-diet interactions may explain why such diets have little effect in some population groups.

Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1.

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Ruud, Johan; Nilsson, Anna; Engström Ruud, Linda; Wang, Wenhua; Nilsberth, Camilla; Iresjö, Britt-Marie; Lundholm, Kent; Engblom, David; Blomqvist, Anders

2013-03-01

It is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexia-cachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing mice was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COX-inhibitors restored appetite and prevented body weight loss without affecting tumor size. Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE(2) levels in plasma - a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE(2)-levels in the cerebrospinal fluid. Neutralization of plasma PGE(2) with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1) affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP(4) receptors selectively in the nervous system developed anorexia. These observations suggest that COX-enzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE(2) and neuronal EP(4) signaling. Copyright © 2013 Elsevier Inc. All rights reserved.

Zinc metabolism in genetically obese (ob/ob) mice

International Nuclear Information System (INIS)

Kennedy, M.L.; Failla, M.L.

1987-01-01

Recent reports indicate that the concentrations and total amounts of several essential trace metals in various tissues of genetically obese rodents differ markedly from those in lean controls. In the present studies the absorption, retention and tissue distribution of zinc and constitutive levels of zinc-metallothionein (Zn-MT) in selected tissues were compared in obese (ob/ob) and lean (+/?) C57BL/6J mice. When 5-, 10- and 22-wk-old mice were administered 1.2 mumol 65 Zn by stomach tube the apparent absorption of 65 Zn by obese mice was 1.5, 2.2 and 3.9 times higher, respectively, than that in age-matched lean mice. Retention of orally administered 65 Zn after 96 h was also substantially higher in obese mice than in lean mice. To assess the possible influences of hyperphagia and intestinal hypertrophy on the enhanced apparent absorption of 65 Zn by obese mice food intake by an additional group of obese mice was restricted to that of age-matched lean controls. When actual absorption of zinc was determined according to the method of Heth and Hoekstra, groups of ad libitum--fed obese, pair-fed obese and lean mice absorbed 38, 32 and 18% of administered 65 Zn, respectively. In contrast, the rate of 65 Zn excretion 2-6 d after oral or subcutaneous administration of the metal was similar for obese and lean mice. Unrestricted and pair-fed obese mice had significantly lower percentages of carcass 65 Zn present in skin, muscle plus bone, spleen and testes and higher percentages present in liver, small intestine and adipose tissue than lean mice

Female preproenkephalin-knockout mice display altered emotional responses

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Ragnauth, A.; Schuller, A.; Morgan, M.; Chan, J.; Ogawa, S.; Pintar, J.; Bodnar, R. J.; Pfaff, D. W.

2001-01-01

The endogenous opioid system has been implicated in sexual behavior, palatable intake, fear, and anxiety. The present study examined whether ovariectomized female transgenic preproenkephalin-knockout (PPEKO) mice and their wild-type and heterozygous controls displayed alterations in fear and anxiety paradigms, sucrose intake, and lordotic behavior. To examine stability of responding, three squads of the genotypes were tested across seasons over a 20-month period. In a fear-conditioning paradigm, PPEKO mice significantly increased freezing to both fear and fear + shock stimuli relative to controls. In the open field, PPEKO mice spent significantly less time and traversed significantly less distance in the center of an open field than wild-type controls. Further, PPEKO mice spent significantly less time and tended to be less active on the light side of a dark–light chamber than controls, indicating that deletion of the enkephalin gene resulted in exaggerated responses to fear or anxiety-provoking environments. These selective deficits were observed consistently across testing squads spanning 20 months and different seasons. In contrast, PPEKO mice failed to differ from corresponding controls in sucrose, chow, or water intake across a range (0.0001–20%) of sucrose concentrations and failed to differ in either lordotic or female approach to male behaviors when primed with estradiol and progesterone, thereby arguing strongly for the selectivity of a fear and anxiety deficit which was not caused by generalized and nonspecific debilitation. These transgenic data strongly suggest that opioids, and particularly enkephalin gene products, are acting naturally to inhibit fear and anxiety. PMID:11172058

Kinetics of selective deposition of Apo SAA2 during development of amyloidosis in mice

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Meek, R.L.; Benditt, E.P.; Hoffman, J.S.

1986-01-01

The major murine serum amyloid proteins (apoSAA 1 , apoSAA 2 ) have been identified, of which only one (apoSAA 2 ) shares amino acid sequence identity with tissue protein AA. To examine the mechanism of this apparent isotypespecific amyloid protein deposition, we have studied apoSAA metabolism at the levels of gene expression and plasma content during amyloidogenesis. In CBA mice, daily intraperitoneal casein administration resulted in a linear increase in splenic amyloid content, beginning within 10 days and reaching approximately 30% of the organ volume at 20 days. Hepatic apoSAA mRNA content, estimated by in vitro translation, was highest at day 1 (3% of total mRNA) and declined thereafter (to 1%, day 20). The relative content of apoSAA 2 mRNA compared with that of apoSAA 1 was unchanged throughout amyloid induction. Simultaneously, a 2-3 fold drop in total serum apoSAA levels was observed with, by contrast, a 10-fold reduction in the serum ratio of apoSAA 2 /apoSAA 1 . These results are consistent with the hypothesis that murine tissue protein AA accumulates by selective deposition of apoSAA 2 from the serum

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

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

2008-01-15

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

Reduced metabolic disease risk profile by voluntary wheel running accompanying juvenile Western diet in rats bred for high and low voluntary exercise.

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Ruegsegger, Gregory N; Toedebusch, Ryan G; Braselton, Joshua F; Roberts, Christian K; Booth, Frank W

2015-12-01

Metabolic disease risk is influenced by genetics and modifiable factors, such as physical activity and diet. Beginning at 6 weeks of age, rats selectively bred for high (HVR) versus low voluntary running distance (LVR) behaviors were housed in a complex design with or without voluntary running wheels being fed either a standard or Western (WD, 42% kcal from fat and added sucrose) diet for 8 weeks. Upon intervention completion, percent body fat, leptin, insulin, and mediobasal hypothalamic mRNAs related to appetite control were assessed. Wheel access led to differences in body weight, food intake, and serum leptin and insulin. Intriguingly, percent body fat, leptin, and insulin did not differ between HVR and LVR lines in response to the two levels of voluntary running, regardless of diet, after the 8 wk. experiment despite HVR eating more calories than LVR regardless of diet and voluntarily running 5-7 times further in wheels than LVR. In response to WD, we observed increases in Cart and Lepr mediobasal hypothalamic mRNA in HVR, but no differences in LVR. Npy mRNA was intrinsically greater in LVR than HVR, while wheel access led to greater Pomc and Cart mRNA in LVR versus HVR. These data suggest that despite greater consumption of WD, HVR animals respond similarly to WD as LVR as a result, in part, of their increased wheel running behavior. Furthermore, high physical activity in HVR may offset the deleterious effects of a WD on adiposity despite greater energy intake in this group. Copyright © 2015 Elsevier Inc. All rights reserved.

PSAPP mice exhibit regionally selective reductions in gliosis and plaque deposition in response to S100B ablation

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Young Keith A

2010-11-01

Full Text Available Abstract Background Numerous studies have reported that increased expression of S100B, an intracellular Ca2+ receptor protein and secreted neuropeptide, exacerbates Alzheimer's disease (AD pathology. However, the ability of S100B inhibitors to prevent/reverse AD histopathology remains controversial. This study examines the effect of S100B ablation on in vivo plaque load, gliosis and dystrophic neurons. Methods Because S100B-specific inhibitors are not available, genetic ablation was used to inhibit S100B function in the PSAPP AD mouse model. The PSAPP/S100B-/- line was generated by crossing PSAPP double transgenic males with S100B-/- females and maintained as PSAPP/S100B+/- crosses. Congo red staining was used to quantify plaque load, plaque number and plaque size in 6 month old PSAPP and PSAPP/S100B-/- littermates. The microglial marker Iba1 and astrocytic marker glial fibrillary acidic protein (GFAP were used to quantify gliosis. Dystrophic neurons were detected with the phospho-tau antibody AT8. S100B immunohistochemistry was used to assess the spatial distribution of S100B in the PSAPP line. Results PSAPP/S100B-/- mice exhibited a regionally selective decrease in cortical but not hippocampal plaque load when compared to PSAPP littermates. This regionally selective reduction in plaque load was accompanied by decreases in plaque number, GFAP-positive astrocytes, Iba1-positive microglia and phospho-tau positive dystrophic neurons. These effects were not attributable to regional variability in the distribution of S100B. Hippocampal and cortical S100B immunoreactivity in PSAPP mice was associated with plaques and co-localized with astrocytes and microglia. Conclusions Collectively, these data support S100B inhibition as a novel strategy for reducing cortical plaque load, gliosis and neuronal dysfunction in AD and suggest that both extracellular as well as intracellular S100B contribute to AD histopathology.

Neuropeptide AF induces anxiety-like and antidepressant-like behavior in mice.

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Palotai, Miklós; Telegdy, Gyula; Tanaka, Masaru; Bagosi, Zsolt; Jászberényi, Miklós

2014-11-01

Little is known about the action of neuropeptide AF (NPAF) on anxiety and depression. Only our previous study provides evidence that NPAF induces anxiety-like behavior in rats. Therefore, the aim of the present study was to investigate the action of NPAF on depression-like behavior and the underlying neurotransmissions in mice. In order to determine whether there are species differences between rats and mice, we have investigated the action of NPAF on anxiety-like behavior in mice as well. A modified forced swimming test (mFST) and an elevated plus maze test (EPMT) were used to investigate the depression and anxiety-related behaviors, respectively. Mice were treated with NPAF 30min prior to the tests. In the mFST, the animals were pretreated with a non-selective muscarinic acetylcholine receptor antagonist, atropine, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a D2/D3/D4 dopamine receptor antagonist, haloperidol, a α1/α2β-adrenergic receptor antagonist, prazosin or a non-selective β-adrenergic receptor antagonist, propranolol 30min before the NPAF administration. In the mFST, NPAF decreased the immobility time and increased the climbing and swimming times. This action was reversed completely by methysergide and partially by atropine, whereas cyproheptadine, haloperidol, prazosin and propranolol were ineffective. In the EPMT, NPAF decreased the time spent in the arms (open/open+closed). Our results demonstrate that NPAF induces anti-depressant-like behavior in mice, which is mediated, at least in part, through 5HT2-serotonergic and muscarinic cholinergic neurotransmissions. In addition, the NPAF-induced anxiety is species-independent, since it develops also in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

Probucol selectively increases oxidation of atherogenic lipoproteins in cholesterol-fed mice and in Watanabe heritable hyperlipidemic rabbits

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Lauridsen, S.T.; Mortensen, Alicja

1999-01-01

The anti-atherogenic and cholesterol-lowering drug probucol (0.5-1%) or quercetin (1%), a natural antioxidant, was given to cholesterol-fed (1.5%) mice for a period of 6 weeks and to Watanabe heritable hyperlipidemic (WHHL) rabbits for a period of 8 weeks to investigate the oxidative changes.......001) and cholesterol-fed mice (579.7 +/- 47.3 nmol/g vs. 408.1 +/- 85.8 nmol/g, P mice: P ... and thereby leads to a decrease in cholesterol levels....

Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit.

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Gary W Arendash

Full Text Available Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF

Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area.

Science.gov (United States)

Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

2013-04-15

Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. Copyright © 2013 Elsevier B.V. All rights reserved.

Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice

Directory of Open Access Journals (Sweden)

Tomishima Yoshiro

2013-01-01

Full Text Available Abstract Background Overdosed acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP causes severe liver injury. We examined the effects of ozagrel, a selective thromboxane A2 (TXA2 synthase inhibitor, on liver injury induced by APAP overdose in mice. Methods Hepatotoxicity was induced to ICR male mice by an intraperitoneal injection with APAP (330 mg/kg. The effects of ozagrel (200 mg/kg treatment 30 min after the APAP injection were evaluated with mortality, serum alanine aminotransferase (ALT levels and hepatic changes, including histopathology, DNA fragmentation, mRNA expression and total glutathione contents. The impact of ozagrel (0.001-1 mg/mL on cytochrome P450 2E1 (CYP2E1 activity in mouse hepatic microsome was examined. RLC-16 cells, a rat hepatocytes cell line, were exposed to 0.25 mM N-acetyl-p-benzoquinone imine (NAPQI, a hepatotoxic metabolite of APAP. In this model, the cytoprotective effects of ozagrel (1–100 muM were evaluated by the WST-1 cell viability assay. Results Ozagel treatment significantly attenuated higher mortality, elevated serum alanine aminotransferase levels, excessive hepatic centrilobular necrosis, hemorrhaging and DNA fragmentation, as well as increase in plasma 2,3-dinor thromboxane B2 levels induced by APAP injection. Ozagrel also inhibited the hepatic expression of cell death-related mRNAs induced by APAP, such as jun oncogene, FBJ osteosarcoma oncogene (fos and C/EBP homologous protein (chop, but did not suppress B-cell lymphoma 2-like protein11 (bim expression and hepatic total glutathione depletion. These results show ozagrel can inhibit not all hepatic changes but can reduce the hepatic necrosis. Ozagrel had little impact on CYP2E1 activity involving the NAPQI production. In addition, ozagrel significantly attenuated cell injury induced by NAPQI in RLC-16. Conclusions We demonstrate that the TXA2 synthase inhibitor, ozagrel, dramatically alleviates liver injury induced by APAP in mice, and suggest

Maternal consumption of canola oil suppressed mammary gland tumorigenesis in C3(1) TAg mice offspring

International Nuclear Information System (INIS)

Ion, Gabriela; Akinsete, Juliana A; Hardman, W Elaine

2010-01-01

Maternal consumption of a diet high in omega 6 polyunsaturated fats (n-6 PUFA) has been shown to increase risk whereas a diet high in omega 3 polyunsaturated fats (n-3 PUFA) from fish oil has been shown to decrease risk for mammary gland cancer in female offspring of rats. The aim of this study was to determine whether increasing n-3 PUFA and reducing n-6 PUFA by using canola oil instead of corn oil in the maternal diet might reduce the risk for breast cancer in female offspring. Female SV 129 mice were divided into two groups and placed on diets containing either 10% w/w corn oil (which is 50% n-6 PUFA, control diet) or 10% w/w canola oil (which is 20% n-6 PUFA, 10% n-3 PUFA, test diet). After two weeks on the diets the females were bred with homozygous C3(1) TAg transgenic mice. Mother mice consumed the assigned diet throughout gestation and nursing of the offspring. After weaning, all female offspring were maintained on the control diet. Compared to offspring of mothers fed the corn oil diet (CO/CO group), offspring of mothers fed the canola oil diet (CA/CO group) had significantly fewer mammary glands with tumors throughout the experiment. At 130 days of age, the CA/CO group had significantly fewer tumors per mouse (multiplicity); the tumor incidence (fraction of mice with any tumor) and the total tumor weight (per mouse that developed tumor) was less than one half that of the CO/CO group. At 170 days of age, the total tumor weight per mouse was significantly less in the CA/CO group and if a tumor developed the rate of tumor growth rate was half that of CO/CO group. These results indicate that maternal consumption of canola oil was associated with delayed appearance of mammary gland tumors and slowed growth of the tumors that developed. Substituting canola oil for corn oil is an easy dietary change for people to make; such a change to the maternal diet may decrease risk for breast cancer in the daughter

Treatment of Experimental Acute Radiation Disease in Mice with Probiotics, Quinolones, and General Gnotobiological Isolation

National Research Council Canada - National Science Library

Korschunov, Valerji

1998-01-01

...) on intestinal microflora, translocation, and mortality was studied in mice treated with 7.0 Gy radiation. Lactobacilli and bifidobacteria, selected by in vitro and in vivo methods, increased survival parameters of the mice...

Recreational fishing selectively captures individuals with the highest fitness potential.

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Sutter, David A H; Suski, Cory D; Philipp, David P; Klefoth, Thomas; Wahl, David H; Kersten, Petra; Cooke, Steven J; Arlinghaus, Robert

2012-12-18

Fisheries-induced evolution and its impact on the productivity of exploited fish stocks remains a highly contested research topic in applied fish evolution and fisheries science. Although many quantitative models assume that larger, more fecund fish are preferentially removed by fishing, there is no empirical evidence describing the relationship between vulnerability to capture and individual reproductive fitness in the wild. Using males from two lines of largemouth bass (Micropterus salmoides) selectively bred over three generations for either high (HV) or low (LV) vulnerability to angling as a model system, we show that the trait "vulnerability to angling" positively correlates with aggression, intensity of parental care, and reproductive fitness. The difference in reproductive fitness between HV and LV fish was particularly evident among larger males, which are also the preferred mating partners of females. Our study constitutes experimental evidence that recreational angling selectively captures individuals with the highest potential for reproductive fitness. Our study further suggests that selective removal of the fittest individuals likely occurs in many fisheries that target species engaged in parental care. As a result, depending on the ecological context, angling-induced selection may have negative consequences for recruitment within wild populations of largemouth bass and possibly other exploited species in which behavioral patterns that determine fitness, such as aggression or parental care, also affect their vulnerability to fishing gear.

In vivo cytogenetic effects of 2-trans hexenal on somatic and germ ...

African Journals Online (AJOL)

The in vivo cytogenetic effects of 2-trans hexenal were evaluated by investigating chromosomal aberrations and sperm head abnormalities in the bone marrow cells of laboratory bred Swiss albino mice. Single intraperitoneal injections of 8, 16 or 32 ìl per kg bodyweight resulted in dose-dependent decreases in the mitotic ...

Anti-inflammatory effect of a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor via the stimulation of heme oxygenase-1 in LPS-activated mice and J774.1 murine macrophages

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Sung Bum Park

2016-08-01

Full Text Available 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1 converts inactive cortisone to the active cortisol. 11β-HSD1 may be involved in the resolution of inflammation. In the present study, we investigate the anti-inflammatory effects of 2-(3-benzoyl-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344, a selective 11β-HSD1 inhibitor, in lipopolysaccharide (LPS-activated C57BL/6J mice and macrophages. LPS increased 11β-HSD1 activity and expression in macrophages, which was inhibited by KR-66344. In addition, KR-66344 increased survival rate in LPS treated C57BL/6J mice. HO-1 mRNA expression level was increased by KR-66344, and this effect was reversed by the HO competitive inhibitor, ZnPP, in macrophages. Moreover, ZnPP reversed the suppression of ROS formation and cell death induced by KR-66344. ZnPP also suppressed animal survival rate in LPS plus KR-66344 treated C57BL/6J mice. In the spleen of LPS-treated mice, KR-66344 prevented cell death via suppression of inflammation, followed by inhibition of ROS, iNOS and COX-2 expression. Furthermore, LPS increased NFκB-p65 and MAPK phosphorylation, and these effects were abolished by pretreatment with KR-66344. Taken together, KR-66344 protects against LPS-induced animal death and spleen injury by inhibition of inflammation via induction of HO-1 and inhibition of 11β-HSD1 activity. Thus, we concluded that the selective 11β-HSD1 inhibitor may provide a novel strategy in the prevention/treatment of inflammatory disorders in patients.

Behavioural changes in mice exposed to low level microwave fields

International Nuclear Information System (INIS)

Goiceanu, C.; Gradinaru, F.; Danulescu, R.; Balaceanu, G.; Sandu, D. D.; Avadanei, O. G.

2001-01-01

The aim of our study is to point out some changes in mice behaviour due possibly to exposure to low-level microwave fields. Animals spontaneous behaviour were monitored and the exploring behaviour and motor activity were assessed. Ten selected Swiss male mice were exposed to low-level microwave fields of about 1 mW/cm 2 power density for a relatively long period of time (13 weeks), comparing to their lifetime. The exposure system consists in a transverse electromagnetic (TEM) Cell. A control lot of ten Swiss male mice was used. All twenty mice were selected to be of same age and of 202 g initial body weight. Each animal was placed in his own holder. The behaviour of the animals, from both exposed and control lots, was assessed by using a battery of three behavioural tests. The test sessions were performed every two weeks. During exposure period it was recorded a progressive but moderate loss of motor activity for both exposed and controls, probably due to weight gain and aging. Concerning exploratory activity there is a significant difference between control and exposed animals. Control mice had approximately constant performances in time. On the other hand exposed mice showed a progressive decrease in time of their exploratory ability. Motor activity of exposed animals does not seem to be affected by microwave exposure, in spite of moderate loss in time of motor activity in both lots, as long as it was recorded a quite similar evolution. The difference in performances of exposed and controls concerning exploratory activity seem to emphasise an effect of long-term low-level microwave exposure. The progressive loss in time of exploratory activity of exposed mice, in contrast with controls, could be due to the interference of microwaves with central nervous activity. (authors)

The effects of a selective inhibitor of c-Fos/activator protein-1 on endotoxin-induced acute kidney injury in mice

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Miyazaki Hiroyuki

2012-11-01

Full Text Available Abstract Background Sepsis has been identified as the most common cause of acute kidney injury (AKI in intensive care units. Lipopolysaccharide (LPS induces the production of several proinflammatory cytokines including tumor necrosis factor (TNF-alpha, a major pathogenetic factor in septic AKI. c-Fos/activator protein (AP-1 controls the expression of these cytokines by binding directly to AP-1 motifs in the cytokine promoter regions. T-5224 is a new drug developed by computer-aided drug design that selectively inhibits c-Fos/AP-1 binding to DNA. In this study, we tested whether T-5224 has a potential inhibitory effect against LPS-induced AKI, by suppressing the TNF-alpha inflammatory response and other downstream effectors. Methods To test this hypothesis, male C57BL/6 mice at 7 weeks old were divided into three groups (control, LPS and T-5224 groups. Mice in the control group received saline intraperitoneally and polyvinylpyrrolidone solution orally. Mice in the LPS group were injected intraperitoneally with a 6 mg/kg dose of LPS and were given polyvinylpyrrolidone solution immediately after LPS injection. In the T-5224 group, mice were administered T-5224 orally at a dose of 300 mg/kg immediately after LPS injection. Serum concentrations of TNF-alpha, interleukin (IL-1beta, IL-6 and IL-10 were measured by ELISA. Moreover, the expression of intercellular adhesion molecule (ICAM-1 mRNA in kidney was examined by quantitative real-time RT-PCR. Finally, we evaluated renal histological changes. Results LPS injection induced high serum levels of TNF-alpha, IL-1beta and IL-6. However, the administration of T-5224 inhibited the LPS-induced increase in these cytokine levels. The serum levels of IL-10 in the LPS group and T-5224 group were markedly elevated compared with the control group. T-5224 also inhibited LPS-induced ICAM-1 mRNA expression. Furthermore histological studies supported an anti-inflammatory role of T-5224. Conclusions In endotoxin

Impaired receptivity and decidualization in DHEA-induced PCOS mice.

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Li, Shu-Yun; Song, Zhuo; Song, Min-Jie; Qin, Jia-Wen; Zhao, Meng-Long; Yang, Zeng-Ming

2016-12-07

Polycystic ovary syndrome (PCOS), a complex endocrine disorder, is a leading cause of female infertility. An obvious reason for infertility in PCOS women is anovulation. However, success rate with high quality embryos selected by assisted reproduction techniques in PCOS patients still remain low with a high rate of early clinical pregnancy loss, suggesting a problem in uterine receptivity. Using a dehydroepiandrosterone-induced mouse model of PCOS, some potential causes of decreased fertility in PCOS patients were explored. In our study, ovulation problem also causes sterility in PCOS mice. After blastocysts from normal mice are transferred into uterine lumen of pseudopregnant PCOS mice, the rate of embryo implantation was reduced. In PCOS mouse uteri, the implantation-related genes are also dysregulated. Additionally, artificial decidualization is severely impaired in PCOS mice. The serum estrogen level is significantly higher in PCOS mice than vehicle control. The high level of estrogen and potentially impaired LIF-STAT3 pathway may lead to embryo implantation failure in PCOS mice. Although there are many studies about effects of PCOS on endometrium, both embryo transfer and artificial decidualization are applied to exclude the effects from ovulation and embryos in our study.

Investigation of the Behavioral Characteristics of Dogs Purpose-Bred and Prepared to Perform Vapor Wake® Detection of Person-Borne Explosives

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Lucia Lazarowski

2018-03-01

significantly lower in the Washouts. Furthermore, differences between groups emerged as early as 3 and 6 months for select measures. We describe the behavioral characteristics targeted for selection in developing the VW phenotype and discuss the relative merit and degree of expression of those characteristics in the success of dogs bred and trained for the VW application.

Investigation of the Behavioral Characteristics of Dogs Purpose-Bred and Prepared to Perform Vapor Wake® Detection of Person-Borne Explosives.

Science.gov (United States)

Lazarowski, Lucia; Haney, Pamela Sue; Brock, Jeanne; Fischer, Terry; Rogers, Bart; Angle, Craig; Katz, Jeffrey S; Waggoner, L Paul

2018-01-01

lower in the Washouts. Furthermore, differences between groups emerged as early as 3 and 6 months for select measures. We describe the behavioral characteristics targeted for selection in developing the VW phenotype and discuss the relative merit and degree of expression of those characteristics in the success of dogs bred and trained for the VW application.

Ultrasonographic reproductive tract measures and pelvis measures as predictors of pregnancy failure and anestrus in restricted bred beef heifers.

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Holm, Dietmar E; Nielen, Mirjam; Jorritsma, Ruurd; Irons, Peter C; Thompson, Peter N

2016-02-01

Previous reports have shown that reproductive tract score (RTS) can predict reproduction outcomes in seasonally bred beef heifers, although the accuracy can vary. Some ultrasonographic measures of the female reproductive tract and pelvis area have also been associated with reproductive outcome in young heifers. The objectives of this study were to determine which transrectal ultrasound or pelvis measures taken at a single examination are independent predictors of reproductive failure and whether the RTS system can be optimized with this information. In this observational study, year-old beef heifers (n = 488) in 2 birth cohorts were followed from just before the first breeding until confirmation of pregnancy. A single pre-breeding examination included body condition score, RTS, ultrasound measures of the reproductive tract (length and diameter of the left and right ovaries, presence and diameter of a CL, largest follicle diameter and left uterus horn diameter) and transverse and vertical diameters of the pelvis. Additional farm records including dam parity, sire, birth weight and birth date, weaning weight, weaning date, prebreeding body weight, AI dates, and semen used were available. Breeding consisted of 50 days of AI, followed 5 to 7 days later by a 42-day bull breeding period. Pregnancy failure was defined as the failure to become pregnant after the AI and bull breeding periods, while anestrus was defined as the failure to be detected in estrus during the 50-day AI period. From the prebreeding data and farm records, independent predictors of pregnancy failure and anestrus were identified using stepwise reduction in multiple logistic regression models. Age at the onset of breeding was the only consistent independent predictor of pregnancy failure and anestrus in both cohorts of this study (P score, uterus horn diameter, absence of a CL, largest follicle of less than 13 mm, and pelvis area (PA) were the prebreeding examination variables that remained in

Selective breeding for infant rat separation-induced ultrasonic vocalizations: developmental precursors of passive and active coping styles.

Science.gov (United States)

Brunelli, Susan A; Hofer, Myron A

2007-09-04

Human depression and anxiety disorders show inherited biases across generations, as do antisocial disorders characterized by aggression. Each condition is preceded in children by behavioral inhibition or aggressive behavior, respectively, and both are characterized by separation anxiety disorders. In affected families, adults and children exhibit different forms of altered autonomic nervous system regulation and hypothalamic-pituitary-adrenal activity in response to stress. Because it is difficult to determine mechanisms accounting for these associations, animal studies are useful for studying the fundamental relationships between biological and behavioral traits. Pharmacologic and behavioral studies suggest that infant rat ultrasonic vocalizations (USV) are a measure of an early anxiety-like state related to separation anxiety. However, it was not known whether or not early ultrasound emissions in infant rats are markers for genetic risk for anxiety states later in life. To address these questions, we selectively bred two lines of rats based on high and low rates of USV to isolation at postnatal (P) 10 days of age. To our knowledge, ours is the only laboratory that has ever selectively bred on the basis of an infantile trait related to anxiety. The High and Low USV lines show two distinct sets of patterns of behavior, physiology and neurochemistry from infancy through adulthood. As adults High line rats demonstrate "anxious"/"depressed" phenotypes in behavior and autonomic nervous system (ANS) regulation to standard laboratory tests. In Lows, on the other hand, behavior and autonomic regulation are consistent with an "aggressive" phenotype. The High and Low USV lines are the first genetic animal models implicating long-term associations of contrasting "coping styles" with early attachment responses. They thus present a potentially powerful model for examining gene-environment interactions in the development of life-long affective regulation.

Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.

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Yuan, Xidi; Klein, Dennis; Kerscher, Susanne; West, Brian L; Weis, Joachim; Katona, Istvan; Martini, Rudolf

2018-05-09

Aging is known as a major risk factor for the structure and function of the nervous system. There is urgent need to overcome such deleterious effects of age-related neurodegeneration. Here we show that peripheral nerves of 24-month-old aging C57BL/6 mice of either sex show similar pathological alterations as nerves from aging human individuals, whereas 12-month-old adult mice lack such alterations. Specifically, nerve fibers showed demyelination, remyelination and axonal lesion. Moreover, in the aging mice, neuromuscular junctions showed features typical for dying-back neuropathies, as revealed by a decline of presynaptic markers, associated with α-bungarotoxin-positive postsynapses. In line with these observations were reduced muscle strengths. These alterations were accompanied by elevated numbers of endoneurial macrophages, partially comprising the features of phagocytosing macrophages. Comparable profiles of macrophages could be identified in peripheral nerve biopsies of aging persons. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by applying an orally administered CSF-1R specific kinase (c-FMS) inhibitor. The 6-month-lasting treatment started before development of degenerative changes at 18 months and reduced macrophage numbers in mice by ∼70%, without side effects. Strikingly, nerve structure was ameliorated and muscle strength preserved. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may pave the way for treating degeneration in the aging peripheral nervous system by targeting macrophages, leading to reduced weakness, improved mobility, and eventually increased quality of life in the elderly. SIGNIFICANCE STATEMENT Aging is a major risk factor for the structure and function of the nervous system. Here we show that peripheral nerves of 24-month-old aging mice show similar degenerative alterations as nerves from aging

Lactation curve of cross-bred buffalo under two production systems in the Amazonian region of Brazil

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A.C. Ribeiro Neto

2010-02-01

Full Text Available This study was conducted at the Agroforestry Research Center of EMBRAPA (CPAFRO, Rondônia, Brazil, to evaluate the lactation curve of crosss-bred buffalo [Murrah (M, Mediterranean (Me and Jafarabadi(J] under two production systems. Production system one (PS1 corresponded to the period of 1984 to 1998 where animals (4471 observation were milked once a day and received only pasture without supplementation. Production system two (PS2 corresponded to the period of 1999 to 2002 where animals (458 observations were milked twice daily with concentrate supplementation to pasture. Eight mathematical functions were used: Inverse Polynomial, Linear Hyperbolic, Incomplete Gamma, Logarithmic, Logarithmic Quadratic, Linear, Quadratic and Jenkins & Ferrel. Statistical analysis was conducted using PROC NLIN of SAS (2005. Results showed that for both production systems, Incomplete Gama was the best function to describe the lactation curve. Values of coefficient of determination, standard-deviation, coefficient of variation and standard-error were 95%, 0.068, 7.20, and 0.003, respectively. The corresponding values for PS2 were 96%, 0.200, 2.12, and 0.003. Values of the lactation curve parameters (a, b, and c for PS1 and PS2, respectively, were (a 7.0035923 and 10.9209, (b -0.1080043 and -0.1614882, (c 0.0434868 and 0.0679365.

Population genetical investigation of the level of mutagenesis and teratological events frequency in ecologically different regions of Kazakhstan

International Nuclear Information System (INIS)

Kashaganova, Zh.A.; Zhapbasov, R.; Kadyrova, N.Zh.; Karimbaeva, K.S.; Mamyrbaeva, A.N.; Altaeva, N.Z.

2008-01-01

Full text: Kazakhstan territory is unique including regions with radioactive pollution of Semipalatinsk nuclear test territory and storage of radioactive waste of uranium mines and metallurgy enterprises, and regions of drying Aral sea. These technogenic factors may cause some types of chromosome aberrations and developmental anomalies in mammals. The level of mutagenesis was estimated basing on chromosome aberrations and genomic mutation frequencies in bone marrow cells of natural rodents populations (Allactaga major Kern, Allactaga saltator Eversman, Cytellus eritrogenus Br.) and domestic animals (sheep, cattle, horse), which inhabit these regions. Sheep populations which are bred in the regions with different climatic conditions were used for teratological investigations. Different generations are met in the populations of mice family rodents caught in the nature. So studying the animals of different ages separately we can estimate the frequency of mutations in the animals of different age inhabiting the same radiation polluted regions. The frequency of chromosome abe rations in mice family rodents from such territories was twice as high as from the clear territories. In some animals chromosome aberration types characteristic for radiation mutagenesis (dicentrics, double acentric fragments) were found. High level of cytogenetical instability in somatic cells of agricultural animals which were bred on the pastures within former nuclear test territories for several generations may be caused by chronic radiation in low doses. The analysis of the spectrum of recorder chromosome aberrations in somatic cells and their dynamics in different animal species inhabiting for several generations these territories being chronically irradiated, allows us to investigate the direction of genetical evolution of mammals genofond structure induced by ecological factors. Comparative analysis of the frequencies of spontaneous abortuses, deadborn and newborn animals with innate

Selective alterations of the host cell architecture upon infection with parvovirus minute virus of mice

International Nuclear Information System (INIS)

Nueesch, Juerg P.F.; Lachmann, Sylvie; Rommelaere, Jean

2005-01-01

During a productive infection, the prototype strain of parvovirus minute virus of mice (MVMp) induces dramatic morphological alterations to the fibroblast host cell A9, resulting in cell lysis and progeny virus release. In order to understand the mechanisms underlying these changes, we characterized the fate of various cytoskeletal filaments and investigated the nuclear/cytoplasmic compartmentalization of infected cells. While most pronounced effects could be seen on micro- and intermediate filaments, manifest in dramatic rearrangements and degradation of filamentous (F-)actin and vimentin structures, only little impact could be seen on microtubules or the nuclear envelope during the entire monitored time of infection. To further analyze the disruption of the cytoskeletal structures, we investigated the viral impact on selective regulatory pathways. Thereby, we found a correlation between microtubule stability and MVM-induced phosphorylation of α/β tubulin. In contrast, disassembly of actin filaments late in infection could be traced back to the disregulation of two F-actin associated proteins gelsolin and Wiscott-Aldrich Syndrome Protein (WASP). Thereby, an increase in the amount of gelsolin, an F-actin severing protein was observed during infection, accounting for the disruption of stress fibers upon infection. Concomitantly, the actin polymerization activity also diminished due to a loss of WASP, the activator protein of the actin polymerization machinery the Arp2/3 complex. No effects could be seen in amount and distribution of other F-actin regulatory factors such as cortactin, cofilin, and profilin. In summary, the selective attack of MVM towards distinct host cell cytoskeletal structures argues for a regulatory feature during infection, rather than a collapse of the host cell as a mere side effect of virus production

Adiponectin has a pivotal role in the cardioprotective effect of CP-3(iv), a selective CD36 azapeptide ligand, after transient coronary artery occlusion in mice.

Science.gov (United States)

Huynh, David N; Bessi, Valérie L; Ménard, Liliane; Piquereau, Jérôme; Proulx, Caroline; Febbraio, Maria; Lubell, William D; Carpentier, André C; Burelle, Yan; Ong, Huy; Marleau, Sylvie

2018-02-01

CD36 is a multiligand receptor involved in lipid metabolism. We investigated the mechanisms underlying the cardioprotective effect of CP-3(iv), an azapeptide belonging to a new class of selective CD36 ligands. The role of CP-3(iv) in mediating cardioprotection was investigated because CD36 signaling leads to activation of peroxisome proliferator-activated receptor-γ, a transcriptional regulator of adiponectin. CP-3(iv) pretreatment reduced infarct size by 54% and preserved hemodynamics in C57BL/6 mice subjected to 30 min coronary ligation and reperfusion but had no effect in CD36-deficient mice. The effects of CP-3(iv) were associated with an increase in circulating adiponectin levels, epididymal fat adiponectin gene expression, and adiponectin transcriptional regulators ( Pparg, Cebpb, Sirt1) after 6 h of reperfusion. Reduced myocardial oxidative stress and apoptosis were observed along with an increase in expression of myocardial adiponectin target proteins, including cyclooxygenase-2, phospho-AMPK, and phospho-Akt. Moreover, CP-3(iv) increased myocardial performance in isolated hearts, whereas blockade of adiponectin with an anti-adiponectin antibody abrogated it. CP-3(iv) exerts cardioprotection against myocardial ischemia and reperfusion (MI/R) injury and dysfunction, at least in part, by increasing circulating and myocardial adiponectin levels. Hence, both paracrine and endocrine effects of adiponectin may contribute to reduced reactive oxygen species generation and apoptosis after MI/R, in a CD36-dependent manner.-Huynh, D. N., Bessi, V. L., Ménard, L., Piquereau, J., Proulx, C., Febbraio, M., Lubell, W. D., Carpentier, A. C., Burelle, Y., Ong, H., Marleau, S. Adiponectin has a pivotal role in the cardioprotective effect of CP-3(iv), a selective CD36 azapeptide ligand, after transient coronary artery occlusion in mice.

Prenatal lipopolysaccharide exposure affects sexual dimorphism in different germlines of mice with a depressive phenotype.

Science.gov (United States)

Reis-Silva, Thiago M; Cohn, Daniel W H; Sandini, Thaísa M; Udo, Mariana S B; Teodorov, Elizabeth; Bernardi, Maria Martha

2016-03-15

The objective of the present study was to investigate whether prenatal lipopolysaccharide (LPS) administration modifies the expression of depressive and non-depressive-like behavior in male and female mice across two generations. The sexual dimorphism of these mice was also examined in the open-field test. Male and female mice of the parental (F0) generation were selected for depressive- or non-depressive-like behavioral profiles using the tail suspension test (TST). Animals with similar profiles were matched for further mating. On gestation day (GD) 15, pregnant F0 mice received LPS (100μg/kg, i.p.) and were allowed to nurture their offspring freely. Adult male and female of the F1 generation were then selected according to behavioral profiles and observed in the open field. Male and female mice of the two behavioral profiles were then mated to obtain the F2 generation. Adults from the F2 generation were also behaviorally phenotyped, and open field behavior was assessed. Male mice that were selected for depressive- and non-depressive-like behaviors and treated or not with LPS in the parental generation exhibited similar proportions of behavioral profiles in both filial lines, but LPS exposure increased the number of depressive-like behavior. An effect of gender was observed in the F1 and F2 generations, in which male mice were more sensitive to the intergenerational effects of LPS in the TST. These data indicate that prenatal LPS exposure on GD15 in the F0 generation influenced the transmission of depressive- and non-depressive-like behavior across filial lines, with sexual dimorphism between phenotypes. Copyright © 2016 Elsevier Inc. All rights reserved.

Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies.

Science.gov (United States)

Paranjpe, Madhav G; Belich, Jessica; Vidmar, Tom J; Elbekai, Reem H; McKeon, Marie; Brown, Caren

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

CYP 2E1 mutant mice are resistant to DDC-induced enhancement of MPTP toxicity.

Science.gov (United States)

Viaggi, C; Vaglini, F; Pardini, C; Sgadò, P; Caramelli, A; Corsini, G U

2007-01-01

In order to reach a deeper insight into the mechanism of diethyldithiocarbamate (DDC)-induced enhancement of MPTP toxicity in mice, we showed that CYP450 (2E1) inhibitors, such as diallyl sulfide (DAS) or phenylethylisothiocyanate (PIC), also potentiate the selective DA neuron degeneration in C57/bl mice. Furthermore we showed that CYP 2E1 is present in the brain and in the basal ganglia of mice (Vaglini et al., 2004). However, because DAS and PIC are not selective CYP 2E1 inhibitors and in order to provide direct evidence for CYP 2E1 involvement in the enhancement of MPTP toxicity, CYP 2E1 knockout mice (GONZ) and wild type animals (SVI) of the same genetic background were treated with MPTP or the combined DDC + MPTP treatment. In CYP 2E1 knockout mice, DDC pretreatment completely fails to enhance MPTP toxicity, although enhancement of MPTP toxicity was regularly present in the SVI control animals. The immunohistochemical study confirms our results and suggests that CYP 2E1 may have a detoxifying role.

Toxoplasma gondii oral infection induces intestinal inflammation and retinochoroiditis in mice genetically selected for immune oral tolerance resistance.

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Raul Ramos Furtado Dias

Full Text Available Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS or resistance (TR to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-γ and TNF-α. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis.

Toxoplasma gondii Oral Infection Induces Intestinal Inflammation and Retinochoroiditis in Mice Genetically Selected for Immune Oral Tolerance Resistance

Science.gov (United States)

Dias, Raul Ramos Furtado; de Carvalho, Eulógio Carlos Queiroz; Leite, Carla Cristina da Silva; Tedesco, Roberto Carlos; Calabrese, Katia da Silva; Silva, Antonio Carlos; DaMatta, Renato Augusto; de Fatima Sarro-Silva, Maria

2014-01-01

Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS) or resistance (TR) to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-γ and TNF-α. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis. PMID:25437299

Alterations in gene expression in mutant amyloid precursor protein transgenic mice lacking Niemann-Pick type C1 protein.

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Mahua Maulik

Full Text Available Niemann-Pick type C (NPC disease, a rare autosomal recessive disorder caused mostly by mutation in NPC1 gene, is pathologically characterized by the accumulation of free cholesterol in brain and other tissues. This is accompanied by gliosis and loss of neurons in selected brain regions, including the cerebellum. Recent studies have shown that NPC disease exhibits intriguing parallels with Alzheimer's disease, including the presence of neurofibrillary tangles and increased levels of amyloid precursor protein (APP-derived β-amyloid (Aβ peptides in vulnerable brain neurons. To evaluate the role of Aβ in NPC disease, we determined the gene expression profile in selected brain regions of our recently developed bigenic ANPC mice, generated by crossing APP transgenic (Tg mice with heterozygous Npc1-deficient mice. The ANPC mice exhibited exacerbated neuronal and glial pathology compared to other genotypes [i.e., APP-Tg, double heterozygous (Dhet, Npc1-null and wild-type mice]. Analysis of expression profiles of 86 selected genes using real-time RT-PCR arrays showed a wide-spectrum of alterations in the four genotypes compared to wild-type controls. The changes observed in APP-Tg and Dhet mice are limited to only few genes involved mostly in the regulation of cholesterol metabolism, whereas Npc1-null and ANPC mice showed alterations in the expression profiles of a number of genes regulating cholesterol homeostasis, APP metabolism, vesicular trafficking and cell death mechanism in both hippocampus and cerebellum compared to wild-type mice. Intriguingly, ANPC and Npc1-null mice, with some exceptions, exhibited similar changes, although more genes were differentially expressed in the affected cerebellum than the relatively spared hippocampus. The altered gene profiles were found to match with the corresponding protein levels. These results suggest that lack of Npc1 protein can alter the expression profile of selected transcripts as well as proteins, and

Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice

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Wei Chen

2017-10-01

Full Text Available The clinical development of the first generation of globally active cannabinoid 1 receptor (CB1R antagonists was suspended because of their adverse neuropsychiatric effects. Selective blockade of peripheral CB1Rs has the potential to provide a viable strategy for the treatment of severe obesity while avoiding these central nervous system side effects. In the current study, a novel compound (TXX-522 was rationally designed based on the parent nucleus of a classical CB1R-selective antagonist/inverse agonist, rimonabant (SR141716A. Docking assays indicate that TXX-522 was bound with the CB1R in a mode similar to that of SR141716A. TXX-522 showed good binding, CB1R-selectivity (over the CB2R, and functional antagonist activities in a range of in vitro molecular and cellular assays. In vivo analysis of the steady state distribution of TXX-522 in the rat brain and blood tissues and the assay of its functional effects on CB1R activity collectively showed that TXX-522 showed minimal brain penetration. Moreover, the in vivo pharmacodynamic study further revealed that TXX-522 had good oral bioavailability and a potent anti-obesity effect, and ameliorated insulin resistance in high-fat diet-induced obese mice. No impact on food intake was observed in this model, confirming the limited brain penetration of this compound. Thus, the current study indicates that TXX-522 is a novel and potent peripherally acting selective CB1R antagonist with the potential to control obesity and related metabolic disorders.

Tests of selection in pooled case-control data: an empirical study.

Science.gov (United States)

Udpa, Nitin; Zhou, Dan; Haddad, Gabriel G; Bafna, Vineet

2011-01-01

For smaller organisms with faster breeding cycles, artificial selection can be used to create sub-populations with different phenotypic traits. Genetic tests can be employed to identify the causal markers for the phenotypes, as a precursor to engineering strains with a combination of traits. Traditional approaches involve analyzing crosses of inbred strains to test for co-segregation with genetic markers. Here we take advantage of cheaper next generation sequencing techniques to identify genetic signatures of adaptation to the selection constraints. Obtaining individual sequencing data is often unrealistic due to cost and sample issues, so we focus on pooled genomic data. We explore a series of statistical tests for selection using pooled case (under selection) and control populations. The tests generally capture skews in the scaled frequency spectrum of alleles in a region, which are indicative of a selective sweep. Extensive simulations are used to show that these approaches work well for a wide range of population divergence times and strong selective pressures. Control vs control simulations are used to determine an empirical False Positive Rate, and regions under selection are determined using a 1% FPR level. We show that pooling does not have a significant impact on statistical power. The tests are also robust to reasonable variations in several different parameters, including window size, base-calling error rate, and sequencing coverage. We then demonstrate the viability (and the challenges) of one of these methods in two independent Drosophila populations (Drosophila melanogaster) bred under selection for hypoxia and accelerated development, respectively. Testing for extreme hypoxia tolerance showed clear signals of selection, pointing to loci that are important for hypoxia adaptation. Overall, we outline a strategy for finding regions under selection using pooled sequences, then devise optimal tests for that strategy. The approaches show promise for

A Transgenic Mouse Model of Poliomyelitis.

Science.gov (United States)

Koike, Satoshi; Nagata, Noriyo

2016-01-01

Transgenic mice (tg mice) that express the human poliovirus receptor (PVR), CD155, are susceptible to poliovirus and develop a neurological disease that resembles human poliomyelitis. Assessment of the neurovirulence levels of poliovirus strains, including mutant viruses produced by reverse genetics, circulating vaccine-derived poliovirus, and vaccine candidates, is useful for basic research of poliovirus pathogenicity, the surveillance of circulating polioviruses, and the quality control of oral live poliovirus vaccines, and does not require the use of monkeys. Furthermore, PVR-tg mice are useful for studying poliovirus tissue tropism and host immune responses. PVR-tg mice can be bred with mice deficient in the genes involved in viral pathogenicity. This report describes the methods used to analyze the pathogenicity and immune responses of poliovirus using the PVR-tg mouse model.

Tests of Selection in Pooled Case-Control Data: An Empirical Study

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Nitin eUdpa

2011-11-01

Full Text Available For smaller organisms with faster breeding cycles, artificial selection can be used to create sub-populations with different phenotypic traits. Genetic tests can be employed to identify the causal markers for the phenotypes, as a precursor to engineering strains with a combination of traits. Traditional approaches involve analyzing crosses of inbred strains to test for co-segregation with genetic markers. Here we take advantage of cheaper next generation sequencing techniques to identifygenetic signatures of adaptation to the selection constraints. Obtaining individual sequencing data is often unrealistic due to cost and sample issues, so we focus on pooled genomic data.In this paper, we explore a series of statistical tests for selection using pooled case (under selection and control populations. Extensive simulations are used to show that these approaches work well for a wide range of population divergence times and strong selective pressures. We show that pooling does not have a significant impact on statistical power. The tests are also robust to reasonable variations in several different parameters, including window size, base-calling error rate, and sequencing coverage. We then demonstrate the viability (and the challenges of one of these methods in two independent Drosophila populations (Drosophila melanogaster bred under selectionfor hypoxia and accelerated development, respectively. Testing for extreme hypoxia tolerance showed clear signals of selection, pointing to loci that are important for hypoxia adaptation.Overall, we outline a strategy for finding regions under selection using pooled sequences, then devise optimal tests for that strategy. The approaches show promise for detecting selection, even several generations after fixation of the beneficial allele has occurred.

A Combined In Vivo HSC Transduction/Selection Approach Results in Efficient and Stable Gene Expression in Peripheral Blood Cells in Mice

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Hongjie Wang

2018-03-01

Full Text Available We recently reported on an in vivo hematopoietic stem cell (HSC gene therapy approach. It involves the subcutaneous injections of G-CSF/AMD3100 to mobilize HSCs from the bone marrow into the peripheral blood stream and the intravenous injection of an integrating helper-dependent adenovirus vector system. HSCs transduced in the periphery homed back to the bone marrow, where they persisted long-term. However, high transgene marking rates found in primitive bone marrow HSCs were not reflected in peripheral blood cells. Here, we tested small-molecule drugs to achieve selective mobilization and transduction of HSCs. We found more efficient GFP marking in bone marrow HSCs but no increased marking in the peripheral blood cells. We then used an in vivo HSC chemo-selection based on a mutant of the O6-methylguanine-DNA methyltransferase (mgmtP140K gene that confers resistance to O6-BG/BCNU and should give stably transduced HSCs a proliferation stimulus and allow for the selective survival and expansion of progeny cells. Short-term exposure of G-CSF/AMD3100-mobilized, in vivo-transduced mice to relatively low selection drug doses resulted in stable GFP expression in up to 80% of peripheral blood cells. Overall, the further improvement of our in vivo HSC transduction approach creates the basis for a simpler HSC gene therapy.

‘‘What's wrong with my monkey?''

DEFF Research Database (Denmark)

Olsson, I. Anna S.; Sandøe, Peter

2010-01-01

in marmosets in some areas of research. The mainstream, broadly utilitarian view of animal research suggests that such a transition will not give rise to greater ethical problems than those presently faced. It can be argued that using marmosets rather than mice will not result in more animal suffering......, readily available in the way that transgenic laboratory mice are currently, prompts excitement in the scientific community; but the idea of monkeys being bred to carry diseases is also contentious. We structure an ethical analysis of the transgenic marmoset case around three questions: whether...

Therapeutic Effects of Bupleurum Polysaccharides in Streptozotocin Induced Diabetic Mice.

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Lingyu Pan

Full Text Available Diabetes mellitus is related to low-grade chronic inflammation and oxidative stress. Bupleurum Polysaccharides (BPs, isolated from Bupleurum smithii var. parvifolium has anti-inflammatory and anti-oxidative properties. However, little is known about its therapeutic effects on diabetes. In this experiment, the effects of BPs on alleviation of diabetes and the underlying mechanisms were investigated. Diabetic mice model was established via successive intraperitoneal injections of streptozotocin (100 mg/kg body weight for two days. Mice with blood glucose levels higher than 16.8mmol/L were selected for experiments. The diabetic mice were orally administered with BPs (30 and 60 mg/kg once a day for 35 days. BPs not only significantly decreased levels of blood glucose, but also increased those of serum insulin and liver glycogen in diabetic mice compared to model mice. Additionally, BPs adminstration improved the insulin expression and suppressed the apoptosis in pancreas of the diabetic mice. Histopathological observations further demonstrated that BPs protected the pancreas and liver from oxidative and inflammatory damages. These results suggest that BPs protect pancreatic β cells and liver hepatocytes and ameliorate diabetes, which is associated with its anti-oxidative and anti-inflammatory properties.

Sweetener Intake by Rats Selectively Bred for Differential Saccharin Intake: Sucralose, Stevia, and Acesulfame Potassium.

Science.gov (United States)

Dess, Nancy K; Dobson, Kiana; Roberts, Brandon T; Chapman, Clinton D

2017-06-01

Behavioral responses to sweeteners have been used to study the evolution, mechanisms, and functions of taste. Occidental low and high saccharin consuming rats (respectively, LoS and HiS) have been selectively outbred on the basis of saccharin intake and are a valuable tool for studying variation among individuals in sweetener intake and its correlates. Relative to HiS rats, LoS rats consume smaller amounts of all nutritive and nonnutritive sweeteners tested to date, except aspartame. The lines also differ in intake of the commercial product Splenda; the roles of sucralose and saccharides in the difference are unclear. The present study extends prior work by examining intake of custom mixtures of sucralose, maltodextrin, and sugars and Splenda by LoS and HiS rats (Experiment 1A-1D), stevia and a constituent compound (rebaudioside A; Experiment 2A-2E), and acesulfame potassium tested at several concentrations or with 4 other sweeteners at one concentration each (Experiment 3A-3B). Results indicate that aversive side tastes limit intake of Splenda, stevia, and acesulfame potassium, more so among LoS rats than among HiS rats. In addition, regression analyses involving 5 sweeteners support the idea that both sweetness and bitterness are needed to account for intake of nonnutritive sweeteners, more so among LoS rats. These findings contribute to well developed and emerging literatures on sweetness and domain-general processes related to gustation. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The effect of dietary folic acid deficiency on the cytotoxic and mutagenic responses to methyl methanesulfonate in wild-type and in 3-methyladenine DNA glycosylase-deficient Aag null mice.

Science.gov (United States)

Branda, Richard F; O'Neill, J Patrick; Brooks, Elice M; Powden, Cheryl; Naud, Shelly J; Nicklas, Janice A

2007-02-03

Folic acid deficiency (FA-) augments DNA damage caused by alkylating agents. The role of DNA repair in modulating this damage was investigated in mice. Weanling wild-type or 3-methyladenine glycosylase (Aag) null mice were maintained on a FA- diet or the same diet supplemented with folic acid (FA+) for 4 weeks. They were then treated with methyl methanesulfonate (MMS), 100mg/kg i.p. Six weeks later, spleen cells were collected for assays of non-selected and 6-thioguanine (TG) selected cloning efficiency to measure the mutant frequency at the Hprt locus. In wild-type mice, there was no significant effect of either MMS treatment or folate dietary content on splenocyte non-selected cloning efficiency. In contrast, non-selected cloning efficiency was significantly higher in MMS-treated Aag null mice than in saline treated controls (diet-gene interaction variable, p=0.04). The non-selected cloning efficiency was significantly higher in the FA+ diet than in the FA- diet group after MMS treatment of Aag null mice. Mutant frequency after MMS treatment was significantly higher in FA- wild-type and Aag null mice and in FA+ Aag null mice, but not in FA+ wild-type mice. For the Aag null mice, mutant frequency was higher in the FA+ mice than in the FA- mice after either saline or MMS treatment. These studies indicate that in wild-type mice treated with MMS, dietary folate content (FA+ or FA-) had no effect on cytotoxicity, but FA- diet increased DNA mutation frequency compared to FA+ diet. In Aag null mice, FA- diet increased the cytotoxic effects of alkylating agents but decreased the risk of DNA mutation.

Selective cognitive deficits and reduced hippocampal brain-derived neurotrophic factor mRNA expression in small-conductance calcium-activated K+ channel deficient mice

DEFF Research Database (Denmark)

Jacobsen, J P R; Redrobe, J P; Hansen, H H

2009-01-01

performed equally well in passive avoidance, object recognition and the Morris water maze. Thus, some aspects of working/short-term memory are disrupted in T/T mice. Using in situ hybridization, we further found the cognitive deficits in T/T mice to be paralleled by reduced brain-derived neurotrophic factor...... the brain following doxycycline treatment. We tested T/T and wild type (WT) littermate mice in five distinct learning and memory paradigms. In Y-maze spontaneous alternations and five-trial inhibitory avoidance the performance of T/T mice was markedly inferior to WT mice. In contrast, T/T and WT mice...

Therapeutic administration of enrofloxacin in mice does not select for fluoroquinolone resistance in Campylobacter jejuni.

Science.gov (United States)

Inglis, G Douglas; Zaytsoff, S J M; Selinger, L Brent; Taboada, Eduardo N; Uwiera, R R E

2018-05-11

Enrofloxacin is registered for therapeutic use in beef cattle to treat bovine respiratory disease in Canada. A murine model was used to experimentally examine the impact of therapeutic administration of enrofloxacin on fluoroquinolone resistance development in Campylobacter jejuni. Administration of enrofloxacin to mice via subcutaneous injection or per os routes resulted in equivalent levels of bioactive enrofloxacin within the intestine, but bioactivity was short-lived (Enrofloxacin administration did not affect densities of total bacteria, Firmicutes, or Bacteroidetes in digesta, and had modest impacts on densities of Enterobacteriaceae. All mice inoculated with C. jejuni NCTC 11168 became persistently colonized by the bacterium. Enrofloxacin reduced C. jejuni cell densities within the cecal and colonic digesta for all treatments, and densities shed in feces as a function of antibiotic duration. None of the C. jejuni isolates recovered from mice after administration of enrofloxacin (n=260) developed resistance to ciprofloxacin regardless of method or duration of administration. Furthermore, only modest shifts in the minimum inhibitory concentration of the isolates by treatment were noted. The study findings indicate that the risk posed by short-term subcutaneous administration of enrofloxacin for the development of fluoroquinolone resistance in mammals is low.

Recurrent Selection and Participatory Plant Breeding for Improvement of Two Organic Open-Pollinated Sweet Corn (Zea mays L. Populations

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Adrienne C. Shelton

2015-04-01

Full Text Available Organic growers face unique challenges when raising sweet corn, and benefit from varieties that maintain high eating quality, germinate consistently, deter insect pests, and resist diseases. Genotype by environment rank changes can occur in the performance of cultivars grown on conventional and organic farms, yet few varieties have been bred specifically for organic systems. The objective of this experiment was to evaluate the changes made to open-pollinated sweet corn populations using recurrent selection and a participatory plant breeding (PPB methodology. From 2008 to 2011, four cycles of two open-pollinated (OP sweet corn populations were selected on a certified organic farm in Minnesota using a modified ear-to-row recurrent selection scheme. Selections were made in collaboration with an organic farmer, with selection criteria based on traits identified by the farmer. In 2012 and 2013, the population cycles were evaluated in a randomized complete block design in two certified organic locations in Wisconsin, with multiple replications in each environment. Significant linear trends were found among cycles of selection for quantitative and qualitative traits, suggesting the changes were due to recurrent selection and PPB methodology for these populations. However, further improvement is necessary to satisfy the requirements for a useful cultivar for organic growers.

Development of aromatic giant-embryo rice by molecular marker-assisted selection

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ZHU Yingdong

2013-12-01

Full Text Available Aromatic rice is loved for its distinctive aroma when cooking and eating.In this research,aromatic normal-embryo rice and non-aromatic giant-embryo rice,"Shangshida No.5",both bred by our laboratory,were selected as the parents for the hybridization.We used conventional breeding techniques as well as fragrance gene marker-assisted selection to derive new aromatic giant-embryo rice "Shangshida No.8".By comparing the agronomic and yield characters of "Shangshida No.5" and "Shangshida No.8",the average of filled grains per panicle of "Shangshida No.5" exceeds "Shangshida No.8" very significantly,while the average of effective panicles of "Shangshida No.8" is slightly more than "Shangshida No.5".Also,in the weight of thousand grains "Shangshida No.8" is slightly heavier than "Shangshida No.5".Thus,their grain weights per plant are close,29.10 g and 28.92 g respectively.By comparing the traits of rice embryo,there is no significant difference in embryo weight and volume.Also,there is no significant difference in weight ratio and volume ratio of embryo.This research has laid a solid foundation for further market development and application of aromatic giant-embryo rice.

Pavlovian conditioning of multiple opioid-like responses in mice.

Science.gov (United States)

Bryant, Camron D; Roberts, Kristofer W; Culbertson, Christopher S; Le, Alan; Evans, Christopher J; Fanselow, Michael S

2009-07-01

Conditional responses in rodents such as locomotion have been reported for drugs of abuse and similar to the placebo response in humans, may be associated with the expectation of reward. We examined several conditional opioid-like responses and the influence of drug expectation on conditioned place preference and concomitant conditional locomotion. Male C57BL/6J mice were conditioned with the selective mu opioid receptor agonist fentanyl (0.2mg/kg, i.p.) in a novel context and subsequently given a vehicle injection. In separate experiments, locomotor activity, Straub tail, hot plate sensitivity, and conditioned place preference (CPP) were measured. Mice exhibited multiple conditional opioid-like responses including conditional hyperlocomotion, a conditional pattern of opioid-like locomotion, Straub tail, analgesia, and place preference. Modulating drug expectation via administration of fentanyl to "demonstrator" mice in the home cage did not affect the expression of conditioned place preference or the concomitant locomotor activity in "observer" mice. In summary, Pavlovian conditioning of an opioid in a novel context induced multiple conditional opioid-like behaviors and provides a model for studying the neurobiological mechanisms of the placebo response in mice.

Genetic and haematopoietic effects of long-term tritiated water ingestion in mice

International Nuclear Information System (INIS)

Carsten, A.L.; Cronkite, E.P.

1976-01-01

The effect of large amounts of tritiated water (HTO) from reactors on the environment is evaluated. Randomly bred mice of the Hale-Stoner-Brookhaven strain have been maintained on HTO (3 μCi/mlitre) for extended periods. First-generation animals on HTO from four weeks of age have been evaluated for changes in growth pattern, and second-generation animals (also on HTO) for breeding efficiency, dominant lethal mutation rate and bone-marrow integrity. A total of 18831 embryos were examined. Statistical analysis of these results using either Student's ''t'' test or Kruskal and Wallis rank test indicates that there was a significant (p<0.01) reduction in viable embryos and an increase in early deaths in matings involving animals drinking HTO. Beginning at eight weeks of age and monthly thereafter, the haematopoietic stem cell content of the bone marrow was determined using the exogenous spleen colony technique. Although the total cellularity of the bone marrow remains comparable in the control and treated groups, the total number of stem cells (CFU) was reduced beginning after approximately 12-20 weeks on the tritium regime. These findings indicate a reduction in the total number of pluripotent stem cells in the marrow together with the ability of this reduced number of cells to maintain normal levels of total cellularity in the bone marrow. Thus, continuous ingestion of HTO at a concentration of 3 μCi/mlitre by mice results in: (1) Reduction in number of viable embryos present in the female at late pregnancy from matings when either the female or both parents have been on HTO; (2) Increase in number of early post-implantation deaths when both parents are on HTO; (3) Reduction in bone-marrow stem cell content after 12 weeks or longer on HTO; (4) No apparent effect on breeding efficiency (percentage of females pregnant) or body weight. These results are discussed in relation to the accumulated radiation dose

Neural and Environmental Factors Impacting Maternal Behavior Differences in High- versus Low-Novelty Seeking Rats

OpenAIRE

Clinton, Sarah M.; Bedrosian, Tracy A.; Abraham, Antony D.; Watson, Stanley J.; Akil, Huda

2010-01-01

Selective breeding of rats exhibiting differences in novelty-induced locomotion revealed that this trait predicts several differences in emotional behavior. Bred High Responders (bHRs) show exaggerated novelty-induced locomotion, aggression, and psychostimulant self-administration, compared to bred Low Responders (bLRs), which are inhibited and prone to anxiety- and depression-like behavior. Our breeding studies highlight the heritability of the bHR/bLR phenotypes, although environmental fact...

Cyclotraxin-B, the first highly potent and selective TrkB inhibitor, has anxiolytic properties in mice.

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Maxime Cazorla

Full Text Available In the last decades, few mechanistically novel therapeutic agents have been developed to treat mental and neurodegenerative disorders. Numerous studies suggest that targeting BDNF and its TrkB receptor could be a promising therapeutic strategy for the treatment of brain disorders. However, the development of potent small ligands for the TrkB receptor has proven to be difficult. By using a peptidomimetic approach, we developed a highly potent and selective TrkB inhibitor, cyclotraxin-B, capable of altering TrkB-dependent molecular and physiological processes such as synaptic plasticity, neuronal differentiation and BDNF-induced neurotoxicity. Cyclotraxin-B allosterically alters the conformation of TrkB, which leads to the inhibition of both BDNF-dependent and -independent (basal activities. Finally, systemic administration of cyclotraxin-B to mice results in TrkB inhibition in the brain with specific anxiolytic-like behavioral effects and no antidepressant-like activity. This study demonstrates that cyclotraxin-B might not only be a powerful tool to investigate the role of BDNF and TrkB in physiology and pathology, but also represents a lead compound for the development of new therapeutic strategies to treat brain disorders.

Serum concentrations of creatine kinase and of triglycerides during lactation in gilts bred older and in multiparous sows fed ad libitum

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Nogueira R.H.G.

2000-01-01

Full Text Available The aim of this paper was to assess the possible variation in blood concentrations of creatine kinase (CK and triglycerides in gilts bred older in comparison with multiparous sows. Ten primiparous and ten Camborough multiparous sows from the fourth to seventh parities were used. Breeding age and weight of gilts averaged respectively 231 days and 149.5kg. All females were moved into individual farrowing crates and were managed under the same conditions. Blood samples were collected by puncturing the coccygeal artery on day 7 before expected farrowing, and on days 2, 7, 14, 21 of lactation and 2 days after weaning. No difference in triglycerides and CK serum concentrations between groups were observed. The CK levels were low before farrowing, increased substantially on days 2 and 7 and decreased toward the end of lactation. The concentrations of triglycerides were slightly high before the parturition, diminished on days 2, 7, 14 and 21 and increased after weaning.

Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac

Science.gov (United States)

Zhou, L; Ma, S L; Yeung, P K K; Wong, Y H; Tsim, K W K; So, K F; Lam, L C W; Chung, S K

2016-01-01

Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1−/−) or Epac2 (Epac2−/−) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2−/− mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2−/− mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2−/− mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis. PMID:27598965

Rapid and selective expansion of nonclonotypic T cells in regulatory T cell-deficient, foreign antigen-specific TCR-transgenic scurfy mice: antigen-dependent expansion and TCR analysis.

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Sharma, Rahul; Ju, Angela Chiao-Ying; Kung, John T; Fu, Shu Man; Ju, Shyr-Te

2008-11-15

Foreign Ag-specific TCR-transgenic (Tg) mice contain a small fraction of T cells bearing the endogenous Vbeta and Valpha chains as well as a population expressing an intermediate level of Tg TCR. Importantly, these minor nonclonotypic populations contain > or = 99% of the CD4(+)Foxp3(+) regulatory T cells (Treg) and, despite low overall Treg expression, peripheral tolerance is maintained. In the OT-II TCR (OVA-specific, Vbeta5(high)Valpha2(high)) Tg scurfy (Sf) mice (OT-II Sf) that lack Treg, nonclonotypic T cells markedly expanded in the periphery but not in the thymus. Expanded T cells expressed memory/effector phenotype and were enriched in blood and inflamed lungs. In contrast, Vbeta5(high)Valpha2(high) clonotypic T cells were not expanded, displayed the naive phenotype, and found mainly in the lymph nodes. Importantly, Vbeta5(neg) T cells were able to transfer multiorgan inflammation in Rag1(-/-) recipients. T cells bearing dual TCR (dual Vbeta or dual Valpha) were demonstrated frequently in the Vbeta5(int) and Valpha2(int) populations. Our study demonstrated that in the absence of Treg, the lack of peripheral expansion of clonotypic T cells is due to the absence of its high-affinity Ag OVA. Thus, the rapid expansion of nonclonotypic T cells in OT-II Sf mice must require Ag (self and foreign) with sufficient affinity. Our study has implications with respect to the roles of Ag and dual TCR in the selection and regulation of Treg and Treg-controlled Ag-dependent T cell expansion in TCR Tg and TCR Tg Sf mice, respectively.

Compulsive Addiction-like Aggressive Behavior in Mice.

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Golden, Sam A; Heins, Conor; Venniro, Marco; Caprioli, Daniele; Zhang, Michelle; Epstein, David H; Shaham, Yavin

2017-08-15

Some people are highly motivated to seek aggressive encounters, and among those who have been incarcerated for such behavior, recidivism rates are high. These observations echo two core features of drug addiction: high motivation to seek addictive substances, despite adverse consequences, and high relapse rates. Here we used established rodent models of drug addiction to determine whether they would be sensitive to "addiction-like" features of aggression in CD-1 mice. In experiments 1 and 2, we trained older CD-1 mice to lever press for opportunities to attack younger C57BL6/J mice. We then tested them for relapse to aggression seeking after forced abstinence or punishment-induced suppression of aggression self-administration. In experiment 3, we trained a large cohort of CD-1 mice and tested them for choice-based voluntary suppression of aggression seeking, relapse to aggression seeking, progressive ratio responding, and punishment-induced suppression of aggression self-administration. We then used cluster analysis to identify patterns of individual differences in compulsive "addiction-like" aggressive behavior. In experiments 1 and 2, we observed strong motivation to acquire operant self-administration of opportunities to aggress and relapse vulnerability during abstinence. In experiment 3, cluster analysis of the aggression-related measures identified a subset of "addicted" mice (∼19%) that exhibited intense operant-reinforced attack behavior, decreased likelihood to select an alternative reinforcer over aggression, heightened relapse vulnerability and progressive ratio responding, and resilience to punishment-induced suppression of aggressive behavior. Using procedures established to model drug addiction, we showed that a subpopulation of CD-1 mice demonstrate "addiction-like" aggressive behavior, suggesting an evolutionary origin for compulsive aggression. Published by Elsevier Inc.

Cellular oncogene expression following exposure of mice to γ-rays

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Anderson, A.; Woloschak, G.E.

1991-01-01

We examined the effects of total body exposure of BCF1 mice to γ-rays (300 cGy) in modulating expression of cellular oncogenes in both gut and liver tissues. We selected specific cellular oncogenes (c-fos, c-myc, c-src, and c-H-ras), based on their normal expression in liver and gut tissues from untreated mice. As early as 5 min. following whole body exposure of BCF1 mice to γ-rays we detected induction of mRNA specific for c-src and c-H-ras in both liver and gut tissues. c-fos RNA was slightly decreased in accumulation in gut but was unaffected in liver tissue from irradiated mice relative to untreated controls. c-myc mRNA accumulation was unaffected in all tissues examined. These experiments document that modulation of cellular oncogene expression can occur as an early event in tissues following irradiation and suggest that this modulation may play a role in radiation-induced carcinogenesis

Thalamic control of sensory selection in divided attention.

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Wimmer, Ralf D; Schmitt, L Ian; Davidson, Thomas J; Nakajima, Miho; Deisseroth, Karl; Halassa, Michael M

2015-10-29

How the brain selects appropriate sensory inputs and suppresses distractors is unknown. Given the well-established role of the prefrontal cortex (PFC) in executive function, its interactions with sensory cortical areas during attention have been hypothesized to control sensory selection. To test this idea and, more generally, dissect the circuits underlying sensory selection, we developed a cross-modal divided-attention task in mice that allowed genetic access to this cognitive process. By optogenetically perturbing PFC function in a temporally precise window, the ability of mice to select appropriately between conflicting visual and auditory stimuli was diminished. Equivalent sensory thalamocortical manipulations showed that behaviour was causally dependent on PFC interactions with the sensory thalamus, not sensory cortex. Consistent with this notion, we found neurons of the visual thalamic reticular nucleus (visTRN) to exhibit PFC-dependent changes in firing rate predictive of the modality selected. visTRN activity was causal to performance as confirmed by bidirectional optogenetic manipulations of this subnetwork. Using a combination of electrophysiology and intracellular chloride photometry, we demonstrated that visTRN dynamically controls visual thalamic gain through feedforward inhibition. Our experiments introduce a new subcortical model of sensory selection, in which the PFC biases thalamic reticular subnetworks to control thalamic sensory gain, selecting appropriate inputs for further processing.

CRF receptor antagonist astressin-B reverses and prevents alopecia in CRF over-expressing mice.

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Lixin Wang

2011-02-01

Full Text Available Corticotropin-releasing factor (CRF signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse injected peripherally once a day for 5 days in 4-9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF₂ receptor antagonist, astressin₂-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.

Case Study: Polycystic Livers in a Transgenic Mouse Line

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Lovaglio, Jamie A.; Artwohl, James E.; Ward, Christopher J.; Diekwisch, Thomas G. H.; Ito, Yoshihiro; Fortman, Jeffrey D.

2014-04-01

Three mice (2 male, 1 female; age, 5 to 16 mo) from a mouse line transgenic for keratin 14 (K14)-driven LacZ expression and on an outbred Crl:CD1(ICR) background, were identified as having distended abdomens and livers that were diffusely enlarged by numerous cysts (diameter, 0.1 to 2.0 cm). Histopathology revealed hepatic cysts lined by biliary type epithelium and mild chronic inflammation, and confirmed the absence of parasites. Among 21 related mice, 5 additional affected mice were identified via laparotomy. Breeding of these 5 mice (after 5 mo of age) did not result in any offspring; the K14 mice with olycystic livers failed to reproduce. Affected male mice had degenerative testicular lesions, and their sperm was immotile. Nonpolycystic K14 control male mice bred well, had no testicular lesions, and had appropriate sperm motility. Genetic analysis did not identify an association of this phenotype with the transgene or insertion site.

Gait disorder as a predictor of spatial learning and memory impairment in aged mice

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Xin Wang

2017-01-01

Full Text Available Objective To investigate whether gait dysfunction is a predictor of severe spatial learning and memory impairment in aged mice. Methods A total of 100 12-month-old male mice that had no obvious abnormal motor ability and whose Morris water maze performances were not significantly different from those of two-month-old male mice were selected for the study. The selected aged mice were then divided into abnormal or normal gait groups according to the results from the quantitative gait assessment. Gaits of aged mice were defined as abnormal when the values of quantitative gait parameters were two standard deviations (SD lower or higher than those of 2-month-old male mice. Gait parameters included stride length, variability of stride length, base of support, cadence, and average speed. After nine months, mice exhibiting severe spatial learning and memory impairment were separated from mice with mild or no cognitive dysfunction. The rate of severe spatial learning and memory impairment in the abnormal and normal gait groups was tested by a chi-square test and the correlation between gait dysfunction and decline in cognitive function was tested using a diagnostic test. Results The 12-month-old aged mice were divided into a normal gait group (n = 75 and an abnormal gait group (n = 25. Nine months later, three mice in the normal gait group and two mice in the abnormal gait group had died. The remaining mice were subjected to the Morris water maze again, and 17 out of 23 mice in the abnormal gait group had developed severe spatial learning and memory impairment, including six with stride length deficits, 15 with coefficient of variation (CV in stride length, two with base of support (BOS deficits, five with cadence dysfunction, and six with average speed deficits. In contrast, only 15 out of 72 mice in the normal gait group developed severe spatial learning and memory impairment. The rate of severe spatial learning and memory impairment was

Short-term selective alleviation of glucotoxicity and lipotoxicity ameliorates the suppressed expression of key β-cell factors under diabetic conditions

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Shimo, Naoki [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan); Matsuoka, Taka-aki, E-mail: matsuoka@endmet.med.osaka-u.ac.jp [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan); Miyatsuka, Takeshi [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan); Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunky-ku, Tokyo, 113-8421 (Japan); Takebe, Satomi; Tochino, Yoshihiro; Takahara, Mitsuyoshi [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan); Kaneto, Hideaki [Division of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki-city, Okayama, 701-0192 (Japan); Shimomura, Iichiro [Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871 (Japan)

2015-11-27

Alleviation of hyperglycaemia and hyperlipidemia improves pancreatic β-cell function in type 2 diabetes. However, the underlying molecular mechanisms are still not well clarified. In this study, we aimed to elucidate how the expression alterations of key β-cell factors are altered by the short-term selective alleviation of glucotoxicity or lipotoxicity. We treated db/db mice for one week with empagliflozin and/or bezafibrate to alleviate glucotoxicity and/or liptotoxicity, respectively. The gene expression levels of Pdx1 and Mafa, and their potential targets, insulin 1, Slc2a2, and Glp1r, were higher in the islets of empagliflozin-treated mice, and levels of insulin 2 were higher in mice treated with both reagents, than in untreated mice. Moreover, compared to the pretreatment levels, Mafa and insulin 1 expression increased in empagliflozin-treated mice, and Slc2a2 increased in combination-treated mice. In addition, empagliflozin treatment enhanced β-cell proliferation assessed by Ki-67 immunostaining. Our date clearly demonstrated that the one-week selective alleviation of glucotoxicity led to the better expression levels of the key β-cell factors critical for β-cell function over pretreatment levels, and that the alleviation of lipotoxicity along with glucotoxicity augmented the favorable effects under diabetic conditions. - Highlights: • One-week selective reduction of gluco- and lipo-toxicity in db/db mice was performed. • Selective glucotoxicity reduction increases key pancreatic β-cell factors expression. • Selective glucotoxicity reduction improves β-cell factors over pretreatment levels. • Selective glucotoxicity reduction turns β-cell mass toward increase. • Lipotoxicity reduction has additive effects on glucotoxicity reduction.

Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice.

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Noah Saederup

2010-10-01

Full Text Available Monocyte subpopulations distinguished by differential expression of chemokine receptors CCR2 and CX3CR1 are difficult to track in vivo, partly due to lack of CCR2 reagents.We created CCR2-red fluorescent protein (RFP knock-in mice and crossed them with CX3CR1-GFP mice to investigate monocyte subset trafficking. In mice with experimental autoimmune encephalomyelitis, CCR2 was critical for efficient intrathecal accumulation and localization of Ly6C(hi/CCR2(hi monocytes. Surprisingly, neutrophils, not Ly6C(lo monocytes, largely replaced Ly6C(hi cells in the central nervous system of these mice. CCR2-RFP expression allowed the first unequivocal distinction between infiltrating monocytes/macrophages from resident microglia.These results refine the concept of monocyte subsets, provide mechanistic insight about monocyte entry into the central nervous system, and present a novel model for imaging and quantifying inflammatory myeloid populations.

Artificial Selection Response due to Polygenic Adaptation from a Multilocus, Multiallelic Genetic Architecture.

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Zan, Yanjun; Sheng, Zheya; Lillie, Mette; Rönnegård, Lars; Honaker, Christa F; Siegel, Paul B; Carlborg, Örjan

2017-10-01

The ability of a population to adapt to changes in their living conditions, whether in nature or captivity, often depends on polymorphisms in multiple genes across the genome. In-depth studies of such polygenic adaptations are difficult in natural populations, but can be approached using the resources provided by artificial selection experiments. Here, we dissect the genetic mechanisms involved in long-term selection responses of the Virginia chicken lines, populations that after 40 generations of divergent selection for 56-day body weight display a 9-fold difference in the selected trait. In the F15 generation of an intercross between the divergent lines, 20 loci explained >60% of the additive genetic variance for the selected trait. We focused particularly on fine-mapping seven major QTL that replicated in this population and found that only two fine-mapped to single, bi-allelic loci; the other five contained linked loci, multiple alleles or were epistatic. This detailed dissection of the polygenic adaptations in the Virginia lines provides a deeper understanding of the range of different genome-wide mechanisms that have been involved in these long-term selection responses. The results illustrate that the genetic architecture of a highly polygenic trait can involve a broad range of genetic mechanisms, and that this can be the case even in a small population bred from founders with limited genetic diversity. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery

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Brown, Nicole; Nagarkatti, Mitzi; Nagarkatti, Prakash S.

2006-01-01

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effects of DES on T-cell differentiation in the thymus using the HY-TCR transgenic (Tg) mouse model in which the female mice exhibit positive selection of T cells bearing the Tg TCR, while the male mice show negative selection of such T cells. In female HY-TCR-Tg mice, exposure to DES showed more pronounced decrease in thymic cellularity when compared to male mice. Additionally, female mice also showed a significant decrease in the proportion of double-positive (DP) T cells in the thymus and HY-TCR-specific CD8 + T cells in the periphery. Male mice exhibiting negative selection also showed decreased thymic cellularity following DES exposure. Moreover, the male mice showed increased proportion of double-negative (DN) T cells in the thymus and decreased proportion of CD8 + T cells. The density of expression of HY-TCR on CD8 + cells was increased following DES exposure in both females and males. Finally, the proliferative response of thymocytes to mitogens and peripheral lymph node T cells to male H-Y antigen was significantly altered in female and male mice following DES treatment. Taken together, these data suggest that DES alters T-cell differentiation in the thymus by interfering with positive and negative selection processes, which in turn modulates the T-cell repertoire in the periphery

Diethylstilbestrol alters positive and negative selection of T cells in the thymus and modulates T-cell repertoire in the periphery

Energy Technology Data Exchange (ETDEWEB)

Brown, Nicole [Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 (United States); Nagarkatti, Mitzi [Department of Microbiology and Immunology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298 (United States); Nagarkatti, Prakash S [Department of Pharmacology and Toxicology, PO Box 980613, Virginia Commonwealth University Medical Center, Richmond, VA 23298-0613 (United States)

2006-04-15

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effects of DES on T-cell differentiation in the thymus using the HY-TCR transgenic (Tg) mouse model in which the female mice exhibit positive selection of T cells bearing the Tg TCR, while the male mice show negative selection of such T cells. In female HY-TCR-Tg mice, exposure to DES showed more pronounced decrease in thymic cellularity when compared to male mice. Additionally, female mice also showed a significant decrease in the proportion of double-positive (DP) T cells in the thymus and HY-TCR-specific CD8{sup +} T cells in the periphery. Male mice exhibiting negative selection also showed decreased thymic cellularity following DES exposure. Moreover, the male mice showed increased proportion of double-negative (DN) T cells in the thymus and decreased proportion of CD8{sup +} T cells. The density of expression of HY-TCR on CD8{sup +} cells was increased following DES exposure in both females and males. Finally, the proliferative response of thymocytes to mitogens and peripheral lymph node T cells to male H-Y antigen was significantly altered in female and male mice following DES treatment. Taken together, these data suggest that DES alters T-cell differentiation in the thymus by interfering with positive and negative selection processes, which in turn modulates the T-cell repertoire in the periphery.

Behavioural profiles of two Wistar rat lines selectively bred for high or low anxiety-related behaviour.

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Liebsch, G; Montkowski, A; Holsboer, F; Landgraf, R

1998-08-01

Over the past years, two breeding lines, derived originally from outbred Wistar rats, have been established that differ markedly and consistently in their anxiety-related behaviour in the elevated plus-maze. At the age of ten weeks, rats were tested once on the elevated plus-maze and the males and females displaying the most anxious and the least anxious behaviour were sib-mated to start a new generation of the high anxiety-related behaviour (HAB) and the low anxiety-related behaviour (LAB) lines, respectively. The resulting difference in emotionality between these two lines was also evident in an open field test and correlated with differences in the forced swim test. In the open field, the HAB rats tended to be less active and explored the central zone of the open field much less than the LAB animals. In the forced swim test, HAB rats started floating earlier, spent significantly more time in this immobile posture and struggled less than LAB rats. However, in an olfactory-cued social discrimination task there was no difference between male and female animals from either line. The overall performance in these various behavioural tests suggests that selective breeding has resulted in rat lines not only differing markedly in their innate anxiety-related behaviour in the plus-maze, but also in other stress-related behavioural performances, suggesting a close link between the emotional evaluation of a novel and stressful situation and an individual's coping strategy.

Battery of behavioral tests in mice to study postoperative delirium

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Peng, Mian; Zhang, Ce; Dong, Yuanlin; Zhang, Yiying; Nakazawa, Harumasa; Kaneki, Masao; Zheng, Hui; Shen, Yuan; Marcantonio, Edward R.; Xie, Zhongcong

2016-01-01

Postoperative delirium is associated with increased morbidity, mortality and cost. However, its neuropathogenesis remains largely unknown, partially owing to lack of animal model(s). We therefore set out to employ a battery of behavior tests, including natural and learned behavior, in mice to determine the effects of laparotomy under isoflurane anesthesia (Anesthesia/Surgery) on these behaviors. The mice were tested at 24 hours before and at 6, 9 and 24 hours after the Anesthesia/Surgery. Composite Z scores were calculated. Cyclosporine A, an inhibitor of mitochondria permeability transient pore, was used to determine potential mitochondria-associated mechanisms of these behavioral changes. Anesthesia/Surgery selectively impaired behaviors, including latency to eat food in buried food test, freezing time and time spent in the center in open field test, and entries and duration in the novel arm of Y maze test, with acute onset and various timecourse. The composite Z scores quantitatively demonstrated the Anesthesia/Surgery-induced behavior impairment in mice. Cyclosporine A selectively ameliorated the Anesthesia/Surgery-induced reduction in ATP levels, the increases in latency to eat food, and the decreases in entries in the novel arm. These findings suggest that we could use a battery of behavior tests to establish a mouse model to study postoperative delirium. PMID:27435513

Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1beta.

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Li, S; Ballou, L R; Morham, S G; Blatteis, C M

2001-08-10

Various lines of evidence have implicated cyclooxygenase (COX)-2 as a modulator of the fever induced by the exogenous pyrogen lipopolysaccharide (LPS). Thus, treatment with specific inhibitors of COX-2 suppresses the febrile response without affecting basal body (core) temperature (T(c)). Furthermore, COX-2 gene-ablated mice are unable to develop a febrile response to intraperitoneal (i.p.) LPS, whereas their COX-1-deficient counterparts produce fevers not different from their wild-type (WT) controls. To extend the apparently critical role of COX-2 for LPS-induced fevers to fevers produced by endogenous pyrogens, we studied the thermal responses of COX-1- and COX-2 congenitally deficient mice to i.p. and intracerebroventricular (i.c.v.) injections of recombinant murine (rm) interleukin (IL)-1beta. We also assessed the effects of one selective COX-1 inhibitor, SC-560, and two selective COX-2 inhibitors, nimesulide (NIM) and dimethylfuranone (DFU), on the febrile responses of WT and COX-1(-/-) mice to LPS and rmIL-1beta, i.p. Finally, we verified the integrity of the animals' responses to PGE2, i.c.v. I.p. and i.c.v. rmIL-1beta induced similar fevers in WT and COX-1 knockout mice, but provoked no rise in the T(c)s of COX-2 null mutants. The fever produced in WT mice by i.p. LPS was not affected by SC-560, but it was attenuated and abolished by NIM and DFU, respectively, while that caused by i.p. rmIL-1beta was converted into a T(c) fall by DFU. There were no differences in the responses to i.c.v. PGE2 among the WT and COX knockout mice. These results, therefore, further support the notion that the production of PGE2 in response to pyrogens is critically dependent on COX-2 expression.

Two generations of selection on restricted best linear unbiased prediction breeding values for income minus feed cost in laying hens.

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Hagger, C

1992-07-01

Two generations of selection on restricted BLUP breeding values were applied in an experiment with laying hens. Selection had been on phenotype of income minus feed cost (IFC) between 21 and 40 wk of age in the previous five generations. The restriction of no genetic change in egg weight was included in the EBV for power-transformed IFC (i.e., IFCt, with t-values of 3.7 and 3.6 in the two generations, respectively). The experiment consisted of two selection lines plus a randomly bred control of 20 male and 80 female breeders each. Observations on 8,844 survivors to 40 wk were available. Relative to the base population average, the restriction reduced genetic gain in IFC from 4.1 and 3.9% to 2.0 and 2.2% per generation in the two selection lines, respectively. Average EBV for egg weight remained nearly constant after a strong increase in the previous five generations. Rates of genetic gain for egg number, body weight, and feed conversion (feed/egg mass) were not affected significantly. In the seventh generation, a genetic gain in feed conversion of 10.3% relative to the phenotypic mean of the base population was obtained.

Pentobarbital Sleep Time in Mouse Lines Selected for Resistance and Susceptibility to Fescue Toxicosis

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Arthur, Kimberly Ann

2002-01-01

In previous work with mouse lines selected for resistance (R) and susceptibility (S) to fescue toxicosis, R mice had higher activities of Phase II liver enzymes glutathione S-transferase and uridine diphosphate glucuronosyl-transferase than S mice. Objectives of this study were: 1. to determine whether selection for toxicosis response had also caused divergence between lines in hepatic Phase I enzyme activity (as assessed by sleep time following sodium pentobarbital anesthesia), 2. to determi...

Afferent input selects NMDA receptor subtype to determine the persistency of hippocampal LTP in freely behaving mice

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Jesús Javier Ballesteros

2016-10-01

Full Text Available The glutamatergic N-methyl-D-aspartate receptor (NMDAR is critically involved in many forms of hippocampus-dependent memory that may be enabled by synaptic plasticity. Behavioral studies with NMDAR antagonists and NMDAR subunit (GluN2 mutants revealed distinct contributions from GluN2A- and GluN2B-containing NMDARs to rapidly and slowly acquired memory performance. Furthermore, studies of synaptic plasticity, in genetically modified mice in vitro, suggest that GluN2A and GluN2B may contribute in different ways to the induction and longevity of synaptic plasticity. In contrast to the hippocampal slice preparation, in behaving mice, the afferent frequencies that induce synaptic plasticity are very restricted and specific. In fact, it is the stimulus pattern, and not variations in afferent frequency that determine the longevity of long-term potentiation (LTP. Here, we explored the contribution of GluN2A and GluN2B to LTP of differing magnitudes and persistencies in freely behaving mice. We applied differing high-frequency stimulation (HFS patterns at 100 Hz to the hippocampal CA1 region, to induce NMDAR-dependent LTP in wild-type (WT mice, that endured for 24h (late (L-LTP. In GluN2A-KO mice, E-LTP (HFS, 50 pulses was significantly reduced in magnitude and duration, whereas LTP (HFS, 2 x 50 pulses and L-LTP (HFS, 4 x 50 pulses were unaffected compared to responses in WT animals. By contrast, pharmacological antagonism of GluN2B in WT had no effect on E-LTP but significantly prevented LTP. E- LTP and LTP were significantly impaired by GluN2B antagonism in GluN2A-KO mice. These data indicate that the pattern of afferent stimulation is decisive for the recruitment of distinct GluN2A and GluN2B signaling pathways that in turn determine the persistency of hippocampal LTP. Whereas brief bursts of patterned stimulation preferentially recruit GluN2A and lead to weak and short-lived forms of LTP, prolonged, more intense, afferent activation recruits GluN2B

Sensorimotor Gating in Neurotensin-1 Receptor Null Mice

Science.gov (United States)

Feifel, D.; Pang, Z.; Shilling, P.D.; Melendez, G.; Schreiber, R.; Button, D.

2009-01-01

BACKGROUND Converging evidence has implicated endogenous neurotensin (NT) in the pathophysiology of brain processes relevant to schizophrenia. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating and considered to be of strong relevance to neuropsychiatric disorders associated with psychosis and cognitive dysfunction. Mice genetically engineered to not express NT display deficits in PPI that model the PPI deficits seen in schizophrenia patients. NT1 receptors have been most strongly implicated in mediating the psychosis relevant effects of NT such as attenuating PPI deficits. To investigate the role of NT1 receptors in the regulation of PPI, we measured baseline PPI in wildtype (WT) and NT1 knockout (KO) mice. We also tested the effects of amphetamine and dizocilpine, a dopamine agonist and NMDA antagonist, respectively, that reduce PPI as well as the NT1 selective receptor agonist, PD149163, known to increase PPI in rats. METHODS Baseline PPI and acoustic startle response were measured in WT and NT1 knockout KO mice. After baseline testing, mice were tested again after receiving intraperatoneal (IP) saline or one of three doses of amphetamine (1.0, 3.0 and 10.0 mg/kg), dizocilpine (0.3, 1.0 and 3.0 mg/kg) and PD149163 (0.5, 2.0 and 6.0 mg/kg) on separate test days. RESULTS Baseline PPI and acoustic startle response in NT1 KO mice were not significantly different from NT1 WT mice. WT and KO mice exhibited similar responses to the PPI-disrupting effects of dizocilpine and amphetamine. PD149163 significantly facilitated PPI (P < 0.004) and decreased the acoustic startle response (P < 0.001) in WT but not NT1 KO mice. CONCLUSIONS The data does not support the regulation of baseline PPI or the PPI disruptive effects of amphetamine or dizocilpine by endogenous NT acting at the NT1 receptor, although they support the antipsychotic potential of pharmacological activation of NT1 receptors by NT1 agonists. PMID:19596359

Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area

International Nuclear Information System (INIS)

Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

2013-01-01

Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. - Highlights: ► The expression of AHR-target genes in blood bovine lymphocytes was evaluated. ► The lymphocyte CYP1B1 expression appears to be related to bulk milk TEQ values. ► Blood lymphocytes from dairy cows might represent a matrix for dioxin biomonitoring

Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area

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Girolami, Flavia [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Spalenza, Veronica [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Carletti, Monica [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Sacchi, Paola [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Rasero, Roberto [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Nebbia, Carlo [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy)

2013-04-15

Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. - Highlights: ► The expression of AHR-target genes in blood bovine lymphocytes was evaluated. ► The lymphocyte CYP1B1 expression appears to be related to bulk milk TEQ values. ► Blood lymphocytes from dairy cows might represent a matrix for dioxin biomonitoring.

p21-LacZ reporter mice reflect p53-dependent toxic insult

International Nuclear Information System (INIS)

Vasey, Douglas B.; Wolf, C. Roland; MacArtney, Thomas; Brown, Ken; Whitelaw, C. Bruce A.

2008-01-01

There is an urgent need to discover less toxic and more selective drugs to treat disease. The use of transgenic mice that report on toxic insult-induced transcription can provide a valuable tool in this regard. To exemplify this strategy, we have generated transgenic mice carrying a p21-LacZ transgene. Transgene activity reflected endogenous p21 gene activation in various tissues, displayed compound-specific spatial expression signatures in the brain and immune tissues and enabled p53-dependent and p53-independent responses to be identified. We discuss the application of these mice in delineating the molecular events in normal cellular growth and disease and for the evaluation of drug toxicity

Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice.

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Benneyworth, Michael A; Smith, Randy L; Barrett, Robert J; Sanders-Bush, Elaine

2005-06-01

The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice. To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice. Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer. As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT(2A/2C) receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(-)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT(2A) receptor-selective antagonist, MDL 100907, or the 5-HT(1A)-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (-)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment. These data suggest that in mice the stimulus effects of LSD have both a 5-HT(2A) receptor and a 5-HT(1A) receptor component.

Genetic interactions between planar cell polarity genes cause diverse neural tube defects in mice

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Jennifer N. Murdoch

2014-10-01

Full Text Available Neural tube defects (NTDs are among the commonest and most severe forms of developmental defect, characterized by disruption of the early embryonic events of central nervous system formation. NTDs have long been known to exhibit a strong genetic dependence, yet the identity of the genetic determinants remains largely undiscovered. Initiation of neural tube closure is disrupted in mice homozygous for mutations in planar cell polarity (PCP pathway genes, providing a strong link between NTDs and PCP signaling. Recently, missense gene variants have been identified in PCP genes in humans with NTDs, although the range of phenotypes is greater than in the mouse mutants. In addition, the sequence variants detected in affected humans are heterozygous, and can often be detected in unaffected individuals. It has been suggested that interactions between multiple heterozygous gene mutations cause the NTDs in humans. To determine the phenotypes produced in double heterozygotes, we bred mice with all three pairwise combinations of Vangl2Lp, ScribCrc and Celsr1Crsh mutations, the most intensively studied PCP mutants. The majority of double-mutant embryos had open NTDs, with the range of phenotypes including anencephaly and spina bifida, therefore reflecting the defects observed in humans. Strikingly, even on a uniform genetic background, variability in the penetrance and severity of the mutant phenotypes was observed between the different double-heterozygote combinations. Phenotypically, Celsr1Crsh;Vangl2Lp;ScribCrc triply heterozygous mutants were no more severe than doubly heterozygous or singly homozygous mutants. We propose that some of the variation between double-mutant phenotypes could be attributed to the nature of the protein disruption in each allele: whereas ScribCrc is a null mutant and produces no Scrib protein, Celsr1Crsh and Vangl2Lp homozygotes both express mutant proteins, consistent with dominant effects. The variable outcomes of these genetic

Tissue Selective Androgen Receptor Modulators (SARMs) Increase Pelvic Floor Muscle Mass in Ovariectomized Mice.

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Ponnusamy, Suriyan; Sullivan, Ryan D; Thiyagarajan, Thirumagal; Tillmann, Heather; Getzenberg, Robert H; Narayanan, Ramesh

2017-03-01

Stress urinary incontinence (SUI), a prevalent condition, is represented by an involuntary leakage of urine that results, at least in part, from weakened or damaged pelvic floor muscles and is triggered by physical stress. Current treatment options are limited with no oral therapies available. The pelvic floor is rich in androgen receptor and molecules with anabolic activity including selective androgen receptor modulators (SARMs) may serve as therapeutic options for individuals with SUI. In this study, two SARMs (GTx-024 and GTx-027) were evaluated in a post-menopausal animal model in order to determine their effect on pelvic floor muscles. Female C57BL/6 mice were ovariectomized and their pelvic muscles allowed to regress. The animals were then treated with vehicle or doses of GTx-024 or GTx-027. Animal total body weight, lean body mass, and pelvic floor muscle weights were measured along with the expression of genes associated with muscle catabolism. Treatment with the SARMs resulted in a restoration of the pelvic muscles to the sham-operated weight. Coordinately, the induction of genes associated with muscle catabolism was inhibited. Although a trend was observed towards an increase in total lean body mass in the SARM-treated groups, no significant differences were detected. Treatment of an ovariectomized mouse model with SARMs resulted in an increase in pelvic floor muscles, which may translate to an improvement of symptoms associated with SUI and serves as the basis for evaluating their clinical use. J. Cell. Biochem. 118: 640-646, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Histomorphological effects of isoniazid induced hepatotoxicity in male albino mice

International Nuclear Information System (INIS)

Humayun, F.; Zareen, N.

2017-01-01

To observe the histomorphological changes of isoniazid induced hepatotoxicity in male albino mice. Methodology: This experimental study was carried out at University of Health Sciences, Lahore, Pakistan from January to December 2013. Forty male albino mice selected by simple random technique, were divided into two groups; A-Control, and B-experimental. Group A comprised of 15, while Group B comprised 25 mice. Both the groups were kept under identical conditions and diet. However, experimental group was treated with an additional oral hepatotoxic dose of isoniazid i.e. 100mg/kg bodyweight daily for 30 days. After 30 days, the animals were sacrificed and livers were dissected out. Gross comparison of the organ and stained sections were histologically compared for morphological differences between the groups. Fischer Exact test was used to analyze the qualitative data and a p<0.05 was considered significant. Results: Group A animals showed the normal liver architecture. Whereas, those of Group B showed deranged hepatic histomorphology. Conclusion: Hepatotoxic dose of Isoniazid caused histomorphological alterations in the liver of male albino mice. (author)

Generation of ERα-floxed and knockout mice using the Cre/LoxP system

International Nuclear Information System (INIS)

Antonson, P.; Omoto, Y.; Humire, P.; Gustafsson, J.-Å.

2012-01-01

Highlights: ► ERα floxed and knockout mice were generated. ► Disruption of the ERα gene results in sterility in both male and female mice. ► ERα −/− mice have ovaries with hemorrhagic follicles and hypoplastic uterus. ► Female ERα −/− mice develop obesity. -- Abstract: Estrogen receptor alpha (ERα) is a nuclear receptor that regulates a range of physiological processes in response to estrogens. In order to study its biological role, we generated a floxed ERα mouse line that can be used to knock out ERα in selected tissues by using the Cre/LoxP system. In this study, we established a new ERα knockout mouse line by crossing the floxed ERα mice with Cre deleter mice. Here we show that genetic disruption of the ERα gene in all tissues results in sterility in both male and female mice. Histological examination of uterus and ovaries revealed a dramatically atrophic uterus and hemorrhagic cysts in the ovary. These results suggest that infertility in female mice is the result of functional defects of the reproductive tract. Moreover, female knockout mice are hyperglycemic, develop obesity and at the age of 4 months the body weight of these mice was more than 20% higher compared to wild type littermates and this difference increased over time. Our results demonstrate that ERα is necessary for reproductive tract development and has important functions as a regulator of metabolism in females.

Delayed puberty but normal fertility in mice with selective deletion of insulin receptors from Kiss1 cells.

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Qiu, Xiaoliang; Dowling, Abigail R; Marino, Joseph S; Faulkner, Latrice D; Bryant, Benjamin; Brüning, Jens C; Elias, Carol F; Hill, Jennifer W

2013-03-01

Pubertal onset only occurs in a favorable, anabolic hormonal environment. The neuropeptide kisspeptin, encoded by the Kiss1 gene, modifies GnRH neuronal activity to initiate puberty and maintain fertility, but the factors that regulate Kiss1 neurons and permit pubertal maturation remain to be clarified. The anabolic factor insulin may signal nutritional status to these neurons. To determine whether insulin sensing plays an important role in Kiss1 neuron function, we generated mice lacking insulin receptors in Kiss1 neurons (IR(ΔKiss) mice). IR(ΔKiss) females showed a delay in vaginal opening and in first estrus, whereas IR(ΔKiss) males also exhibited late sexual maturation. Correspondingly, LH levels in IR(ΔKiss) mice were reduced in early puberty in both sexes. Adult reproductive capacity, body weight, fat composition, food intake, and glucose regulation were comparable between the 2 groups. These data suggest that impaired insulin sensing by Kiss1 neurons delays the initiation of puberty but does not affect adult fertility. These studies provide insight into the mechanisms regulating pubertal timing in anabolic states.

An experimental model for the study of cognitive disorders: the hippocampus and associative learning in mice.

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Delgado-García, José M; Gruart, Agnès

2008-12-01

The availability of transgenic mice mimicking selective human neurodegenerative and psychiatric disorders calls for new electrophysiological and microstimulation techniques capable of being applied in vivo in this species. In this article, we will concentrate on experiments and techniques developed in our laboratory during the past few years. Thus we have developed different techniques for the study of learning and memory capabilities of wild-type and transgenic mice with deficits in cognitive functions, using classical conditioning procedures. These techniques include different trace (tone/SHOCK and shock/SHOCK) conditioning procedures ? that is, a classical conditioning task involving the cerebral cortex, including the hippocampus. We have also developed implantation and recording techniques for evoking long-term potentiation (LTP) in behaving mice and for recording the evolution of field excitatory postsynaptic potentials (fEPSP) evoked in the hippocampal CA1 area by the electrical stimulation of the commissural/Schaffer collateral pathway across conditioning sessions. Computer programs have also been developed to quantify the appearance and evolution of eyelid conditioned responses and the slope of evoked fEPSPs. According to the present results, the in vivo recording of the electrical activity of selected hippocampal sites during classical conditioning of eyelid responses appears to be a suitable experimental procedure for studying learning capabilities in genetically modified mice, and an excellent model for the study of selected neuropsychiatric disorders compromising cerebral cortex functioning.

The effect of diet and litter size on the elimination of 2,4,5,2',4',5'-[14C]hexachlorobiphenyl from lactating mice

International Nuclear Information System (INIS)

Ring, B.J.; Seitz, K.R.; Gallenberg, L.A.; Vodicnik, M.J.

1990-01-01

It was shown that 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) administered to adult female mice accumulated in their nursing offspring more rapidly than a dose administered to weanling mice when treated animals were bred at equivalent ages. This suggested that the PCB was eliminated from the maternal animal relative to its time of sequestration into storage depots. Using a model which more closely approximates conditions during human lactation, the influence of a high-fat diet and decreased litter size on this phenomenon was examined. Female ICR mice were treated with 4 mg/kg [14C]-6-CB as 13-g weanlings (dW) at 3 weeks of age or as adults (dA) at 11 weeks of age. All animals were mated at 11 weeks of age. On Day 1 of pregnancy, mice were placed on a low-fat (11.5% of the total calories) or high-fat (43.8% of total calories) diet. At parturition, litters were adjusted to either two or eight within each diet group. Elimination of maternal 6-CB was determined by assessing radioactivity in offspring carcasses on Day 15 of gestation or Day 1, 3, 5, 10, or 15 postpartum. Consumption of a high-fat diet significantly extended the t1/2 of elimination of 6-CB from mothers nursing a litter of two in the dW group (low fat = 7.3 days; high fat = 12.4 days) and in both the dW and dA groups nursing litters of eight (dW: low fat = 4.6 days; high fat = 6.8 days; and dA: low fat = 1.8 days; high fat = 3.0 days). Within diet and group, reducing litter size to two also significantly decreased the rate of elimination of 6-CB from maternal animals. 6-CB was eliminated to offspring more rapidly from the dA group when compared to the dW group regardless of diet in animals nursing litters of eight. This relationship was not observed in maternal animals nursing litters of two. In general, exposure to a high-fat diet increased the t1/2 of elimination of 6-CB from maternal animals

YIELD CAPACITY AND CHEMICAL COMPOSITION OF GREEN BEANS IN CULTIVARS OF KIDNEY BEAN BRED AT OMSK AGRARIAN UNIVERSITY IN THE SOUTH FOREST-STEPPE OF WESTERN SIBERIA

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N. G. Kazydub

2017-01-01

Full Text Available In  2014-2016  the  assessment of  kidney bean  cultivars bred at Omsk State Agrarian University on yield capacity, quality, and biochemical  chemical compounds  in green beans, such as proteins, zinc, iodine, iron and sucrose was carried  out  in  the  south  forest-steppe  of  Western Siberia. The technological  parameters of  green  beans: the  shape  of  cross-section  area; pulpiness,  fibrous  or non-fibrous,  and bean thickness were estimated. Threeyear study showed that all tested cultivars bred at Omsk State  Agrarian  University  surpassed  control  cultivar  in yield capacity,  chemical composition  and technological parameters of green beans. The cultivar ‘Pamiyaty Rizhovoy’ gave a highest yield: 563.4 g/m2  in 2014; 622.8 g/m2 in 2015; and 620.4 g/m2  in 2016. It is worth noticing that this cultivar is also distinguished by contents of micro and macroelements: 21.20-28.68  mg/kg  of zinc; 0.012-0.018 mg/kg of iodine; and 1.8-3.2 mg/kg of iron. In the course of the study, it was noticed the dependence of  yield  capacity  on  hydrothermal  coefficient  (HC. In 2014-2015 the yield capacity was a lowest when the moisturization was insufficient at 0.7 HC. With increase of HC the yield was higher. With sufficient moisturization at 1.0 HC the highest yield of green beans was observed in 2016.  The estimation  of  kidney  bean  cultivars  bred  at Omsk State  Agrarian University showed  that  all beans were  distinguished  by  high  quality  parameters  in  the phase  of  technical  maturity,  such  as  pulpiness,  nonfibrous, thickness 0.5 to  1.0 cm, and green and yellow colors.  The  highest  protein  content  comparing  to  the control  cultivar  ‘Zolushka’  was  detected  in  ‘Marusya’ 23.60%  in  2014,  20.94%  in  2015;  and  ‘Zoloto  Sibiry’ 19.79%  in  2016.  The  observed  results  confirmed  that contents  change of

An Animal Model of Genetic Vulnerability to Behavioral Disinhibition and Responsiveness to Reward-Related Cues: Implications for Addiction

OpenAIRE

Flagel, Shelly B; Robinson, Terry E; Clark, Jeremy J; Clinton, Sarah M; Watson, Stanley J; Seeman, Phillip; Phillips, Paul E M; Akil, Huda

2009-01-01

Rats selectively bred based on high or low reactivity to a novel environment were characterized for other behavioral and neurobiological traits thought to be relevant to addiction vulnerability. The two lines of animals, which differ in their propensity to self-administer drugs, also differ in the value they attribute to cues associated with reward, in impulsive behavior, and in their dopamine system. When a cue was paired with food or cocaine reward bred high-responder rats (bHRs) learned to...

Tissue distribution of tritiated digoxin and quabain in mice

International Nuclear Information System (INIS)

Klopper, J.F.; Atkins, H.L.

1976-01-01

Tissue concentration of tritiated digoxin in human subjects appears to be selective in that after a single dose of the radioactive tracer a myocardial concentration of digoxin on an average 24 to 30 times higher than the serum concentration is reached. In patients studied 3.5 to 84 hours after administration of tritiated digoxin, the dose in the heart was found to vary between 1.95 to 4.83 percent. Should it be possible to label digoxin or another cardiac glycoside with a suitable gamma-emitting tracer, its use as a cardiac imaging agent should thus be feasible. This study was undertaken to determine the tissue distribution in mice of tritiated digoxin at various time intervals post injection; and to determine if these values showed any correlation to the previously determined human data. A preliminary study in mice using 3 H-digitoxin revealed no selective uptake in the heart with high uptakes in the liver and gut. Since ouabain has a more rapid clinical onset of action than digoxin, its tissue distribution was included in the study and compared to that of digoxin

The Effect of Ecstasy Administration during Pregnancy on Mice Fetuses

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Y Mostafavi Pour-Manshadi

2011-09-01

Full Text Available Introduction: Ecstasy or 3,4-Methylenedioxymethamphetamine(MDMA is a psychotropic and addictive substance that young people tend to use it to reduce their psychological and social tensions. The purpose of this study was to assess the influence of ecstasy consumption on the fetus of pregnant mice during the second and third weeks of pregnancy. Methods: 20 adult female mice were randomly selected(5 for control group and 15 for experimental group. Two intraperitoneal injections of ecstasy(5mg/Kg was used in the experimental group, on 7th and 14th days of pregnancy, while, in the control group, only distilled water was injected intraperitoneally. On 18th day of pregnancy, mice were placed in separate cages. The condition of palate, skull, external ear, eye, fingers and toes and sindactily, weight, and fertility potentials of newborn mice were studied using stereo microscope. Results: From 163 newborn mice in two groups, no abnormalities were observed in the skull and the external ear. There wasn’t any significant difference between male and female sex ratio between two groups (p=.08. Hypoplasia of the fingers was significantly different between the two groups(p<0.001. The frequency of sindactily was not significantly different between two groups(p=0. 11. Female fertility potential was significantly different between two groups(p<0.001. Conclusion: Adminstration of ecstasy during pregnancy may affect the organogenesis and fertility potential of newborn mice. Therefore, more studies are needed in this regard.

Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice

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Buckman, Laura B.; Thompson, Misty M.; Lippert, Rachel N.; Blackwell, Timothy S.; Yull, Fiona E.; Ellacott, Kate L.J.

2014-01-01

Objective Introduction of a high-fat diet to mice results in a period of voracious feeding, known as hyperphagia, before homeostatic mechanisms prevail to restore energy intake to an isocaloric level. Acute high-fat diet hyperphagia induces astrocyte activation in the rodent hypothalamus, suggesting a potential role of these cells in the homeostatic response to the diet. The objective of this study was to determine physiologic role of astrocytes in the acute homeostatic response to high-fat feeding. Methods We bred a transgenic mouse model with doxycycline-inducible inhibition of NFkappaB (NFκB) signaling in astrocytes to determine the effect of loss of NFκB-mediated astrocyte activation on acute high-fat hyperphagia. ELISA was used to measure the levels of markers of astrocyte activation, glial-fibrillary acidic protein (GFAP) and S100B, in the medial basal hypothalamus. Results Inhibition of NFκB signaling in astrocytes prevented acute high-fat diet-induced astrocyte activation and resulted in a 15% increase in caloric intake (P < 0.01) in the first 24 h after introduction of the diet. Conclusions These data reveal a novel homeostatic role for astrocytes in the acute physiologic regulation of food intake in response to high-fat feeding. PMID:25685690

Behavioral phenotyping of mice in pharmacological and toxicological research.

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Karl, Tim; Pabst, Reinhard; von Hörsten, Stephan

2003-07-01

The evaluation of behavioral effects is an important component for the in vivo screening of drugs or potentially toxic compounds in mice. Ideally, such screening should be composed of monitoring general health, sensory functions, and motor abilities, right before specific behavioral domains are tested. A rational strategy in the design and procedure of testing as well as an effective composition of different well-established and reproducible behavioral tests can minimize the risk of false positive and false negative results in drug screening. In the present review we describe such basic considerations in planning experiments, selecting strains of mice, and propose groups of behavioral tasks suitable for a reliable detection of differences in specific behavioral domains in mice. Screening of general health and neurophysiologic functions (reflexes, sensory abilities) and motor function (pole test, wire hang test, beam walking, rotarod, accelerod, and footprint) as well as specific hypothesis-guided testing in the behavioral domains of learning and memory (water maze, radial maze, conditioned fear, and avoidance tasks), emotionality (open field, hole board, elevated plus maze, and object exploration), nociception (tail flick, hot plate), psychiatric-like conditions (porsolt swim test, acoustic startle response, and prepulse inhibition), and aggression (isolation-induced aggression, spontaneous aggression, and territorial aggression) are described in further detail. This review is designed to describe a general approach, which increases reliability of behavioral screening. Furthermore, it provides an overview on a selection of specific procedures suitable for but not limited to behavioral screening in pharmacology and toxicology.

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

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Guo, Weirui; Molinaro, Gemma; Collins, Katie A; Hays, Seth A; Paylor, Richard; Worley, Paul F; Szumlinski, Karen K; Huber, Kimberly M

2016-02-17

Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5(R/R)) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5(R/R) mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease. Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and

Effect of Tamoxifen on Seminiferous Tubules Structure during Pregnancy in Adult Mice

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J Soleimani Rad

2016-03-01

Full Text Available Introduction: Tamoxifen is a nonsteroidal drug which mainly treats breast cancer. It is also applied for stimulation of ovulation and remedy of infertility. Regarding the tamoxifen binding to estrogen receptors and the possible role of estrogens in spermatogenesis, the present study aimed to histologically evaluate spermatogenesis in the seminiferous ducts of mice, whose mothers had received tamoxifen during pregnancy. Methods: In the present study, 30 female and 15 male mice of NMRI race were selected for mating. Since 13th day of pregnancy, the experimental group received tamoxifen with the dosage of 5 mg/kg intra-peritoneally for 7 days, wherease the control group received normal saline. After childbirth of the mated mice, male infants were selected and monitored in the standard laboratory conditions. After reaching the age of puberty (6-8Weeks, adult mice were sacrificed by the cervical dislocation, and the testes were removed for histological evaluation of spermatogenesis. After routine histological processing, the samples were studied by the light microscope. Results: Histological studies showed that spermatogenic and Sertoli cells in the seminiferous tubules in control and experimental groups were significantly different, though no difference was observed in the number of Leydig cells in the both groups. Conclusion: The findings of the present study showed that tamoxifen exposure during development can cause histological changes in the seminiferous tubules, which can lead to infertility in the male rat.

Strain-specific patterns of autonomic nervous system activity and heart failure susceptibility in mice.

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Shusterman, Vladimir; Usiene, Irmute; Harrigal, Chivonne; Lee, Joon Sup; Kubota, Toru; Feldman, Arthur M; London, Barry

2002-06-01

Transgenic mice are widely used to study cardiac function, but strain-dependent differences in autonomic nervous system activity (ANSA) have not been explored. We compared 1) short-term pharmacological responses of cardiac rhythm in FVB vs. C57Black6/SV129 wild-type mice and 2) long-term physiological dynamics of cardiac rhythm and survival in tumor necrosis factor (TNF)-alpha transgenic mice with heart failure (TNF-alpha mice) on defined backgrounds. Ambulatory telemetry electrocardiographic recordings and response to saline, adrenergic, and cholinergic agents were examined in FVB and C57Black6/SV129 mice. In FVB mice, baseline heart rate (HR) was higher and did not change after injection of isoproterenol or atropine but decreased with propranolol. In C57Black6/SV129 mice, HR did not change with propranolol but increased with isoproterenol or atropine. Mean HR, but not indexes of HR variability, was an excellent predictor of response to autonomic agents. The proportion of surviving animals was higher in TNF-alpha mice on an FVB background than on a mixed FVB/C57Black6 background. The homeostatic states of ANSA are strain specific, which can explain the interstrain differences in mean HR, pharmacological responses, and survival of animals with congestive heart failure. Strain-specific differences should be considered in selecting the strains of mice used for transgenic and gene targeting experiments.

Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice.

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Filiano, Anthony J; Martens, Lauren Herl; Young, Allen H; Warmus, Brian A; Zhou, Ping; Diaz-Ramirez, Grisell; Jiao, Jian; Zhang, Zhijun; Huang, Eric J; Gao, Fen-Biao; Farese, Robert V; Roberson, Erik D

2013-03-20

Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knock-out (Grn(-/-)) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn(+/-)) mice, which model progranulin haploinsufficiency. We found that Grn(+/-) mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn(-/-) mice, behavioral deficits in Grn(+/-) mice occurred in the absence of gliosis or increased expression of tumor necrosis factor-α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn(+/-) mice. Our findings indicate that FTD-related deficits resulting from progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons.

Quench Protection and Magnet Powe Supply Requirements for the MICE Focusing and Coupling Magnets

International Nuclear Information System (INIS)

Green, Michael A.; Witte, Holger

2005-01-01

This report discusses the quench protection and power supply requirements of the MICE superconducting magnets. A section of the report discusses the quench process and how to calculate the peak voltages and hotspot temperature that result from a magnet quench. A section of the report discusses conventional quench protection methods. Thermal quench back from the magnet mandrel is also discussed. Selected quench protection methods that result in safe quenching of the MICE focusing and coupling magnets are discussed. The coupling of the MICE magnets with the other magnets in the MICE is described. The consequences of this coupling on magnet charging and quenching are discussed. Calculations of the quenching of a magnet due quench back from circulating currents induced in the magnet mandrel due to quenching of an adjacent magnet are discussed. The conclusion of this report describes how the MICE magnet channel will react when one or magnets in that channel are quenched

Prevalence of intestinal helminth infection among school children in Maksegnit and Enfranz Towns, northwestern Ethiopia, with emphasis on Schistosoma mansoni infection.

Science.gov (United States)

Gashaw, Fikru; Aemero, Mulugeta; Legesse, Mengistu; Petros, Beyene; Teklehaimanot, Tilahun; Medhin, Girmay; Berhe, Nega; Mekonnen, Yalemtsehay; Erko, Berhanu

2015-10-31

Schistosomiasis is endemic in Ethiopia and previously unknown transmission foci have been reported from time to time in different parts of the country. Further surveys are required in areas where endemicity of the disease is not known to cover them with control program if transmission is taking place. This study, therefore, aims to assess the magnitude of schistosomiasis mansoni and soil-transmitted helminthiasis in Maksegnit and Enfranz Towns, northwestern Ethiopia. Cross-sectional parasitological and malacological surveys were conducted in three schools found in Maksegnit and Enfranz Towns. Stool specimens were collected from 550 randomly selected school children (age range 5 to 17 years) and processed for microscopic examination using Kato-Katz method (single smear per stool sample). Malacological survey was conducted in Gumara and Garno Rivers found in the study areas. Biomphalaria pfeifferi snails collected from the two rivers were individually exposed to artificial light in order to induce cercarial shedding. Laboratory-bred Swiss albino mice were exposed to the cercariae and definite identification of the schistosome species was made based on morphology. The overall prevalence of S. mansoni infection was found to be 49%; however, it varied by schools, with Selam having 60.7%, and Maksegnit Number 1 and 2 having 45.8 and 39.6%, respectively. The respective mean intensity of S. mansoni infection among school children in Selam, Maksegnit Number 1 and Maksegnit Number 2 Schools were 243, 194 and 183 eggs per gram of stool (epg). In all the study areas there was no difference in prevalence of S. mansoni infection in relation to age, however, the prevalence varied by sex, with males having highest prevalence (54.5% vs 44.1%) (p = 0.012). Adult S. mansoni worms were harvested from mice exposed to cercariae shed from B. pfeifferi on the 6(th) week post-exposure. The prevalence of Ascaris lumbricoides single infection was 16.5% while its co-infection with S

Reduced striatal dopamine DA D2 receptor function in dominant-negative GSK-3 transgenic mice.

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Gomez-Sintes, Raquel; Bortolozzi, Analia; Artigas, Francesc; Lucas, José J

2014-09-01

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with constitutive activity involved in cellular architecture, gene expression, cell proliferation, fate decision and apoptosis, among others. GSK-3 expression is particularly high in brain where it may be involved in neurological and psychiatric disorders such as Alzheimer׳s disease, bipolar disorder and major depression. A link with schizophrenia is suggested by the antipsychotic drug-induced GSK-3 regulation and by the involvement of the Akt/GSK-3 pathway in dopaminergic neurotransmission. Taking advantage of the previous development of dominant negative GSK-3 transgenic mice (Tg) showing a selective reduction of GSK-3 activity in forebrain neurons but not in dopaminergic neurons, we explored the relationship between GSK-3 and dopaminergic neurotransmission in vivo. In microdialysis experiments, local quinpirole (DA D2-R agonist) in dorsal striatum reduced dopamine (DA) release significantly less in Tg mice than in wild-type (WT) mice. However, local SKF-81297 (selective DA D1-R agonist) in dorsal striatum reduced DA release equally in both control and Tg mice indicating a comparable function of DA D1-R in the direct striato-nigral pathway. Likewise, systemic quinpirole administration - acting preferentially on presynaptic DA D2- autoreceptors to modulate DA release-reduced striatal DA release similarly in both control and Tg mice. Quinpirole reduced locomotor activity and induced c-fos expression in globus pallidus (both striatal DA D2-R-mediated effects) significantly more in WT than in Tg mice. Taking together, the present results show that dominant negative GSK-3 transgenic mice show reduced DA D2-R-mediated function in striatum and further support a link between dopaminergic neurotransmission and GSK-3 activity. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

Nanoparticles Containing Curcumin Useful for Suppressing Macrophages In Vivo in Mice.

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Chie Amano

Full Text Available To explore a novel method using liposomes to suppress macrophages, we screened food constituents through cell culture assays. Curcumin was one of the strongest compounds exhibiting suppressive effects on macrophages. We subsequently tried various methods to prepare liposomal curcumin, and eventually succeeded in preparing liposomes with sufficient amounts of curcumin to suppress macrophages by incorporating a complex of curcumin and bovine serum albumin. The diameter of the resultant nanoparticles, the liposomes containing curcumin, ranged from 60 to 100 nm. Flow cytometric analyses revealed that after intraperitoneal administration of the liposomes containing curcumin into mice, these were incorporated mainly by macrophages positive for F4/80, CD36, and CD11b antigens. Peritoneal cells prepared from mice injected in vivo with the liposomes containing curcumin apparently decreased interleukin-6-producing activities. Major changes in body weight and survival rates in the mice were not observed after administrating the liposomes containing curcumin. These results indicate that the liposomes containing curcumin are safe and useful for the selective suppression of macrophages in vivo in mice.

Alteration in the endogenous intestinal flora of swiss webster mice by experimental Angiostrongylus costaricensis infection

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Vandack Nobre

2004-11-01

Full Text Available The association between worm infections and bacterial diseases has only recently been emphasized. This study examined the effect of experimental Angiostrongylus costaricensis infection on endogenous intestinal flora of Swiss Webster mice. Eight mice aging six weeks were selected for this experiment. Four were infected with A. costaricensis and the other four were used as controls. Twenty eight days after the worm infection, all mice in both groups were sacrificed and samples of the contents of the ileum and colon were obtained and cultured for aerobic and anaerobic bacteria. In the mice infected with A. costaricensis there was a significant increase in the number of bacteria of the endogenous intestinal flora, accompanied by a decrease in the number of Peptostreptococcus spp. This alteration in the intestinal flora of mice infected by the nematode may help to understand some bacterial infections described in humans.

Distinct mechanisms are responsible for osteopenia and growth retardation in OASIS-deficient mice.

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Murakami, Tomohiko; Hino, Shin-Ichiro; Nishimura, Riko; Yoneda, Toshiyuki; Wanaka, Akio; Imaizumi, Kazunori

2011-03-01

Old astrocyte specifically induced substance (OASIS), which is a new type of endoplasmic reticulum (ER) stress transducer, is a basic leucine zipper transcription factor of the CREB/ATF family that contains a transmembrane domain and is processed by regulated intramembrane proteolysis in response to ER stress. OASIS is selectively expressed in certain types of cells such as astrocytes and osteoblasts. We have previously demonstrated that OASIS activates transcription of the type I collagen gene Col1a1 and contributes to the secretion of bone matrix proteins in osteoblasts, and that OASIS-/- mice exhibit osteopenia and growth retardation. In the present study, we examined whether osteopenia in OASIS-/- mice is rescued by OASIS introduction into osteoblasts. We generated OASIS-/- mice that specifically expressed OASIS in osteoblasts using a 2.3-kb osteoblast-specific type I collagen promoter (OASIS-/-;Tg mice). Histological analysis of OASIS-/-;Tg mice revealed that osteopenia in OASIS-/- mice was rescued by osteoblast-specific expression of the OASIS transgene. The decreased expression levels of type I collagen mRNAs in the bone tissues of OASIS-/- mice were recovered by the OASIS transgene accompanied by the rescue of an abnormal expansion of the rough ER in OASIS-/- osteoblasts. In contrast, growth retardation in OASIS-/- mice did not improve in OASIS-/-;Tg mice. Interestingly, the serum levels of growth hormone (GH) and insulin-like growth factor (IGF)-1 were downregulated in OASIS-/- mice compared with those in wild-type mice. These decreased GH and IGF-1 levels in OASIS-/- mice did not change when OASIS was introduced into osteoblasts. Taken together, these results indicate that OASIS regulates skeletal development by osteoblast-dependent and -independent mechanisms. Copyright © 2010 Elsevier Inc. All rights reserved.

Differential Expression of Phosphorylated Mitogen-Activated Protein Kinase (pMAPK) in the Lateral Amygdala of Mice Selectively Bred for High and Low Fear

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2013-07-02

conditions, box geometry, flooring surface (smooth surface with sawdust bedding as opposed to the conducting rod floor), wall color and olfactory cues...lateral nucleus of the amygdala. Behavioral neuroscience 107:444-50 112. Romanski LM, LeDoux JE. 1992. Equipotentiality of thalamo-amygdala and

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

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Kukar, Thomas; Prescott, Sonya; Eriksen, Jason L; Holloway, Vallie; Murphy, M Paul; Koo, Edward H; Golde, Todd E; Nicolle, Michelle M

2007-01-01

Background Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice. Results A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning. Conclusion We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its

Chronic administration of R-flurbiprofen attenuates learning impairments in transgenic amyloid precursor protein mice

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Koo Edward H

2007-07-01

Full Text Available Abstract Background Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs is associated with a reduced incidence of Alzheimer's disease (AD. We and others have shown that certain NSAIDs reduce secretion of Aβ42 in cell culture and animal models, and that the effect of NSAIDs on Aβ42 is independent of the inhibition of cyclooxygenase by these compounds. Since Aβ42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Aβ42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil as a selective Aβ42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Aβ loads in Tg2576 APP mice. Results A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day was administered to young Tg2576 mice prior to robust plaque or Aβ pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Aβ was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Aβ plaque burden but no significant improvement in spatial learning. Conclusion We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition

Direct behavioral and neurophysiological evidence for retronasal olfaction in mice.

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Michelle R Rebello

Full Text Available The neuroscience of flavor perception is hence becoming increasingly important to understand food flavor perception that guides food selection, ingestion and appreciation. We recently provided evidence that rats can use the retronasal mode of olfaction, an essential element of human flavor perception. We showed that in rats, like humans, odors can acquire a taste. We and others also defined how the input of the olfactory bulb (OB -not functionally imageable in humans- codes retronasal smell in anesthetized rat. The powerful awake transgenic mouse, however, would be a valuable additional model in the study of flavor neuroscience. We used a go/no-go behavioral task to test the mouse's ability to detect and discriminate the retronasal odor amyl acetate. In this paradigm a tasteless aqueous odor solution was licked by water-restricted head-fixed mice from a lick spout. Orthonasal contamination was avoided. The retronasal odor was successfully discriminated by mice against pure distilled water in a concentration-dependent manner. Bulbectomy removed the mice's ability to discriminate the retronasal odor but not tastants. The OB showed robust optical calcium responses to retronasal odorants in these awake mice. These results suggest that mice, like rats, are capable of smelling retronasally. This direct neuro-behavioral evidence establishes the mouse as a useful additional animal model for flavor research.

Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation

Science.gov (United States)

Reno, Candace M.; Puente, Erwin C.; Sheng, Zhenyu; Daphna-Iken, Dorit; Bree, Adam J.; Routh, Vanessa H.; Kahn, Barbara B.

2017-01-01

GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impaired c-fos activation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose. PMID:27797912

Working Memory Training Promotes General Cognitive Abilities in Genetically Heterogeneous Mice

OpenAIRE

Light, Kenneth R.; Kolata, Stefan; Wass, Christopher; Denman-Brice, Alexander; Zagalsky, Ryan; Matzel, Louis D.

2010-01-01

In humans, aspects of working memory capacity (i.e., resistance to interference or selective attention) correlate strongly with measures indicative of general intelligence [1–7], and likewise, the efficacy of working memory capacity and its related process, selective attention, are each strongly predictive of the aggregate performance of individual mice in cognitive test batteries [8,9]. Since by its nature, working memory is taxed during most cognitive tasks, it has been suggested that the e...

Rosiglitazone Improves Survival and Hastens Recovery from Pancreatic Inflammation in Obese Mice

Science.gov (United States)

Pini, Maria; Rhodes, Davina H.; Castellanos, Karla J.; Cabay, Robert J.; Grady, Eileen F.; Fantuzzi, Giamila

2012-01-01

Obesity increases severity of acute pancreatitis (AP) by unclear mechanisms. We investigated the effect of the PPAR-gamma agonist rosiglitazone (RGZ, 0.01% in the diet) on severity of AP induced by administration of IL-12+ IL-18 in male C57BL6 mice fed a low fat (LFD) or high fat diet (HFD), under the hypothesis that RGZ would reduce disease severity in HFD-fed obese animals. In both LFD and HFD mice without AP, RGZ significantly increased body weight and % fat mass, with significant upregulation of adiponectin and suppression of erythropoiesis. In HFD mice with AP, RGZ significantly increased survival and hastened recovery from pancreatic inflammation, as evaluated by significantly improved pancreatic histology, reduced saponification of visceral adipose tissue and less severe suppression of erythropoiesis at Day 7 post-AP. This was associated with significantly lower circulating and pancreas-associated levels of IL-6, Galectin-3, osteopontin and TIMP-1 in HFD + RGZ mice, particularly at Day 7 post-AP. In LFD mice with AP, RGZ significantly worsened the degree of intrapancreatic acinar and fat necrosis as well as visceral fat saponification, without affecting other parameters of disease severity or inflammation. Induction of AP lead to major suppression of adiponectin levels at Day 7 in both HFD and HFD + RGZ mice. In conclusion, RGZ prevents development of severe AP in obese mice even though it significantly increases adiposity, indicating that obesity can be dissociated from AP severity by improving the metabolic and inflammatory milieu. However, RGZ worsens selective parameters of AP severity in LFD mice. PMID:22815875

SELECTING ANGORA GOATS TO CONSUME MORE JUNIPER

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Christopher John Lupton

2009-02-01

Full Text Available This research project was initiated in 2003 to develop a more effective tool for biological management of invading juniper species on rangelands through herbivory by Angora goats.  After we had established that juniper consumption in free-ranging goats has a genetic component (heritability = 13%, male and female goats were bred selectively for above- (high and below-average (low juniper consumption that was estimated by fecal near-infrared reflectance spectroscopy. Divergent lines are being produced to facilitate the identification of physiological mechanisms that permit some goats to consume considerably more juniper than others as a regular component of their diet.  Because diet is known to affect growth and fiber production, another objective of the project is to establish the effects of the selection protocol on body weights, fleece weights, and fiber characteristics.  Mature females (age > 1.5 yr and kids were maintained on rangeland and shorn twice a year.  Extreme high- and low-consuming yearling males (10 of each per year were evaluated annually in a central performance test.  The selection protocol resulted in average EBV for percentage juniper consumption of 3.9 and -0.4 (P 0.1 in body weight, mohair production and properties between high and low consumers.  However, the adult data for the extreme males indicated that high consuming males have lower body weights than low consumers (53.8 vs. 57.9 kg, P = 0.01. Differences in body weight and several mohair production and quality traits have also been detected in the mature females but at this early stage of the selection program, no substantial differences have been observed and certainly none that would have an economic impact for producers.  Ultimately, we expect to demonstrate that the high-consuming line controls juniper more effectively than either the low-consuming line or unselected Angora goats.  Subsequently, we plan to release high juniper

Human CD4 restores normal T cell development and function in mice deficient in murine CD4

OpenAIRE

1994-01-01

The ability of a human coreceptor to function in mice was investigated by generating human CD4 (hCD4)-expressing transgenic mice on a mouse CD4-deficient (mCD4-/-) background. From developing thymocyte to matured T lymphocyte functions, hCD4 was shown to be physiologically active. By examining the expansion and deletion of specific V beta T cell families in mutated mice with and without hCD4, it was found that hCD4 can participate in positive and negative selection. Mature hCD4 single positiv...

Effect of zearalenone on reproductive parameters and expression of selected testicular genes in mice

Czech Academy of Sciences Publication Activity Database

Žatecká, Eva; Děd, Lukáš; Elzeinová, Fatima; Kubátová, Alena; Dorosh, Andriy; Margaryan, Hasmik; Dostálová, Pavla; Korenková, Vlasta; Hošková, K.; Pěknicová, Jana

2014-01-01

Roč. 45, june (2014), s. 20-30 ISSN 0890-6238 R&D Projects: GA ČR(CZ) GAP503/12/1834; GA MŠk(CZ) ED1.1.00/02.0109 Institutional research plan: CEZ:AV0Z50520701 Institutional support: RVO:86652036 Keywords : zearalenone * fertility * reproductive parameters in male mice * spermatogenesis * gene expression * qPCR Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.227, year: 2014

Endothelial arginine resynthesis contributes to the maintenance of vasomotor function in male diabetic mice.

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Ramesh Chennupati

Full Text Available Argininosuccinate synthetase (ASS is essential for recycling L-citrulline, the by-product of NO synthase (NOS, to the NOS substrate L-arginine. Here, we assessed whether disturbed arginine resynthesis modulates endothelium-dependent vasodilatation in normal and diabetic male mice.Endothelium-selective Ass-deficient mice (Assfl/fl/Tie2Cretg/- = Ass-KOTie2 were generated by crossing Assfl/fl mice ( = control with Tie2Cre mice. Gene ablation in endothelial cells was confirmed by immunohistochemistry. Blood pressure (MAP was recorded in 34-week-old male mice. Vasomotor responses were studied in isolated saphenous arteries of 12- and 34-week-old Ass-KOTie2 and control animals. At the age of 10 weeks, diabetes was induced in control and Ass-KOTie2 mice by streptozotocin injections. Vasomotor responses of diabetic animals were studied 10 weeks later. MAP was similar in control and Ass-KOTie2 mice. Depletion of circulating L-arginine by arginase 1 infusion or inhibition of NOS activity with L-NAME resulted in an increased MAP (10 and 30 mmHg, respectively in control and Ass-KOTie2 mice. Optimal arterial diameter, contractile responses to phenylephrine, and relaxing responses to acetylcholine and sodium nitroprusside were similar in healthy control and Ass-KOTie2 mice. However, in diabetic Ass-KOTie2 mice, relaxation responses to acetylcholine and endothelium-derived NO (EDNO were significantly reduced when compared to diabetic control mice.Absence of endothelial citrulline recycling to arginine did not affect blood pressure and systemic arterial vasomotor responses in healthy mice. EDNO-mediated vasodilatation was significantly more impaired in diabetic Ass-KOTie2 than in control mice demonstrating that endothelial arginine recycling becomes a limiting endothelial function in diabetes.

Deletion of vanilloid receptor (TRPV1) in mice alters behavioral effects of ethanol

Science.gov (United States)

Blednov, Y.A.; Harris, R.A.

2009-01-01

The vanilloid receptor TRPV1 is activated by ethanol and this may be important for some of the central and peripheral actions of ethanol. To determine if this receptor has a role in ethanol-mediated behaviors, we studied null mutant mice in which the Trpv1 gene was deleted. Mice lacking this gene showed significantly higher preference for ethanol and consumed more ethanol in a two-bottle choice test as compared with wild type littermates. Null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol (2 g/kg). However, there were no differences between null mutant and wild type mice in severity of ethanol-induced acute withdrawal (4 g/kg) or conditioned taste aversion to ethanol (2.5 g/kg). Two behavioral phenotypes (decreased sensitivity to ethanol-induced sedation and faster recovery from ethanol-induced motor incoordination) seen in null mutant mice were reproduced in wild type mice by injection of a TRPV1 antagonist, capsazepine (10 mg/kg). These two ethanol behaviors were changed in the opposite direction after injection of capsaicin, a selective TRPV1 agonist, in wild type mice. The studies provide the first evidence that TRPV1 is important for specific behavioral actions of ethanol. PMID:19705551

Tetranectin Knockout Mice Develop Features of Parkinson Disease

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Er-song Wang

2014-07-01

Full Text Available Background/Aims: Aggregation of insoluble α-synuclein to form Lewy bodies (LBs may contribute to the selective loss of midbrain dopaminergic neurons in Parkinson disease (PD. Lack of robust animal models has impeded elucidation of the molecular mechanisms of LB formation and other critical aspects of PD pathogenesis. Methods: We established a mouse model with targeted deletion of the plasminogen-binding protein tetranectin (TN gene (TN-/- and measured the behavioral and histopathological features of PD. Results: Aged (15-to 20-month-old TN-/- mice displayed motor deficits resembling PD symptoms, including limb rigidity and both slower ambulation (bradykinesia and reduced rearing activity in the open field. In addition, these mice exhibited more numerous α-synuclein-positive LB-like inclusions within the substantia nigra pars compacta (SNc and reduced numbers of SNc dopaminergic neurons than age-matched wild type (WT mice. These pathological changes were also accompanied by loss of dopamine terminals in the dorsal striatum. Conclusion: The TN-/- mouse exhibits several key features of PD and so may be a valuable model for studying LB formation and testing candidate neuroprotective therapies for PD and other synucleinopathies.

Differential testosterone secretory capacity of the testes of aggressive and nonaggressive house mice during ontogeny

OpenAIRE

de Ruiter, Anne J H; Koolhaas, Jaap M; van Oortmerssen, Geert A; Bohus, Bela

1992-01-01

In this study, testosterone secretory capacity of testicular Leydig cells during ontogeny was determined in males of an aggressive and a nonaggressive genetic selection line of wild house mice. Neonates, 23-day-old prepubertals, and adult male mice were studied. A morphometric method was used to quantify 3-beta-hydroxy steroid dehydrogenase (3-beta-HSD)-stained Leydig cells in testicular sections to determine testosterone secretory capacity. We consider this parameter to reflect circulating t...

Working memory training promotes general cognitive abilities in genetically heterogeneous mice.

Science.gov (United States)

Light, Kenneth R; Kolata, Stefan; Wass, Christopher; Denman-Brice, Alexander; Zagalsky, Ryan; Matzel, Louis D

2010-04-27

In both humans and mice, the efficacy of working memory capacity and its related process, selective attention, are each strongly predictive of individuals' aggregate performance in cognitive test batteries [1-9]. Because working memory is taxed during most cognitive tasks, the efficacy of working memory may have a causal influence on individuals' performance on tests of "intelligence" [10, 11]. Despite the attention this has received, supporting evidence has been largely correlational in nature (but see [12]). Here, genetically heterogeneous mice were assessed on a battery of five learning tasks. Animals' aggregate performance across the tasks was used to estimate their general cognitive abilities, a trait that is in some respects analogous to intelligence [13, 14]. Working memory training promoted an increase in animals' selective attention and their aggregate performance on these tasks. This enhancement of general cognitive performance by working memory training was attenuated if its selective attention demands were reduced. These results provide evidence that the efficacy of working memory capacity and selective attention may be causally related to an animal's general cognitive performance and provide a framework for behavioral strategies to promote those abilities. Furthermore, the pattern of behavior reported here reflects a conservation of the processes that regulate general cognitive performance in humans and infrahuman animals. Copyright © 2010 Elsevier Ltd. All rights reserved.

Hierarchy in the home cage affects behaviour and gene expression in group-housed C57BL/6 male mice.

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Horii, Yasuyuki; Nagasawa, Tatsuhiro; Sakakibara, Hiroyuki; Takahashi, Aki; Tanave, Akira; Matsumoto, Yuki; Nagayama, Hiromichi; Yoshimi, Kazuto; Yasuda, Michiko T; Shimoi, Kayoko; Koide, Tsuyoshi

2017-08-01

Group-housed male mice exhibit aggressive behaviour towards their cage mates and form a social hierarchy. Here, we describe how social hierarchy in standard group-housed conditions affects behaviour and gene expression in male mice. Four male C57BL/6 mice were kept in each cage used in the study, and the social hierarchy was determined from observation of video recordings of aggressive behaviour. After formation of a social hierarchy, the behaviour and hippocampal gene expression were analysed in the mice. Higher anxiety- and depression-like behaviours and elevated gene expression of hypothalamic corticotropin-releasing hormone and hippocampal serotonin receptor subtypes were observed in subordinate mice compared with those of dominant mice. These differences were alleviated by orally administering fluoxetine, which is an antidepressant of the selective serotonin reuptake inhibitor class. We concluded that hierarchy in the home cage affects behaviour and gene expression in male mice, resulting in anxiety- and depression-like behaviours being regulated differently in dominant and subordinate mice.

Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice.

Science.gov (United States)

Chen, Yong; Boettger, Michael K; Reif, Andreas; Schmitt, Angelika; Uçeyler, Nurcan; Sommer, Claudia

2010-03-02

Although it has been largely demonstrated that nitric oxide synthase (NOS), a key enzyme for nitric oxide (NO) production, modulates inflammatory pain, the molecular mechanisms underlying these effects remain to be clarified. Here we asked whether cytokines, which have well-described roles in inflammatory pain, are downstream targets of NO in inflammatory pain and which of the isoforms of NOS are involved in this process. Intraperitoneal (i.p.) pretreatment with 7-nitroindazole sodium salt (7-NINA, a selective neuronal NOS inhibitor), aminoguanidine hydrochloride (AG, a selective inducible NOS inhibitor), L-N(G)-nitroarginine methyl ester (L-NAME, a non-selective NOS inhibitor), but not L-N(5)-(1-iminoethyl)-ornithine (L-NIO, a selective endothelial NOS inhibitor), significantly attenuated thermal hyperalgesia induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA). Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed a significant increase of nNOS, iNOS, and eNOS gene expression, as well as tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1beta), and interleukin-10 (IL-10) gene expression in plantar skin, following CFA. Pretreatment with the NOS inhibitors prevented the CFA-induced increase of the pro-inflammatory cytokines TNF and IL-1beta. The increase of the anti-inflammatory cytokine IL-10 was augmented in mice pretreated with 7-NINA or L-NAME, but reduced in mice receiving AG or L-NIO. NNOS-, iNOS- or eNOS-knockout (KO) mice had lower gene expression of TNF, IL-1beta, and IL-10 following CFA, overall corroborating the inhibitor data. These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression.

Enhanced susceptibility to stress and seizures in GAD65 deficient mice.

Science.gov (United States)

Qi, Jin; Kim, Minjung; Sanchez, Russell; Ziaee, Saba M; Kohtz, Jhumku D; Koh, Sookyong

2018-01-01

Reduced gamma-aminobutyric acid (GABA) inhibition has been implicated in both anxiety and epilepsy. GAD65-/- (NOD/LtJ) mice have significantly decreased basal GABA levels in the brain and a lowered threshold for seizure generation. One fifth of GAD65 -/- mice experienced stress-induced seizures upon exposure to an open field at 4 weeks of age. In each successive week until 8 weeks of age, the latency to seizures decreased with prior seizure experience. 100% of GAD65-/- mice exhibited stress-induced seizures by the end of 8 weeks. GAD65-/- mice also exhibited marked impairment in open field exploratory behavior and deficits in spatial learning acquisition on a Barnes maze. Anxiety-like behavior in an open field was observed prior to seizure onset and was predictive of subsequent seizures. Immunohistochemical characterization of interneuron subtypes in GAD65-/- mice showed a selective decrease in GABA and neuropeptide Y (NPY) levels and no change in calbindin (CLB) or calretinin (CLR) immunoreactivity in the hippocampus. Stem cells from the medial ganglionic eminence (MGE) were injected into the hippocampal hilus to restore GABAergic interneurons. One week after transplantation, MGE-transplanted mice demonstrated significant seizure resistance compared to sham surgical controls. The percent area of GFP+ MGE graft in the hippocampus correlated significantly with the increase in seizure latency. Our data indicate that impaired GABAergic neurotransmission can cause anxiety-like behavior and stress-induced seizures that can be rescued by MGE stem cell transplantation.

Genetic selection for coping style predicts stressor susceptibility

NARCIS (Netherlands)

Veenema, AH; Meijer, OC; de Kloet, ER; Koolhaas, JM

Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which show distinctly different coping styles, also display a differential regulation of the hypothalamic-pituitary-adrenal axis after exposure to an acute stressor. To test the hypothesis that coping style predicts

Generation of ER{alpha}-floxed and knockout mice using the Cre/LoxP system

Energy Technology Data Exchange (ETDEWEB)

Antonson, P., E-mail: per.antonson@ki.se [Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 83 Huddinge (Sweden); Omoto, Y.; Humire, P. [Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 83 Huddinge (Sweden); Gustafsson, J.-A. [Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 83 Huddinge (Sweden); Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204 (United States)

2012-08-10

Highlights: Black-Right-Pointing-Pointer ER{alpha} floxed and knockout mice were generated. Black-Right-Pointing-Pointer Disruption of the ER{alpha} gene results in sterility in both male and female mice. Black-Right-Pointing-Pointer ER{alpha}{sup -/-} mice have ovaries with hemorrhagic follicles and hypoplastic uterus. Black-Right-Pointing-Pointer Female ER{alpha}{sup -/-} mice develop obesity. -- Abstract: Estrogen receptor alpha (ER{alpha}) is a nuclear receptor that regulates a range of physiological processes in response to estrogens. In order to study its biological role, we generated a floxed ER{alpha} mouse line that can be used to knock out ER{alpha} in selected tissues by using the Cre/LoxP system. In this study, we established a new ER{alpha} knockout mouse line by crossing the floxed ER{alpha} mice with Cre deleter mice. Here we show that genetic disruption of the ER{alpha} gene in all tissues results in sterility in both male and female mice. Histological examination of uterus and ovaries revealed a dramatically atrophic uterus and hemorrhagic cysts in the ovary. These results suggest that infertility in female mice is the result of functional defects of the reproductive tract. Moreover, female knockout mice are hyperglycemic, develop obesity and at the age of 4 months the body weight of these mice was more than 20% higher compared to wild type littermates and this difference increased over time. Our results demonstrate that ER{alpha} is necessary for reproductive tract development and has important functions as a regulator of metabolism in females.

Origem e distribuição dos nervos femorais em fetos suínos (SUS Scrofa Domesticus – Linneaus, 1758) do cruzamento das linhagens Dan Bred e AGPIC337

OpenAIRE

Herrera, Gustavo Cavinato

2016-01-01

Estudou-se em 30 fetos suínos oriundos do cruzamento das linhagens Dan Bred e AGPIC337, natimortos, a origem e distribuição do nervo femoral, os quais foram fixados em solução de formaldeído a 10%. Em 96,67% dos animais o número de vértebras lombares foram seis e em 3,33% sete. O nervo femoral originou-se de L4 e L5 (66,67%), L5 e L6 (26,67%) e L3 e L4 (6,66%). Em relação a sua distribuição emitiu ramos para os músculos psoas maior, psoas menor, ilíaco, pectíneo, quadríceps femoral em 100% do...

Modulation of seizure activity in mice by metabotropic glutamate receptor ligands

DEFF Research Database (Denmark)

Dalby, Nils Ole; Thomsen, C

1996-01-01

The anticonvulsant properties of ligands at metabotropic glutamate receptors (mGluRs) were examined in different seizure models by use of intracerebroventricular infusion. The mGluR1a antagonist/mGluR2 agonist, (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG] dose-dependently antagonized...... pentylenetetrazol- and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-2-carboxylate (DMCM)-induced clonic convulsions in mice with ED50 values of 400 and 180 nmol/mice, respectively. A modest increase in electrical seizure threshold was observed in mice injected with (S)-4C3HPG. No effect on seizures induced...... by systemic administration of N-methyl-D-aspartate was observed by prior intracerebroventricular infusion of (S)-4C3HPG. The more selective (but less potent) mGluR1a antagonist, (S)-4-carboxyphenylglycine, was a weak anticonvulsant in similar seizure models with the exception of convulsions induced...

Difference in Perseverative Errors during a Visual Attention Task with Auditory Distractors in Alpha-9 Nicotinic Receptor Subunit Wild Type and Knock-Out Mice.

Science.gov (United States)

Jorratt, Pascal; Delano, Paul H; Delgado, Carolina; Dagnino-Subiabre, Alexies; Terreros, Gonzalo

2017-01-01

The auditory efferent system is a neural network that originates in the auditory cortex and projects to the cochlear receptor through olivocochlear (OC) neurons. Medial OC neurons make cholinergic synapses with outer hair cells (OHCs) through nicotinic receptors constituted by α9 and α10 subunits. One of the physiological functions of the α9 nicotinic receptor subunit (α9-nAChR) is the suppression of auditory distractors during selective attention to visual stimuli. In a recent study we demonstrated that the behavioral performance of alpha-9 nicotinic receptor knock-out (KO) mice is altered during selective attention to visual stimuli with auditory distractors since they made less correct responses and more omissions than wild type (WT) mice. As the inhibition of the behavioral responses to irrelevant stimuli is an important mechanism of the selective attention processes, behavioral errors are relevant measures that can reflect altered inhibitory control. Errors produced during a cued attention task can be classified as premature, target and perseverative errors. Perseverative responses can be considered as an inability to inhibit the repetition of an action already planned, while premature responses can be considered as an index of the ability to wait or retain an action. Here, we studied premature, target and perseverative errors during a visual attention task with auditory distractors in WT and KO mice. We found that α9-KO mice make fewer perseverative errors with longer latencies than WT mice in the presence of auditory distractors. In addition, although we found no significant difference in the number of target error between genotypes, KO mice made more short-latency target errors than WT mice during the presentation of auditory distractors. The fewer perseverative error made by α9-KO mice could be explained by a reduced motivation for reward and an increased impulsivity during decision making with auditory distraction in KO mice.

Dissociation of Frontotemporal Dementia–Related Deficits and Neuroinflammation in Progranulin Haploinsufficient Mice

Science.gov (United States)

Filiano, Anthony J.; Martens, Lauren Herl; Young, Allen H.; Warmus, Brian A.; Zhou, Ping; Diaz-Ramirez, Grisell; Jiao, Jian; Zhang, Zhijun; Huang, Eric J.; Gao, Fen-Biao; Farese, Robert V.; Roberson, Erik D.

2013-01-01

Frontotemporal dementia (FTD) is a neurodegenerative disease with hallmark deficits in social and emotional function. Heterozygous loss-of-function mutations in GRN, the progranulin gene, are a common genetic cause of the disorder, but the mechanisms by which progranulin haploinsufficiency causes neuronal dysfunction in FTD are unclear. Homozygous progranulin knockout (Grn−/−) mice have been studied as a model of this disorder and show behavioral deficits and a neuroinflammatory phenotype with robust microglial activation. However, homozygous GRN mutations causing complete progranulin deficiency were recently shown to cause a different neurological disorder, neuronal ceroid lipofuscinosis, suggesting that the total absence of progranulin may have effects distinct from those of haploinsufficiency. Here, we studied progranulin heterozygous (Grn+/−) mice, which model progranulin haploinsufficiency. We found that Grn+/− mice developed age-dependent social and emotional deficits potentially relevant to FTD. However, unlike Grn−/− mice, behavioral deficits in Grn+/− mice occurred in the absence of gliosis or increased expression of tumor necrosis factor–α. Instead, we found neuronal abnormalities in the amygdala, an area of selective vulnerability in FTD, in Grn+/− mice. Our findings indicate that FTD-related deficits due to progranulin haploinsufficiency can develop in the absence of detectable gliosis and neuroinflammation, thereby dissociating microglial activation from functional deficits and suggesting an important effect of progranulin deficiency on neurons. PMID:23516300