PREGNANCY LOSS IN THE F344 RAT CAUSED BY BROMODICHLOROMETHANE: EFFECTS ON SERUM LUTEINIZING HORMONE LEVELS

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PREGNANCY LOSS IN THE F344 RAT CAUSED BY BROMODICHLOROMETHANE: EFFECTS ON SERUM LUTEINIZING HORMONE LEVELS Bielmeier1, S.R., D.S. Best2, and M.G. Narotsky2; 1University of North Carolina at Chapel Hill, Curriculum in Toxicology, 2Reproductive Toxicology Division, U.S. Enviro...

Lewis and Fischer 344 rats as a model for genetic differences in spatial learning and memory: Cocaine effects.

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Fole, Alberto; Miguéns, Miguel; Morales, Lidia; González-Martín, Carmen; Ambrosio, Emilio; Del Olmo, Nuria

2017-06-02

Lewis (LEW) and Fischer 344 (F344) rats are considered a model of genetic vulnerability to drug addiction. We previously showed important differences in spatial learning and memory between them, but in contrast with previous experiments demonstrating cocaine-induced enhanced learning in Morris water maze (MWM) highly demanding tasks, the eight-arm radial maze (RAM) performance was not modified either in LEW or F344 rats after chronic cocaine treatment. In the present work, chronically cocaine-treated LEW and F344 adult rats have been evaluated in learning and memory performance using the Y-maze, two RAM protocols that differ in difficulty, and a reversal protocol that tests cognitive flexibility. After one of the RAM protocols, we quantified dendritic spine density in hippocampal CA1 neurons and compared it to animals treated with cocaine but not submitted to RAM. LEW cocaine treated rats showed a better performance in the Y maze than their saline counterparts, an effect that was not evident in the F344 strain. F344 rats significantly took more time to learn the RAM task and made a greater number of errors than LEW animals in both protocols tested, whereas cocaine treatment induced deleterious effects in learning and memory in the highly difficult protocol. Moreover, hippocampal spine density was cocaine-modulated in LEW animals whereas no effects were found in F344 rats. We propose that differences in addictive-like behavior between LEW and F344 rats could be related to differences in hippocampal learning and memory processes that could be on the basis of individual vulnerability to cocaine addiction. Copyright © 2017 Elsevier Inc. All rights reserved.

The Fischer 344 rat as a model of presbycusis.

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Syka, Josef

2010-06-01

Due to the rising number of the aged human population all over the world, presbycusis is a phenomenon that deserves the increasing attention of the medical community as regards to prevention and treatment. This requires finding appropriate animal models for human presbycusis that will be useful in future experiments. Among the available rat strains, the Fischer 344 (F344) strain promises to serve as a model producing prompt and profound presbycusis. Hearing thresholds begin to increase in this strain during the first year of life; toward the end of the second year, the thresholds are very high. The threshold shifts progress independently in both ears. The rapid deterioration of distortion product otoacoustic emissions, with the majority of outer hair cells (OHC) being present and morphologically intact, is apparently produced by the disruption of prestin. The age-related changes within inner ear function are accompanied by deterioration of acoustical signal processing within central auditory system, mainly due to impaired GABA inhibition. The loss of GABA inhibition in old animals is expressed primarily in the inferior colliculus but is also present in the cochlear nuclei and the auditory cortex. Sound-evoked behavioral reactions are also impaired in old F344 rats. Taken together, the described characteristics of the aging F344 rat auditory system supports the idea that this strain may serve as a suitable model for studying the mechanisms of presbycusis, its prevention and treatment. Copyright 2009 Elsevier B.V. All rights reserved.

NTP Toxicology and Carcinogenesis Studies of Molybdenum Trioxide (CAS No. 1313-27-5) in F344 Rats and B6C3F1 Mice (Inhalation Studies).

Science.gov (United States)

1997-04-01

females. In both male and female mice, the incidences of hyperplasia of the laryngeal epithelium in level II of the larynx increased with increasing exposure concentration. The increase was statistically significant only in mice exposed to 100 mg/m(3) with 82% of male and 70% of female mice affected. GENETIC TOXICOLOGY: Molybdenum trioxide was not mutagenic in any of five strains of Salmonella typhimurium, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells in vitro. All tests were conducted with and without S9 metabolic activation enzymes. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of molybdenum trioxide in male F344/N rats based on a marginally significant positive trend of alveolar/bronchiolar adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of molybdenum trioxide in female F344/N rats exposed to 10, 30, or 100 mg/m(3). There was some evidence of carcinogenic activity of molybdenum trioxide in male B6C3F1 mice based on increased incidences of alveolar/bronchiolar carcinoma and adenoma or carcinoma (combined). There was some evidence of carcinogenic activity of molybdenum trioxide in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenoma and adenoma or carcinoma (combined). Exposure of male and female rats to molybdenum trioxide by inhalation resulted in increased incidences of chronic alveolar inflammation, hyaline degeneration of the respiratory epithelium, hyaline degeneration of the olfactory epithelium (females), and squamous metaplasia of the epiglottis. Exposure of male and female mice to molybdenum trioxide by inhalation resulted in increased incidences of metaplasia of the alveolar epithelium, histiocyte cellular infiltration (males), hyaline degeneration of the respiratory epithelium, hyaline degeneration of the olfactory epithelium (females

Deposition of ultrafine aerosols in F344/N rat nasal casts

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Cheng, Y S; Hansen, G K; Su, Y F; Yeh, H C; Morgan, K T [Chemical Industry Institute of Toxicology, Research Triangle Park, NC (United States)

1988-12-01

Determination of regional respiratory deposition of inhaled aerosols is critical for evaluation of the health effects of air pollutants. Information on deposition of larger particles (> 0.02 {mu}m) in the nasal passages of laboratory animals is available; the deposition fraction increases with increasing particle size. Little information on ultrafine particles less than 0.2 {mu}m is available. Molds (models) were prepared from replica casts of the nasal passages of F344/N rats, using clear casting plastic. Total deposition of ultrafine aerosols in these casts was then determined using a unidirectional flow system. Measured pressure drops in the casts were a function of flow rate to the power of 1.4-1.6, indicating that the flow through the nasal passage was not laminar. Deposition data were obtained from these casts, using monodisperse sodium chloride aerosols with particle size ranging from 0.2 to 0.005 {mu}m, at inspiratory and expiratory flow rates of 200 to 600 cc/min. Similar deposition data were obtained for the three casts studied. The deposition efficiency was greatest for the smallest particles, and decreased with increasing particle size and flow rate, indicating that diffusion was the dominant mechanism for deposition. At an inspiratory flow rate of 400 cc/min, which is comparable to a respiratory minute volume of 200 cc/min for mature male F344/N rats, deposition efficiencies reached 40 and 70% for 0.01 and 0.005 {mu}m particles, respectively. Turbulent diffusion was considered to be the dominant mechanism for deposition of ultrafine particles in the nasal passage. This information is important for understanding the toxicity and carcinogenicity of submicrometer particles, including diesel soot, radon progeny and vapors. (author)

THE FAILURE OF CHLOROFORM ADMINISTERED IN THE DRINKING WATER TO INDUCE RENAL TUBULAR CELL NEOPLASIA IN MALE F344/N RATS

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The failure of chloroform administered in drinking water to induce renal tubular cell neoplasia in male F344/N rats Chloroform (TCM) has been demonstrated to be a renal carcinogen in the male Osborne-Mendel rat when administered either by corn oil gavage or in drin...

Disposition of oxymetholone in F344 rats

International Nuclear Information System (INIS)

Sanders, J.M.; Matthews, H.B.

1991-01-01

The use of oxymetholone (OXM), a synthetic anabolic steroid structurally related to testosterone, has reportedly resulted in incidences of hepatic toxicity, including tumor formation. In order to characterize further the biological fate of this suspected carcinogen, the present study has investigated the disposition of OXM in F344 rats. Concentrations of OXM-derived radioactivity peaked in blood within 4 hr following oral administration of 5 mg 14 C OXM/kg to male rats, indicating rapid absorption from the GI tract. Liver contained 2-4 times the concentration of OXM-derived radioactivity in blood 4-8 hr after gavage. Within 24 hr, 15 ± 1% of total dose was excreted in urine and 61 ± 6% was excreted in feces. By 72 hr, 17 ± 1% and 80% ± 1% of the total dose had been excreted in urine and feces, respectively. Increasing the dose to 50 mg/kg did not alter the rate or route of 14 C excretion. Fecal elimination of 14 C appeared to be the result of biliary excretion of 14 C appeared to be the result of biliary excretion of OXM-derived radioactivity since approximately 35% of an iv dose of 5 mg/kg was excreted in bile over 7 hr. IV administration resulted in a 6-8 fold increase in blood concentrations of OXM-derived radioactivity 24 hr post-dosing, versus rats gavaged with a similar dose. The major portion of 14 C present in blood appeared to be bound to constituents of plasma. Consecutive daily doses of 50 mg/kg administered by gavage resulted in a 5 fold increase in blood concentrations of OXM equivalents/ml within 7 days, with no increase thereafter. Data developed in this study indicate that upon absorption of OXM from the gut, OXM-derived radioactivity, with an estimated biological half-life of 12-24 hr., sequesters in blood and is eliminated primarily in feces

Toxicology and carcinogenesis studies of acrylamide (CASRN 79-06-1) in F344/N rats and B6C3F1 mice (feed and drinking water studies).

Science.gov (United States)

2012-07-01

Acrylamide, a water-soluble α,β-unsaturated amide, is a contaminant in baked and fried starchy foods, including french fries, potato chips, and bread, as a result of Maillard reactions involving asparagine and reducing sugars. Additional sources of acrylamide exposure include cigarettes, laboratory procedures involving polyacrylamide gels, and various occupations (e.g, monomer production and polymerization processes). Acrylamide is carcinogenic in experimental animals. To obtain data for developing quantitative risk assessments for dietary exposures to acrylamide, the Food and Drug Administration nominated acrylamide for an in-depth toxicological evaluation by the National Toxicology Program. As part of this evaluation, male and female B6C3F1/Nctr (C57BL/6N x C3H/HeN MTV-) mice and male and female F344/N Nctr rats were exposed to acrylamide (at least 99.4% pure) in drinking water for 2 years. 2-WEEK STUDY IN RATS: Groups of four male and four female F344/N rats were administered 0, 0.14, 0.35, 0.70, 1.41, 3.52, or 7.03 mM acrylamide in the drinking water (0, 10, 25, 50, 100, 250, or 500 ppm acrylamide) or 0.0, 7.4, 18.5, 37, 74, 185, or 370 mg acrylamide per kg diet for 14 days. One male rat administered 7.03 mM acrylamide in the drinking water died on day 14. Male and female rats receiving 7.03 mM acrylamide weighed 56% and 64% of controls, respectively. Male and female rats fed 370 mg acrylamide per kg diet weighed 74% and 83% of controls, respectively. Female rats receiving 3.52 mM acrylamide in drinking water and male rats fed 185 mg acrylamide per kg diet weighed 85% and 89% of controls, respectively. Rats receiving 7.03 mM acrylamide in drinking water or 370 mg acrylamide per kg diet exhibited hind-leg paralysis on day 14. Mild to moderate dilatation of the urinary bladder was observed in all rats given 370 mg acrylamide per kg diet, and in three of four male rats and all four female rats given 7.03 mM acrylamide in drinking water, and in one of four male

Validation of fumonisin biomarkers in F344 rats

International Nuclear Information System (INIS)

Cai Qingsong; Tang Lili; Wang Jiasheng

2007-01-01

Fumonisins (FNs) are ubiquitous contaminants of cereal grains. Fumonisin B 1 (FB 1 ) was linked to several animal and human diseases. To validate FB 1 biomarkers for studying human disease risks, F344 rats were administered by gavage with either a single dose of 0, 10 or 25 mg FB 1 /kg body weight (BW) or repeated doses of 0, 1.0, or 2.5 mg FB 1 /kg BW/day for 5 weeks. FB 1 excretion and FB 1 -induced metabolic alterations of sphingolipids in rat urine, feces and serum were assessed. Dose-dependent urinary and fecal excretion of free FB 1 were found in both single-dose- and repeat-dose-treated rats. In the single-dose study, urinary sphinganine (Sa) to sphingosine (So) ratio (Sa/So) reached a maximum at day 7 for the high-dose group and at day 5 for the low-dose group, whereas serum Sa/So showed only marginal changes. In the repeat-dose study, urinary Sa/So was persistently elevated at 2 weeks, while serum Sa/So was unchanged. Time course changes of sphinganine 1-phosphate (SaP) and sphingosine 1-phosphate (SoP) were also examined. Although serum Sa/So and SaP/SoP ratios showed no signs of time- or dose-dependent changes, a 10-fold increase in urinary SaP/SoP was observed, suggesting that urinary SaP/SoP is a more sensitive biomarker for FB 1 exposure. The accumulation of SaP and SoP was evident in the time course of SaP/Sa and SoP/So, which may reflect activity changes of enzymes closely related to the metabolism and catabolism of SaP and SoP. These results provide concrete evidence towards the practical use of excreted FB 1 , Sa/So and SaP/SoP as biomarkers of exposure to FNs

Toxicology and carcinogenesis studies of nitrofurantoin (CAS No. 67-20-9) in F344/n rats and B6C3F1 mice (feed studies). Technical report

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French, J.E.

1989-09-01

Two-year toxicology and carcinogenesis studies were conducted by administering diets containing 0, 600, or 1,300 ppm nitrofurantoin to groups of 50 female rats for 103 weeks. Groups of 50 male rats and 50 mice of each sex were fed diets containing 0, 1,300 or 2,500 ppm for 103 weeks. Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of nitrofurantoin for male F344/N rats as shown by increased incidences of uncommon kidney tubular cell neoplasms. Uncommon osteosarcomas of the bone and neoplasms of the subcutaneous tissue were observed in dosed male rats. Incidences of interstitial cell adenomas of the testis and neoplasms of the preputial gland were decreased in the 2,500-ppm group of male rats. There was no evidence of carcinogenic activity of nitrofurantoin for female F344/N rats fed diets containing 600 ppm or 1,300 ppm for 2 years. Female rats may have been able to tolerate higher doses. There was no evidence of carcinogenic activity of nitrofurantoin for male B6C3F(1) mice fed diets containing 1,300 ppm or 2,500 ppm for 2 years. There was clear evidence of carcinogenic activity of nitrofurantoin for female B6C3F(1) mice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary.

[Effect of selenium deficiency on the F344 inbred line offspring rats' neuro-behavior, ability of learning and memory].

Science.gov (United States)

Hong, Liang-Li; Tian, Dong-Ping; Su, Min; Shen, Xiu-Na; Gao, Yuxia

2006-01-01

To establish the selenium (Se) deficient animal model on F344 inbred line rats and observe the effects of a long-term Se-deficiency on the offspring's neuro-behavior, abilities of learning and memory. Feeding F344 inbred line rats on Se-deficient diet to establish Se-deficient animal model. For the offspring, the body weight, physiological indexes nervous reflections for growth and development were monitored during the early postnatal period. The Se-deficient diet contained less than 0.01 mg/kg and the glutathione peroxidase (GSH-Px) activity in blood of the Se-deficient group rats is lower than the Se-normal group after feeding on Se-deficient diet for 4 weeks. For the offspring, the birth weight and the body weight of Se-deficient group were obviously lower than the Se-normal group before weaning. Se-deficient offspring rats differed from Se-normal controls in lower scores in surface righting reflex (RR) test at postnatal 4th day after delivery, cliff avoidance test at postnatal 7th day and auditory acuity trial at postnatal 10th day respectively. But these differences disappear after a few days in the same tests. In addition, no significant differences between two groups in suspending test and walking ability test at postnatal 12th and 14th day. In open field test, Se-deficient male offspring stayed less time in the middle grid and moved less. In Morris water maze test, the Se-deficient offspring spent more time to find the hidden platform at the 6th and 9th training tests in the place navigation trial. Furthermore, the Se-deficient group spent less time in target quadrant when giving the spatial probe trial. A Se-deficient animal model have been established on F344 inbred line rats successfully. A long-term Se deficiency could retard the development of the offspring in uterus and after delivery. Se deficiency also decreased the offspring's abilities of spatial learning and memory in Morris water maze test and resulted in the male offspring's nervousness to new

EFFECTS OF BROMODICHLOROMETHANE ON EX VIVO AND IN VITRO LUTEAL FUNCTION AND BROMODICHLOROMETHANE TISSUE DOSIMETRY IN THE PREGNANT F344 RAT

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Bromodichloromethane (BDCM), a drinking water disinfection by-product, causes pregnancy loss, i.e. full-litter resorption, in F344 rats when treated during the luteinizing hormone (LH)-dependent period. This effect is associated with reduced maternal serum progesterone (P) and LH...

The effect of substituents in the aromatic ring on carcinogenicity of N-nitrosomethylaniline in F344 rats.

Science.gov (United States)

Kroeger-Koepke, M B; Reuber, M D; Iype, P T; Lijinsky, W; Michejda, C J

1983-01-01

N-Nitroso-N-methylaniline (NMA) and N-nitroso-N-methyl-4-fluoroaniline (p-F-NMA), both non-mutagenic in Salmonella typhimurium and N-nitroso-N-methyl-4-nitroaniline (p-NO2-NMA), a potent mutagen, were tested for carcinogenicity in F344 rats. NMA was shown to induce a high level of tumors in the upper gastrointestinal tract, particularly in the esophagus. Male rats treated with NMA died with tumors at a slightly higher rate than females, although the final tumor yield was the same. Most of the rats treated with p-F-NMA also developed tumors of the esophagus, but they died less rapidly than the NMA treated rats, indicating that p-F-NMA is a slightly weaker carcinogen than NMA. The powerful, directly acting mutagen, p-NO2-NMA did not appear to induce tumors at all since its tumor spectrum was essentially identical to that of the untreated control rats. Thus, the carcinogenic activities of NMA and its substituted analogs do not appear to correlate with bacterial mutagenesis assays. Additionally, NMA, p-F-NMA and N-nitroso-N-methyl-4-bromoaniline, the last a strong mutagen in S. typhimurium, were shown not to induce sister chromatid exchanges in CHO cells and in a clone of a CHO:liver cell hybrid which had previously been shown to be sensitive to chemical agents which require metabolic activation.

Validation of fumonisin biomarkers in F344 rats

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Qingsong, Cai; Lili, Tang [Department of Environmental Toxicology and Institute of Environmental and Human Health, Box 41163, Texas Tech University, Lubbock, TX 79409-1163 (United States); Wang Jiasheng [Department of Environmental Toxicology and Institute of Environmental and Human Health, Box 41163, Texas Tech University, Lubbock, TX 79409-1163 (United States)], E-mail: js.wang@ttu.edu

2007-11-15

Fumonisins (FNs) are ubiquitous contaminants of cereal grains. Fumonisin B{sub 1} (FB{sub 1}) was linked to several animal and human diseases. To validate FB{sub 1} biomarkers for studying human disease risks, F344 rats were administered by gavage with either a single dose of 0, 10 or 25 mg FB{sub 1}/kg body weight (BW) or repeated doses of 0, 1.0, or 2.5 mg FB{sub 1}/kg BW/day for 5 weeks. FB{sub 1} excretion and FB{sub 1}-induced metabolic alterations of sphingolipids in rat urine, feces and serum were assessed. Dose-dependent urinary and fecal excretion of free FB{sub 1} were found in both single-dose- and repeat-dose-treated rats. In the single-dose study, urinary sphinganine (Sa) to sphingosine (So) ratio (Sa/So) reached a maximum at day 7 for the high-dose group and at day 5 for the low-dose group, whereas serum Sa/So showed only marginal changes. In the repeat-dose study, urinary Sa/So was persistently elevated at 2 weeks, while serum Sa/So was unchanged. Time course changes of sphinganine 1-phosphate (SaP) and sphingosine 1-phosphate (SoP) were also examined. Although serum Sa/So and SaP/SoP ratios showed no signs of time- or dose-dependent changes, a 10-fold increase in urinary SaP/SoP was observed, suggesting that urinary SaP/SoP is a more sensitive biomarker for FB{sub 1} exposure. The accumulation of SaP and SoP was evident in the time course of SaP/Sa and SoP/So, which may reflect activity changes of enzymes closely related to the metabolism and catabolism of SaP and SoP. These results provide concrete evidence towards the practical use of excreted FB{sub 1}, Sa/So and SaP/SoP as biomarkers of exposure to FNs.

Dose–response assessment of nephrotoxicity from a twenty-eight-day combined-exposure to melamine and cyanuric acid in F344 rats

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Gamboa da Costa, Gonçalo, E-mail: goncalo.gamboa@fda.hhs.gov [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Jacob, Cristina C.; Von Tungeln, Linda S. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Hasbrouck, Nicholas R. [Center for Veterinary Medicine, Laurel, MD 20708 (United States); Olson, Greg R. [Toxicologic Pathology Associates, Jefferson, AR 72079 (United States); Hattan, David G. [Center for Food Safety and Applied Nutrition, College Park, MD 20740 (United States); Reimschuessel, Renate [Center for Veterinary Medicine, Laurel, MD 20708 (United States); Beland, Frederick A. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States)

2012-07-15

The adulteration of pet food with melamine and derivatives, including cyanuric acid, has been implicated in the kidney failure and death of cats and dogs in the USA and other countries. In a previous 7-day dietary study in F344 rats, we established a no-observed-adverse-effect level (NOAEL) for a co-exposure to melamine and cyanuric acid of 8.6 mg/kg bw/day of each compound, and a benchmark dose lower confidence limit (BMDL) of 8.4–10.9 mg/kg bw/day of each compound. To ascertain the role played by the duration of exposure, we treated F344 rats for 28 days. Groups of male and female rats were fed diet containing 0 (control), 30, 60, 120, 180, 240, or 360 ppm of both melamine and cyanuric acid. The lowest dose that produced histopathological alterations in the kidney was 120 ppm, versus 229 ppm in the 7-day study. Wet-mount analysis of kidney sections demonstrated the formation of melamine cyanurate spherulites in one male and two female rats at the 60 ppm dose and in one female rat at the 30 ppm dose, establishing a NOAEL of 2.1 mg/kg bw/day for males and < 2.6 mg/kg bw/day for females, and BMDL values as low as 1.6 mg/kg bw/day for both sexes. These data demonstrate that the length of exposure is an important component in the threshold of toxicity from a co-exposure to these compounds and suggest that the current risk assessments based on exposures to melamine alone may not reflect sufficiently the risk of a co-exposure to melamine and cyanuric acid. -- Highlights: ► A 28-day dietary co-exposure to melamine and cyanuric acid was conducted in F344 rats. ► The NOAELs were 2.1 mg/kg bw/day for males and < 2.6 mg/kg bw/day for females. ► BMDL values as low as 1.6 mg/kg bw/day for both sexes were determined. ► The length of exposure plays an important role in the threshold of toxicity. ► Current assessments may underestimate the risk of melamine and cyanuric acid.

Dose–response assessment of nephrotoxicity from a twenty-eight-day combined-exposure to melamine and cyanuric acid in F344 rats

International Nuclear Information System (INIS)

Gamboa da Costa, Gonçalo; Jacob, Cristina C.; Von Tungeln, Linda S.; Hasbrouck, Nicholas R.; Olson, Greg R.; Hattan, David G.; Reimschuessel, Renate; Beland, Frederick A.

2012-01-01

The adulteration of pet food with melamine and derivatives, including cyanuric acid, has been implicated in the kidney failure and death of cats and dogs in the USA and other countries. In a previous 7-day dietary study in F344 rats, we established a no-observed-adverse-effect level (NOAEL) for a co-exposure to melamine and cyanuric acid of 8.6 mg/kg bw/day of each compound, and a benchmark dose lower confidence limit (BMDL) of 8.4–10.9 mg/kg bw/day of each compound. To ascertain the role played by the duration of exposure, we treated F344 rats for 28 days. Groups of male and female rats were fed diet containing 0 (control), 30, 60, 120, 180, 240, or 360 ppm of both melamine and cyanuric acid. The lowest dose that produced histopathological alterations in the kidney was 120 ppm, versus 229 ppm in the 7-day study. Wet-mount analysis of kidney sections demonstrated the formation of melamine cyanurate spherulites in one male and two female rats at the 60 ppm dose and in one female rat at the 30 ppm dose, establishing a NOAEL of 2.1 mg/kg bw/day for males and < 2.6 mg/kg bw/day for females, and BMDL values as low as 1.6 mg/kg bw/day for both sexes. These data demonstrate that the length of exposure is an important component in the threshold of toxicity from a co-exposure to these compounds and suggest that the current risk assessments based on exposures to melamine alone may not reflect sufficiently the risk of a co-exposure to melamine and cyanuric acid. -- Highlights: ► A 28-day dietary co-exposure to melamine and cyanuric acid was conducted in F344 rats. ► The NOAELs were 2.1 mg/kg bw/day for males and < 2.6 mg/kg bw/day for females. ► BMDL values as low as 1.6 mg/kg bw/day for both sexes were determined. ► The length of exposure plays an important role in the threshold of toxicity. ► Current assessments may underestimate the risk of melamine and cyanuric acid.

Fischer-344 Tp53-knockout rats exhibit a high rate of bone and brain neoplasia with frequent metastasis

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Sarah A. Hansen

2016-10-01

Full Text Available Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344 rat to create the F344-Tp53tm1(EGFP-PacQly/Rrrc (F344-Tp53 strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets.

Inhibition of gap junctional Intercellular communication in WB-F344 rat liver epithelial cells by triphenyltin chloride through MAPK and PI3-kinase pathways

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Tsai Ming-Che

2010-06-01

Full Text Available Abstract Background Organotin compounds (OTCs have been widely used as stabilizers in the production of plastic, agricultural pesticides, antifoulant plaints and wood preservation. The toxicity of triphenyltin (TPT compounds was known for their embryotoxic, neurotoxic, genotoxic and immunotoxic effects in mammals. The carcinogenicity of TPT was not well understood and few studies had discussed the effects of OTCs on gap junctional intercellular communication (GJIC of cells. Method In the present study, the effects of triphenyltin chloride (TPTC on GJIC in WB-F344 rat liver epithelial cells were evaluated, using the scrape-loading dye transfer technique. Results TPTC inhibited GJIC after a 30-min exposure in a concentration- and time-dependent manner. Pre-incubation of cells with the protein kinase C (PKC inhibitor did not modify the response, but the specific MEK 1 inhibitor PD98059 and PI3K inhibitor LY294002 decreased substantially the inhibition of GJIC by TPTC. After WB-F344 cells were exposed to TPTC, phosphorylation of Cx43 increased as seen in Western blot analysis. Conclusions These results show that TPTC inhibits GJIC in WB-F344 rat liver epithelial cells by altering the Cx43 protein expression through both MAPK and PI3-kinase pathways.

Chronic carcinogenicity study of gasoline vapor condensate (GVC) and GVC containing methyl tertiary-butyl ether in F344 rats.

Science.gov (United States)

Benson, Janet M; Gigliotti, Andrew P; March, Thomas H; Barr, Edward B; Tibbetts, Brad M; Skipper, Betty J; Clark, Charles R; Twerdok, Lorraine

2011-01-01

Chronic inhalation studies were conducted to compare the toxicity and potential carcinogenicity of evaporative emissions from unleaded gasoline (GVC) and gasoline containing the oxygenate methyl tertiary-butyl ether (MTBE; GMVC). The test materials were manufactured to mimic vapors people would be exposed to during refueling at gas stations. Fifty F344 rats per gender per exposure level per test article were exposed 6 h/d, 5 d/wk for 104 wk in whole body chambers. Target total vapor concentrations were 0, 2, 10, or 20 g/m³ for the control, low-, mid-, and high-level exposures, respectively. Endpoints included survival, body weights, clinical observations, organs weights, and histopathology. GVC and GMVC exerted no marked effects on survival or clinical observations and few effects on organ weights. Terminal body weights were reduced in all mid- and high-level GVC groups and high-level GMVC groups. The major proliferative lesions attributable to gasoline exposure with or without MTBE were renal tubule adenomas and carcinomas in male rats. GMV exposure led to elevated testicular mesothelioma incidence and an increased trend for thyroid carcinomas in males. GVMC inhalation caused an increased trend for testicular tumors with exposure concentration. Mid- and high-level exposures of GVC and GMVC led to elevated incidences of nasal respiratory epithelial degeneration. Overall, in these chronic studies conducted under identical conditions, the health effects in F344 rats following 2 yr of GVC or GMVC exposure were comparable in the production of renal adenomas and carcinomas in male rats and similar in other endpoints.

Chronic Carcinogenicity Study of Gasoline Vapor Condensate (GVC) and GVC Containing Methyl Tertiary-Butyl Ether in F344 Rats

Science.gov (United States)

Benson, Janet M.; Gigliotti, Andrew P.; March, Thomas H.; Barr, Edward B.; Tibbetts, Brad M.; Skipper, Betty J.; Clark, Charles R.; Twerdok, Lorraine

2011-01-01

Chronic inhalation studies were conducted to compare the toxicity and potential carcinogenicity of evaporative emissions from unleaded gasoline (GVC) and gasoline containing the oxygenate methyl tertiary-butyl ether (MTBE; GMVC). The test materials were manufactured to mimic vapors people would be exposed to during refueling at gas stations. Fifty F344 rats per gender per exposure level per test article were exposed 6 h/d, 5 d/wk for 104 wk in whole body chambers. Target total vapor concentrations were 0, 2, 10, or 20 g/m3 for the control, low-, mid-, and high-level exposures, respectively. Endpoints included survival, body weights, clinical observations, organs weights, and histopathology. GVC and GMVC exerted no marked effects on survival or clinical observations and few effects on organ weights. Terminal body weights were reduced in all mid- and high-level GVC groups and high-level GMVC groups. The major proliferative lesions attributable to gasoline exposure with or without MTBE were renal tubule adenomas and carcinomas in male rats. GMV exposure led to elevated testicular mesothelioma incidence and an increased trend for thyroid carcinomas in males. GVMC inhalation caused an increased trend for testicular tumors with exposure concentration. Mid- and high-level exposures of GVC and GMVC led to elevated incidences of nasal respiratory epithelial degeneration. Overall, in these chronic studies conducted under identical conditions, the health effects in F344 rats following 2 yr of GVC or GMVC exposure were comparable in the production of renal adenomas and carcinomas in male rats and similar in other endpoints. PMID:21432714

Chronic Carcinogenicity Study of Gasoline Vapor Condensate (GVC) and GVC Containing Methyl Tertiary-Butyl Ether in F344 Rats

OpenAIRE

Benson, Janet M.; Gigliotti, Andrew P.; March, Thomas H.; Barr, Edward B.; Tibbetts, Brad M.; Skipper, Betty J.; Clark, Charles R.; Twerdok, Lorraine

2011-01-01

Chronic inhalation studies were conducted to compare the toxicity and potential carcinogenicity of evaporative emissions from unleaded gasoline (GVC) and gasoline containing the oxygenate methyl tertiary-butyl ether (MTBE; GMVC). The test materials were manufactured to mimic vapors people would be exposed to during refueling at gas stations. Fifty F344 rats per gender per exposure level per test article were exposed 6 h/d, 5 d/wk for 104 wk in whole body chambers. Target total vapor concentra...

Progressive impairment of directional and spatially precise trajectories by TgF344-AD Rats in the Morris Water Task

OpenAIRE

Thompson, Shannon; Harvey, Ryan; Clark, Benjamin; Drake, Emma; Berkowitz, Laura

2018-01-01

Spatial navigation is impaired in early stages of Alzheimers disease (AD), and may be a defining behavioral marker of preclinical AD. Nevertheless, limitations of diagnostic criteria for AD and within animal models of AD make characterization of preclinical AD difficult. A new rat model (TgF344-AD) of AD overcomes many of these limitations, though spatial navigation has not been comprehensively assessed. Using the hidden and cued platform variants of the Morris water task, a longitudinal asse...

Toxicology and Carcinogenesis Studies of Furfuryl Alcohol (CAS No. 98-00-0) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Science.gov (United States)

1999-02-01

Furfuryl alcohol-based resins are used as binding agents in foundry sand and as corrosion inhibitors in mortar, grout, and cement. Because of their heat resistance, furan resins are used in the manufacture of fiberglass-reinforced plastic equipment. Furfuryl alcohol was selected for evaluation because of the absence of data on its carcinogenic potential and its large production volume, widespread use in manufacturing, and ubiquitous presence in consumer goods. Male and female F344/N rats and B6C3F1 mice were exposed to furfuryl alcohol (greater than 98% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female rats exposed to 250 ppm died by day 2 of the study, and one male rat exposed to 125 ppm died on day 5. Final mean body weights of male and female rats exposed to 125 ppm were significantly less than those of the chamber control groups. Male rats exposed to 31, 63, or 125 ppm and female rats exposed to 125 ppm gained less weight than the chamber control groups. Clinical findings included dyspnea, hypoactivity, and nasal and ocular discharge in males and females exposed to 63, 125, or 250 ppm. All exposed animals developed lesions in the nasal respiratory epithelium and olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female mice exposed to 250 ppm died by day 4 of the study, and one female mouse exposed to 125 ppm died on day

In vivo genotoxicity of furan in F344 rats at cancer bioassay doses

International Nuclear Information System (INIS)

Ding, Wei; Petibone, Dayton M.; Latendresse, John R.; Pearce, Mason G.; Muskhelishvili, Levan; White, Gene A.; Chang, Ching-Wei; Mittelstaedt, Roberta A.; Shaddock, Joseph G.; McDaniel, Lea P.; Doerge, Daniel R.; Morris, Suzanne M.; Bishop, Michelle E.; Manjanatha, Mugimane G.; Aidoo, Anane; Heflich, Robert H.

2012-01-01

Furan, a potent rodent liver carcinogen, is found in many cooked food items and thus represents a human cancer risk. Mechanisms for furan carcinogenicity were investigated in male F344 rats using the in vivo Comet and micronucleus assays, combined with analysis of histopathological and gene expression changes. In addition, formamidopyrimidine DNA glycosylase (Fpg) and endonuclease III (EndoIII)-sensitive DNA damage was monitored as a measure of oxidative DNA damage. Rats were treated by gavage on four consecutive days with 2, 4, and 8 mg/kg bw furan, doses that were tumorigenic in 2-year cancer bioassays, and with two higher doses, 12 and 16 mg/kg. Rats were killed 3 h after the last dose, a time established as producing maximum levels of DNA damage in livers of furan-treated rats. Liver Comet assays indicated that both DNA strand breaks and oxidized purines and pyrimidines increased in a near-linear dose-responsive fashion, with statistically significant increases detected at cancer bioassay doses. No DNA damage was detected in bone marrow, a non-target tissue for cancer, and peripheral blood micronucleus assays were negative. Histopathological evaluation of liver from furan-exposed animals produced evidence of inflammation, single-cell necrosis, apoptosis, and cell proliferation. In addition, genes related to apoptosis, cell-cycle checkpoints, and DNA-repair were expressed at a slightly lower level in the furan-treated livers. Although a mixed mode of action involving direct DNA binding cannot be ruled out, the data suggest that furan induces cancer in rat livers mainly through a secondary genotoxic mechanism involving oxidative stress, accompanied by inflammation, cell proliferation, and toxicity. -- Highlights: ► Furan is a potent rodent liver carcinogen and represents a human cancer risk. ► Furan induces DNA damage in rat liver at cancer bioassay doses. ► Furan induces oxidative stress, inflammation and cell proliferation in rat liver. ► Expression of

Amphetamine self-administration and dopamine function: assessment of gene × environment interactions in Lewis and Fischer 344 rats.

Science.gov (United States)

Meyer, Andrew C; Bardo, Michael T

2015-07-01

Previous research suggests both genetic and environmental influences on substance abuse vulnerability. The current work sought to investigate the interaction of genes and environment on the acquisition of amphetamine self-administration as well as amphetamine-stimulated dopamine (DA) release in nucleus accumbens shell using in vivo microdialysis. Inbred Lewis (LEW) and Fischer (F344) rat strains were raised in either an enriched condition (EC), social condition (SC), or isolated condition (IC). Acquisition of amphetamine self-administration (0.1 mg/kg/infusion) was determined across an incrementing daily fixed ratio (FR) schedule. In a separate cohort of rats, extracellular DA and the metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the nucleus accumbens shell following an acute amphetamine injection (1 mg/kg). "Addiction-prone" LEW rats had greater acquisition of amphetamine self-administration on a FR1 schedule compared to "addiction-resistant" F344 rats when raised in the SC environment. These genetic differences were negated in both the EC and IC environments, with enrichment buffering against self-administration and isolation enhancing self-administration in both strains. On a FR5 schedule, the isolation-induced increase in amphetamine self-administration was greater in F344 than LEW rats. While no group differences were obtained in extracellular DA, gene × environment differences were obtained in extracellular levels of the metabolite DOPAC. In IC rats only, LEW rats showed attenuation in the amphetamine-induced decrease in DOPAC compared to F344 rats. IC LEW rats also had an attenuated DOPAC response to amphetamine compared to EC LEW rats. The current results demonstrate gene × environment interactions in amphetamine self-administration and amphetamine-induced changes in extracellular DOPAC in nucleus accumbens (NAc) shell. However, the behavioral and neurochemical differences were not related directly, indicating that

Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

International Nuclear Information System (INIS)

Matthews, Jessica L.; Schultz, Irvin R.; Easterling, Michael R.; Melnick, Ronald L.

2010-01-01

A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite α-halocarboxymethylglutathione (αH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibrated with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical-and species-specific parameters.

Distribution and excretion of anthraquinone in the male F-344 rat

International Nuclear Information System (INIS)

Steup, M.B.; Winter, S.M.; Sipes, I.G.

1990-01-01

Anthraquinone (AQ) is used extensively in the synthesis of anthraquinone dyes and has recently found application in the production of wood pulp for making paper. This has raised concern about potential environmental exposure from discharge of AQ into surface waters and sediments. In this study, the excretion and tissue distribution of radioactivity were examined in male F-344 rats following a single oral dose of radiolabelled AQ. 14 C-AQ was administered by gavage at 3.5 and 35 mg/kg in corn oil (5 ml/kg) and excretion of the radiolabel in the urine and feces was monitored over a period of 96 hr. The animals were then terminated and tissues were sampled and analyzed for radioactivity. Cumulative excretion was similar at both dose levels with approximately 41% and 55% of the dosed radioactivity appearing in the urine and feces respectively. The majority of the radiolabel was excreted within 48 hr of dose administration. Less than 3% of the administered radioactivity remained in the tissues. Highest tissue concentrations of AQ derived radioactivity were found in the liver, kidney and blood. Preliminary HPLC analyses of the urine revealed little unchanged parent compound, but several metabolites

NTP toxicity studies of dimethylaminopropyl chloride, hydrochloride (CAS No. 5407-04-5) administered by Gavage to F344/N rats and B6C3F1 mice.

Science.gov (United States)

Abdo, Km

2007-07-01

Dimethylaminopropyl chloride, hydrochloride is used primarily as an industrial and research organic chemical intermediate acting as an alkylating reagent in Grignard and other types of reactions. It is also used as a pharmaceutical intermediate for the synthesis of many types of drugs, as an agricultural chemical intermediate, as a photographic chemical intermediate, and as a biochemical reagent for enzyme and other studies. Human occupational or other accidental exposure can occur by inhalation, ingestion, or skin absorption. Male and female F344/N rats and B6C3F1 mice received dimethylaminopropyl chloride, hydrochloride (greater than 99% pure) in water by gavage for 2 weeks or 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. In the 2-week toxicity studies, groups of five male and five female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg dimethylaminopropyl chloride, hydrochloride/kg body weight in deionized water by gavage, 5 days per week for 16 days. All dosed male and female rats and mice survived until the end of the 2-week study; one vehicle control female mouse died early. Mean body weights of all dosed groups of rats and mice were similar to those of the vehicle control groups. No gross or microscopic lesions were considered related to dimethylaminopropyl chloride, hydrochloride administration. In the 3-month toxicity studies, groups of 10 male and 10 female F344/N rats and B6C3F1 mice were administered doses of 0, 6.25, 12.5, 25, 50, or 100 mg/kg in deionized water by gavage, 5 days per week for 3 months. One male rat in the 50 mg/kg group died during week 12 of the study, and one female mouse in the 100 mg/kg group died during week 9 and another during week 13. The final mean body weights of 50 mg/kg male rats and 50 mg/kg female mice were significantly less than those of the vehicle controls. Possible chemical-related clinical findings in rats

Orally administered glycidol and its fatty acid esters as well as 3-MCPD fatty acid esters are metabolized to 3-MCPD in the F344 rat.

Science.gov (United States)

Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Akagi, Jun-ichi; Fujiwara, Satoshi; Ochiai, Ryosuke; Tsujino, Kazushige; Nishikawa, Akiyoshi; Ogawa, Kumiko

2015-12-01

IARC has classified glycidol and 3-monochloropropane-1,2-diol (3-MCPD) as group 2A and 2B, respectively. Their esters are generated in foodstuffs during processing and there are concerns that they may be hydrolyzed to the carcinogenic forms in vivo. Thus, we conducted two studies. In the first, we administered glycidol and 3-MCPD and associated esters (glycidol oleate: GO, glycidol linoleate: GL, 3-MCPD dipalmitate: CDP, 3-MCPD monopalmitate: CMP, 3-MCPD dioleate: CDO) to male F344 rats by single oral gavage. After 30 min, 3-MCPD was detected in serum from all groups. Glycidol was detected in serum from the rats given glycidol or GL and CDP and CDO in serum from rats given these compounds. In the second, we examined if metabolism occurs on simple reaction with rat intestinal contents (gastric, duodenal and cecal contents) from male F344 gpt delta rats. Newly produced 3-MCPD was detected in all gut contents incubated with the three 3-MCPD fatty acid esters and in gastric and duodenal contents incubated with glycidol and in duodenal and cecal contents incubated with GO. Although our observation was performed at 1 time point, the results showed that not only 3-MCPD esters but also glycidol and glycidol esters are metabolized into 3-MCPD in the rat. Copyright © 2015 Elsevier Inc. All rights reserved.

Assessment of immunotoxicity in female Fischer 344/N and Sprague Dawley rats and female B6C3F1 mice exposed to hexavalent chromium via the drinking water.

Science.gov (United States)

Shipkowski, Kelly A; Sheth, Christopher M; Smith, Matthew J; Hooth, Michelle J; White, Kimber L; Germolec, Dori R

2017-12-01

Sodium dichromate dihydrate (SDD), an inorganic compound containing hexavalent chromium (Cr(VI)), is a common environmental contaminant of groundwater sources due to widespread industrial use. There are indications in the literature that Cr(VI) may induce immunotoxic effects following dermal exposure, including acting as both an irritant and a sensitizer; however, the potential immunomodulatory effects of Cr(VI) following oral exposure are relatively unknown. Following the detection of Cr(VI) in drinking water sources, the National Toxicology Program (NTP) conducted extensive evaluations of the toxicity and carcinogenicity of SDD following drinking water exposure, including studies to assess the potential for Cr(VI) to modulate immune function. For the immunotoxicity assessments, female Fischer 344/N (F344/N) and Sprague Dawley (SD) rats and female B 6 C 3 F 1 mice were exposed to SDD in drinking water for 28 consecutive days and evaluated for alterations in cellular and humoral immune function as well as innate immunity. Rats were exposed to concentrations of 0, 14.3, 57.3, 172, or 516 ppm SDD while mice were exposed to concentrations of 0, 15.6, 31.3, 62.5, 125, or 250 ppm SDD. Final mean body weight and body weight gain were decreased relative to controls in 250 ppm B 6 C 3 F 1 mice and 516 ppm SD rats. Water consumption was significantly decreased in F344/N and SD rats exposed to 172 and 516 ppm SDD; this was attributed to poor palatability of the SDD drinking water solutions. Several red blood cell-specific parameters were significantly (5-7%) decreased in 250 ppm mice; however, these parameters were unaffected in rats. Sporadic increases in the spleen IgM antibody response to sheep red blood cells (SRBC) were observed, however, these increases were not dose-dependent and were not reproducible. No significant effects were observed in the other immunological parameters evaluated. Overall, exposure to Cr(VI) in drinking water had limited effects on

Effects of high fat fish oil and high fat corn oil diets on initiation of AOM-induced colonic aberrant crypt foci in male F344 rats

NARCIS (Netherlands)

Dommels, Y.E.M.; Heemskerk, S.; Berg, H. van den; Alink, G.M.; Bladeren, P.J. van; Ommen, B. van

2003-01-01

Modulating effects of high fat fish oil (HFFO) and high fat corn oil (HFCO) diets on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were studied in male F344 rats following 8 weeks of dietary treatment. The incidence of AOM-induced ACF was significantly lower in the proximal colon of

Life cycle analysis of kidney gene expression in male F344 rats.

Directory of Open Access Journals (Sweden)

Joshua C Kwekel

Full Text Available Age is a predisposing condition for susceptibility to chronic kidney disease and progression as well as acute kidney injury that may arise due to the adverse effects of some drugs. Age-related differences in kidney biology, therefore, are a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of genes expressed in the kidney at various life cycle stages will impact susceptibility to adverse drug reactions. Therefore, establishing changes in baseline expression data between these life stages is the first and necessary step in evaluating this hypothesis. Untreated male F344 rats were sacrificed at 2, 5, 6, 8, 15, 21, 78, and 104 weeks of age. Kidneys were collected for histology and gene expression analysis. Agilent whole-genome rat microarrays were used to query global expression profiles. An ANOVA (p1.5 in relative mRNA expression, was used to identify 3,724 unique differentially expressed genes (DEGs. Principal component analyses of these DEGs revealed three major divisions in life-cycle renal gene expression. K-means cluster analysis identified several groups of genes that shared age-specific patterns of expression. Pathway analysis of these gene groups revealed age-specific gene networks and functions related to renal function and aging, including extracellular matrix turnover, immune cell response, and renal tubular injury. Large age-related changes in expression were also demonstrated for the genes that code for qualified renal injury biomarkers KIM-1, Clu, and Tff3. These results suggest specific groups of genes that may underlie age-specific susceptibilities to adverse drug reactions and disease. This analysis of the basal gene expression patterns of renal genes throughout the life cycle of the rat will improve the use of current and future renal biomarkers and inform our assessments of kidney injury and disease.

Hippocampal phosphoproteomics of F344 rats exposed to 1-bromopropane

International Nuclear Information System (INIS)

Huang, Zhenlie; Ichihara, Sahoko; Oikawa, Shinji; Chang, Jie; Zhang, Lingyi; Hu, Shijie; Huang, Hanlin; Ichihara, Gaku

2015-01-01

1-Bromopropane (1-BP) is neurotoxic in both experimental animals and human. To identify phosphorylated modification on the unrecognized post-translational modifications of proteins and investigate their role in 1-BP-induced neurotoxicity, changes in hippocampal phosphoprotein expression levels were analyzed quantitatively in male F344 rats exposed to 1-BP inhalation at 0, 400, or 1000 ppm for 8 h/day for 1 or 4 weeks. Hippocampal protein extracts were analyzed qualitatively and quantitatively by Pro-Q Diamond gel staining and SYPRO Ruby staining coupled with two-dimensional difference in gel electrophoresis (2D-DIGE), respectively, as well as by matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) to identify phosphoproteins. Changes in selected proteins were further confirmed by Manganese II (Mn 2+ )-Phos-tag SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Bax and cytochrome c protein levels were determined by western blotting. Pro-Q Diamond gel staining combined with 2D-DIGE identified 26 phosphoprotein spots (p < 0.05), and MALDI-TOF/MS identified 18 up-regulated proteins and 8 down-regulated proteins. These proteins are involved in the biological process of response to stimuli, metabolic processes, and apoptosis signaling. Changes in the expression of phosphorylated 14-3-3 θ were further confirmed by Mn 2+ -Phos-tag SDS-PAGE. Western blotting showed overexpression of Bax protein in the mitochondria with down-regulation in the cytoplasm, whereas cytochrome c expression was high in the cytoplasm but low in the mitochondria after 1-BP exposure. Our results suggest that the pathogenesis of 1-BP-induced hippocampal damage involves inhibition of antiapoptosis process. Phosphoproteins identified in this study can potentially serve as biomarkers for 1-BP-induced neurotoxicity. - Highlights: • 1-BP modified hippocampal phosphoproteome in rat and 23 altered proteins were identified. • 1-BP changed phosphorylation of GRP78

Hippocampal phosphoproteomics of F344 rats exposed to 1-bromopropane

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Huang, Zhenlie [Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510-300 (China); Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Ichihara, Sahoko [Graduate School of Regional Innovation Studies, Mie University, Tsu 514-8507 (Japan); Oikawa, Shinji [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 514-8507 (Japan); Chang, Jie [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Graduate School of Regional Innovation Studies, Mie University, Tsu 514-8507 (Japan); Zhang, Lingyi [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510 (Japan); Hu, Shijie [Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510-300 (China); Huang, Hanlin, E-mail: huanghl@gdoh.org [Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510-300 (China); Ichihara, Gaku, E-mail: gak@rs.tus.ac.jp [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510 (Japan)

2015-01-15

1-Bromopropane (1-BP) is neurotoxic in both experimental animals and human. To identify phosphorylated modification on the unrecognized post-translational modifications of proteins and investigate their role in 1-BP-induced neurotoxicity, changes in hippocampal phosphoprotein expression levels were analyzed quantitatively in male F344 rats exposed to 1-BP inhalation at 0, 400, or 1000 ppm for 8 h/day for 1 or 4 weeks. Hippocampal protein extracts were analyzed qualitatively and quantitatively by Pro-Q Diamond gel staining and SYPRO Ruby staining coupled with two-dimensional difference in gel electrophoresis (2D-DIGE), respectively, as well as by matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) to identify phosphoproteins. Changes in selected proteins were further confirmed by Manganese II (Mn{sup 2+})-Phos-tag SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Bax and cytochrome c protein levels were determined by western blotting. Pro-Q Diamond gel staining combined with 2D-DIGE identified 26 phosphoprotein spots (p < 0.05), and MALDI-TOF/MS identified 18 up-regulated proteins and 8 down-regulated proteins. These proteins are involved in the biological process of response to stimuli, metabolic processes, and apoptosis signaling. Changes in the expression of phosphorylated 14-3-3 θ were further confirmed by Mn{sup 2+}-Phos-tag SDS-PAGE. Western blotting showed overexpression of Bax protein in the mitochondria with down-regulation in the cytoplasm, whereas cytochrome c expression was high in the cytoplasm but low in the mitochondria after 1-BP exposure. Our results suggest that the pathogenesis of 1-BP-induced hippocampal damage involves inhibition of antiapoptosis process. Phosphoproteins identified in this study can potentially serve as biomarkers for 1-BP-induced neurotoxicity. - Highlights: • 1-BP modified hippocampal phosphoproteome in rat and 23 altered proteins were identified. • 1-BP changed phosphorylation

Wheel running improves REM sleep and attenuates stress-induced flattening of diurnal rhythms in F344 rats.

Science.gov (United States)

Thompson, Robert S; Roller, Rachel; Greenwood, Benjamin N; Fleshner, Monika

2016-05-01

Regular physical activity produces resistance to the negative health consequences of stressor exposure. One way that exercise may confer stress resistance is by reducing the impact of stress on diurnal rhythms and sleep; disruptions of which contribute to stress-related disease including mood disorders. Given the link between diurnal rhythm disruptions and stress-related disorders and that exercise both promotes stress resistance and is a powerful non-photic biological entrainment cue, we tested if wheel running could reduce stress-induced disruptions of sleep/wake behavior and diurnal rhythms. Adult, male F344 rats with or without access to running wheels were instrumented for biotelemetric recording of diurnal rhythms of locomotor activity, heart rate, core body temperature (CBT), and sleep (i.e. REM, NREM, and WAKE) in the presence of a 12 h light/dark cycle. Following 6 weeks of sedentary or exercise conditions, rats were exposed to an acute stressor known to disrupt diurnal rhythms and produce behaviors associated with mood disorders. Prior to stressor exposure, exercise rats had higher CBT, more locomotor activity during the dark cycle, and greater %REM during the light cycle relative to sedentary rats. NREM and REM sleep were consolidated immediately following peak running to a greater extent in exercise, compared to sedentary rats. In response to stressor exposure, exercise rats expressed higher stress-induced hyperthermia than sedentary rats. Stressor exposure disrupted diurnal rhythms in sedentary rats; and wheel running reduced these effects. Improvements in sleep and reduced diurnal rhythm disruptions following stress could contribute to the health promoting and stress protective effects of exercise.

Expression of calmodulin mRNA in rat olfactory neuroepithelium.

Science.gov (United States)

Biffo, S; Goren, T; Khew-Goodall, Y S; Miara, J; Margolis, F L

1991-04-01

A calmodulin (CaM) cDNA was isolated by differential hybridization screening of a lambda gt10 library prepared from rat olfactory mucosa. This cDNA fragment, containing most of the open reading frame of the rat CaMI gene, was subcloned and used to characterize steady-state expression of CaM mRNA in rat olfactory neuroepithelium and bulb. Within the bulb mitral cells are the primary neuronal population expressing CaM mRNA. The major CaM mRNA expressed in the olfactory mucosa is 1.7 kb with smaller contributions from mRNAs of 4.0 and 1.4 kb. CaM mRNA was primarily associated with the olfactory neurons and, despite the cellular complexity of the tissue and the known involvement of CaM in diverse cellular processes, was only minimally evident in sustentacular cells, gland cells or respiratory epithelium. Following bulbectomy CaM mRNA declines in the olfactory neuroepithelium as does olfactory marker protein (OMP) mRNA. In contrast to the latter, CaM mRNA makes a partial recovery by one month after surgery. These results, coupled with those from in situ hybridization, indicate that CaM mRNA is expressed in both mature and immature olfactory neurons. The program regulating CaM gene expression in olfactory neurons is distinct from those controlling expression of B50/GAP43 in immature, or OMP in mature, neurons respectively.

Two-week aerosol inhalation study on polyethylene glycol (PEG) 3350 in F-344 rats.

Science.gov (United States)

Klonne, D R; Dodd, D E; Losco, P E; Troup, C M; Tyler, T R

1989-03-01

PEGs in the 3000 to 4000 MW range are used in many pharmaceutical and cosmetic applications; they produce little ocular or dermal irritation and have extremely low acute and subchronic toxicity by oral and dermal routes of administration. However, little information exists on the potential of aerosols of these materials to produce adverse health effects. F-344 rats were exposed to aerosols of PEG 3350 (20% w:w in water) at 0, 109, 567, or 1008 (highest attainable) mg/m3 for 6 hr/d, 5 d/wk for 2 wk. No exposure-related toxicity was found with regard to clinical signs, ophthalmology, serum chemistry, urinalysis, or gross pathology. Exposure-related effects included: a 50% increase in the neutrophil count (males only) at 1008 mg/m3; decreased body weight gain (16%) for both the 567 and 1008 mg/m3 groups (males only); absolute lung weights of both sexes were increased 10 and 18% for the 567 and 1008 mg/m3 groups, respectively. A slight increase in the number of macrophages in the alveoli was the only change observed histologically in all PEG 3350-exposed groups. Therefore, inhalation of aerosols of PEG 3350 at concentrations up to 1008 mg/m3 produced relatively little toxicity in rats, the lung was the target organ, and the no-observable-effect-level was between 109 to 567 mg/m3.

NTP Toxicology and Carcinogenesis Studies of Chloroprene (CAS No. 126-99-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Science.gov (United States)

1998-09-01

Chloroprene is used almost exclusively in the manufacture of neoprene (polychloroprene). Chloroprene was chosen for study because it is a high-volume production chemical with limited information on its carcinogenic potential and because it is the 2-chloro analogue of 1,3-butadiene, a potent, multi-species, multi-organ carcinogen. Male and female F344/N rats and B6C3F1 mice were exposed to chloroprene (greater than 96% pure) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, and B6C3F1 mice (bone marrow cells and peripheral blood erythrocytes). 16-Day Study in Rats: Groups of 10 male and 10 female F344/N rats were exposed to 0, 32, 80, 200, or 500 ppm chloroprene by inhalation, 6 hours per day, 5 days per week, for 16 days. Three 500 ppm males died on day 2 or 3 of the study. Mean body weight gains of 200 ppm males and females and 500 ppm females were significantly less than those of the chamber control groups. On the first day of exposure, rats exposed to 500 ppm were hypoactive and unsteady and had rapid shallow breathing. These effects were also observed to some degree in animals exposed to 200 ppm. After the second day of exposure, the effects in these groups worsened, and hemorrhage from the nose was observed. A normocytic, normochromic, responsive anemia; thrombocytopenia; and increases in serum activities of alanine aminotransferase, glutamate dehydrogenase, and sorbitol dehydrogenase occurred on day 4 in 200 ppm females and 500 ppm males. Kidney weights of 80 and 500 ppm females were significantly greater than those of the chamber control group, as were the liver weights of 200 and 500 ppm females. The incidences of minimal to mild olfactory epithelial degeneration of the nose in all exposed groups of males and females were significantly greater than those in the chamber control groups. The incidence of squamous metaplasia of the respiratory epithelium was

Horseradish extract promotes urinary bladder carcinogenesis when administered to F344 rats in drinking water.

Science.gov (United States)

Cho, Young-Man; Hasumura, Mai; Imai, Toshio; Takami, Shigeaki; Nishikawa, Akiyoshi; Ogawa, Kumiko

2017-07-01

Horseradish extract (HRE), consisting mainly of a mixture of allyl isothiocyanate and other isothiocyanates, has been used as a food additive. To evaluate the potential hazards of HRE, a 104-week chronic study, a 2-week analysis of cell proliferation in the urinary bladder and a medium-term promotion bioassay of HRE were conducted with administration at concentrations of up to 0.04% HRE in the drinking water to male F344 rats. In the 104-week chronic study with 32 male rats per group, no treatment-related increases in the incidences of neoplastic lesions in any organ, including urinary bladder, were observed, except for simple hyperplasia in the urinary bladder in rats treated with HRE at concentrations of more than 0.01% (5.0 mg kg -1 body weight day -1 ). In the promotion study, HRE treatment after N-butyl-N-(4-hydroxybutyl)nitrosamine initiation caused a clear increase in papillary or nodular hyperplasia, papilloma, and urothelial carcinoma of the urinary bladder in the groups given HRE for 13 weeks at doses higher than 0.005%, 0.01%, and 0.04% (2.7, 5.4 and 20.5 mg kg -1 body weight day -1 ), respectively. In the 2-week cell proliferation analysis, treatment with HRE at concentrations greater than 0.005% (3.9 mg kg -1 body weight day -1 ) caused transient increases in 5-bromo-2'-deoxyuridine labeling indices in the urothelium. Although clear tumor induction was not observed, administration of relatively low-dose HRE increased cell proliferation in the urothelium and exerted obvious promoting effects on rat urinary bladder carcinogenesis. Further studies are needed to elucidate the mode of action of HRE in the rat urinary bladder to facilitate data extrapolation from the present study and provide insights into risk assessment. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Degeneration and recovery of rat olfactory epithelium following inhalation of dibasic esters.

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Keenan, C M; Kelly, D P; Bogdanffy, M S

1990-08-01

Dibasic esters (DBE) are solvent mixtures used in the paint and coating industry. To evaluate the potential subchronic toxicity of DBE, groups of male and female rats were exposed for periods of up to 13 weeks to DBE concentrations of 0, 20, 76, or 390 mg/m3. After approximately 7 and 13 weeks of exposure, 10 rats per sex per group were subjected to clinical chemical, hematological, and urine analyses. Following 7 or 13 weeks of exposure, 10 or 20 rats per sex per group, respectively, were euthanized. An additional 10 rats were euthanized following a 6-week recovery period. A standard profile of tissues, including four levels of nasal cavity, was evaluated histopathologically. After 7 weeks of exposure, slight degeneration of the olfactory epithelium was observed in both male and female rats at 76 and 390 mg/m3. After 13 weeks, degeneration of the olfactory epithelium was present at all DBE concentrations in female rats, but only at the mid and high concentrations in male rats. The severity and incidence of the lesions were concentration related for both sexes with female rats being more sensitive than males. Following the recovery period, histological changes compatible with repair in the olfactory mucosa included an absence of degeneration, focal disorganization of the olfactory epithelium, and respiratory metaplasia. All other tissues were macroscopically normal. No other signs of toxicity were indicated by the other parameters evaluated. Inhalation studies of other esters demonstrate similar pathology in the olfactory epithelium. Since olfactory mucosa is rich in carboxylesterase activity, acids may be the toxic metabolites of these compounds. This hypothetical mechanism may explain the sensitivity of olfactory tissue to the effects of DBE.

DIMETHYLARSINIC ACID ALTERS EXPRESSION OF OXIDATIVE STRESS AND DNA REPAIR GENES IN A DOSE DEPENDENT MANNER IN THE TRANSITIONAL EPITHELIUM OF THE URINARY BLADDER FROM FEMALE F344 RATS.

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Dose-dependent alteration of oxidative stress and DNA repair gene expression by Dimethylarsinic acid [DMA(V)] in transitional epithelium of urinary bladder from female F344 rats.Arsenic (As) is a major concern as millions of people are at risk from drinking arsenic contaminat...

Deficits in synaptic function occur at medial perforant path-dentate granule cell synapses prior to Schaffer collateral-CA1 pyramidal cell synapses in the novel TgF344-Alzheimer's Disease Rat Model.

Science.gov (United States)

Smith, Lindsey A; McMahon, Lori L

2018-02-01

Alzheimer's disease (AD) pathology begins decades prior to onset of clinical symptoms, and the entorhinal cortex and hippocampus are among the first and most extensively impacted brain regions. The TgF344-AD rat model, which more fully recapitulates human AD pathology in an age-dependent manner, is a next generation preclinical rodent model for understanding pathophysiological processes underlying the earliest stages of AD (Cohen et al., 2013). Whether synaptic alterations occur in hippocampus prior to reported learning and memory deficit is not known. Furthermore, it is not known if specific hippocampal synapses are differentially affected by progressing AD pathology, or if synaptic deficits begin to appear at the same age in males and females in this preclinical model. Here, we investigated the time-course of synaptic changes in basal transmission, paired-pulse ratio, as an indirect measure of presynaptic release probability, long-term potentiation (LTP), and dendritic spine density at two hippocampal synapses in male and ovariectomized female TgF344-AD rats and wildtype littermates, prior to reported behavioral deficits. Decreased basal synaptic transmission begins at medial perforant path-dentate granule cell (MPP-DGC) synapses prior to Schaffer-collateral-CA1 (CA3-CA1) synapses, in the absence of a change in paired-pulse ratio (PPR) or dendritic spine density. N-methyl-d-aspartate receptor (NMDAR)-dependent LTP magnitude is unaffected at CA3-CA1 synapses at 6, 9, and 12months of age, but is significantly increased at MPP-DGC synapses in TgF344-AD rats at 6months only. Sex differences were only observed at CA3-CA1 synapses where the decrease in basal transmission occurs at a younger age in males versus females. These are the first studies to define presymptomatic alterations in hippocampal synaptic transmission in the TgF344-AD rat model. The time course of altered synaptic transmission mimics the spread of pathology through hippocampus in human AD and provides

Hydrogen peroxide stimulates cell motile activity through LPA receptor-3 in liver epithelial WB-F344 cells

Energy Technology Data Exchange (ETDEWEB)

Shibata, Ayano; Tanabe, Eriko; Inoue, Serina; Kitayoshi, Misaho; Okimoto, Souta; Hirane, Miku; Araki, Mutsumi [Division of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Fukushima, Nobuyuki [Division of Molecular Neurobiology, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Tsujiuchi, Toshifumi, E-mail: ttujiuch@life.kindai.ac.jp [Division of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan)

2013-04-12

Highlights: •Hydrogen peroxide stimulates cell motility of WB-F344 cells. •LPA{sub 3} is induced by hydrogen peroxide in WB-F344 cells. •Cell motility by hydrogen peroxide is inhibited in LPA{sub 3} knockdown cells. •LPA signaling is involved in cell migration by hydrogen peroxide. -- Abstract: Hydrogen peroxide which is one of reactive oxygen species (ROS) mediates a variety of biological responses, including cell proliferation and migration. In the present study, we investigated whether lysophosphatidic acid (LPA) signaling is involved in cell motile activity stimulated by hydrogen peroxide. The rat liver epithelial WB-F344 cells were treated with hydrogen peroxide at 0.1 or 1 μM for 48 h. In cell motility assays, hydrogen peroxide treated cells showed significantly high cell motile activity, compared with untreated cells. To measure the expression levels of LPA receptor genes, quantitative real time RT-PCR analysis was performed. The expressions of LPA receptor-3 (Lpar3) in hydrogen peroxide treated cells were significantly higher than those in control cells, but not Lpar1 and Lpar2 genes. Next, to assess the effect of LPA{sub 3} on cell motile activity, the Lpar3 knockdown cells from WB-F344 cells were also treated with hydrogen peroxide. The cell motile activity of the knockdown cells was not stimulated by hydrogen peroxide. Moreover, in liver cancer cells, hydrogen peroxide significantly activated cell motility of Lpar3-expressing cells, but not Lpar3-unexpressing cells. These results suggest that LPA signaling via LPA{sub 3} may be mainly involved in cell motile activity of WB-F344 cells stimulated by hydrogen peroxide.

Mucosal immunization with live attenuated Francisella novicida U112ΔiglB protects against pulmonary F. tularensis SCHU S4 in the Fischer 344 rat model.

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Aimee L Signarovitz

Full Text Available The need for an efficacious vaccine against Francisella tularensis is a consequence of its low infectious dose and high mortality rate if left untreated. This study sought to characterize a live attenuated subspecies novicida-based vaccine strain (U112ΔiglB in an established second rodent model of pulmonary tularemia, namely the Fischer 344 rat using two distinct routes of vaccination (intratracheal [i.t.] and oral. Attenuation was verified by comparing replication of U112ΔiglB with wild type parental strain U112 in F344 primary alveolar macrophages. U112ΔiglB exhibited an LD(50>10(7 CFU compared to the wild type (LD(50 = 5 × 10(6 CFU i.t.. Immunization with 10(7 CFU U112ΔiglB by i.t. and oral routes induced antigen-specific IFN-γ and potent humoral responses both systemically (IgG2a>IgG1 in serum and at the site of mucosal vaccination (respiratory/intestinal compartment. Importantly, vaccination with U112ΔiglB by either i.t. or oral routes provided equivalent levels of protection (50% survival in F344 rats against a subsequent pulmonary challenge with ~25 LD(50 (1.25 × 10(4 CFU of the highly human virulent strain SCHU S4. Collectively, these results provide further evidence on the utility of a mucosal vaccination platform with a defined subsp. novicida U112ΔiglB vaccine strain in conferring protective immunity against pulmonary tularemia.

Negligible colon cancer risk from food-borne acrylamide exposure in male F344 rats and nude (nu/nu mice-bearing human colon tumor xenografts.

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Jayadev Raju

Full Text Available Acrylamide, a possible human carcinogen, is formed in certain carbohydrate-rich foods processed at high temperature. We evaluated if dietary acrylamide, at doses (0.5, 1.0 or 2.0 mg/kg diet reflecting upper levels found in human foods, modulated colon tumorigenesis in two rodent models. Male F344 rats were randomized to receive diets without (control or with acrylamide. 2-weeks later, rats in each group received two weekly subcutaneous injections of either azoxymethane (AOM or saline, and were killed 20 weeks post-injections; colons were assessed for tumors. Male athymic nude (nu/nu mice bearing HT-29 human colon adenocarcinoma cells-derived tumor xenografts received diets without (control or with acrylamide; tumor growth was monitored and mice were killed 4 weeks later. In the F344 rat study, no tumors were found in the colons of the saline-injected rats. However, the colon tumor incidence was 54.2% and 66.7% in the control and the 2 mg/kg acrylamide-treated AOM-injected groups, respectively. While tumor multiplicity was similar across all diet groups, tumor size and burden were higher in the 2 mg/kg acrylamide group compared to the AOM control. These results suggest that acrylamide by itself is not a "complete carcinogen", but acts as a "co-carcinogen" by exacerbating the effects of AOM. The nude mouse study indicated no differences in the growth of human colon tumor xenografts between acrylamide-treated and control mice, suggesting that acrylamide does not aid in the progression of established tumors. Hence, food-borne acrylamide at levels comparable to those found in human foods is neither an independent carcinogen nor a tumor promoter in the colon. However, our results characterize a potential hazard of acrylamide as a colon co-carcinogen in association with known and possibly other environmental tumor initiators/promoters.

Effects of sucrose and cornstarch on 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-induced colon and liver carcinogenesis in F344 rats

DEFF Research Database (Denmark)

Lindecrona, R.H.; Dragsted, Lars Ove; Poulsen, Morten

2004-01-01

The purpose of the present study was to compare the effect of sucrose and cornstarch on colon and liver carcinogenesis induced by 0.02% of the food-borne carcinogen 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) in the feed. Male F344 rats were allocated to four groups. Two groups were fed diets...... high in either cornstarch (68%) or sucrose (34% sucrose/34% cornstarch) and were initiated with IQ. The remaining two groups received the same two diets but did not receive any IQ. In both liver and colon, administration of IQ resulted in a higher level of DNA adducts. In animals not dosed with IQ......, sucrose increased the adduct level in both organs but to a lower level than IQ. However, simultaneous administration of IQ and sucrose did not further increase the adduct level. Both IQ and sucrose increased the expression of the DNA-repair enzyme ERCC1 in the liver. In the colon, the number of large...

Proteomic identification of carbonylated proteins in F344 rat hippocampus after 1-bromopropane exposure

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Huang, Zhenlie [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466‐8550 (Japan); Department of Toxicology, Guangdong Prevention and Treatment Center for Occupational Diseases, Guangzhou 510‐300 (China); Ichihara, Sahoko [Graduate School of Regional Innovation Studies, Mie University, Tsu 514‐8507 (Japan); Oikawa, Shinji [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 514‐8507 (Japan); Chang, Jie; Zhang, Lingyi; Subramanian, Kaviarasan; Mohideen, Sahabudeen Sheik [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466‐8550 (Japan); Ichihara, Gaku, E-mail: gak@med.nagoya-u.ac.jp [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466‐8550 (Japan)

2012-08-15

1-Bromopropane (1-BP) is neurotoxic in both experimental animals and humans. Previous proteomic analysis of rat hippocampus implicated alteration of protein expression in oxidative stress, suggesting that oxidative stress plays a role in 1-BP-induced neurotoxicity. To understand this role at the protein level, we exposed male F344 rats to 1-BP at 0, 400, or 1000 ppm for 8 h/day for 1 week or 4 weeks by inhalation and quantitated changes in hippocampal protein carbonyl using a protein carbonyl assay, two-dimensional gel electrophoresis (2-DE), immunoblotting, and matrix-assisted laser-desorption ionization time-of-flight mass spectrometry (MALDI-TOF-TOF/MS). Hippocampal reactive oxygen species and protein carbonyl were significantly increased, demonstrating 1-BP-associated induction of oxidative stress and protein damage. MALDI-TOF-TOF/MS identified 10 individual proteins with increased carbonyl modification (p < 0.05; fold-change ≥ 1.5). The identified proteins were involved in diverse biological processes including glycolysis, ATP production, tyrosine catabolism, GTP binding, guanine degradation, and neuronal metabolism of dopamine. Hippocampal triosephosphate isomerase (TPI) activity was significantly reduced and negatively correlated with TPI carbonylation (p < 0.001; r = 0.83). Advanced glycation end-product (AGE) levels were significantly elevated both in the hippocampus and plasma, and hippocampal AGEs correlated negatively with TPI activity (p < 0.001; r = 0.71). In conclusion, 1-BP-induced neurotoxicity in the rat hippocampus seems to involve oxidative damage of cellular proteins, decreased TPI activity, and elevated AGEs. -- Highlights: ► 1-BP increases hippocampal ROS levels and hippocampal and plasma protein carbonyls. ► 1-BP increases TPI carbonylation and decreases TPI activity in the hippocampus. ► 1-BP increases hippocampal and plasma AGE levels.

Neurotoxicity of carbonyl sulfide in F344 rats following inhalation exposure for up to 12 weeks

International Nuclear Information System (INIS)

Morgan, Daniel L.; Little, Peter B.; Herr, David W.; Moser, Virginia C.; Collins, Bradley; Herbert, Ronald; Johnson, G. Allan; Maronpot, Robert R.; Harry, G. Jean; Sills, Robert C.

2004-01-01

Carbonyl sulfide (COS), a high-priority Clean Air Act chemical, was evaluated for neurotoxicity in short-term studies. F344 rats were exposed to 75-600 ppm COS 6 h per day, 5 days per week for up to 12 weeks. In rats exposed to 500 or 600 ppm for up to 4 days, malacia and microgliosis were detected in numerous neuroanatomical regions of the brain by conventional optical microscopy and magnetic resonance microscopy (MRM). After a 2-week exposure to 400 ppm, rats were evaluated using a functional observational battery. Slight gait abnormality was detected in 50% of the rats and hypotonia was present in all rats exposed to COS. Decreases in motor activity, and forelimb and hindlimb grip strength were also detected. In rats exposed to 400 ppm for 12 weeks, predominant lesions were in the parietal cortex area 1 (necrosis) and posterior colliculus (neuronal loss, microgliosis, hemorrhage), and occasional necrosis was present in the putamen, thalamus, and anterior olivary nucleus. Carbonyl sulfide specifically targeted the auditory system including the olivary nucleus, nucleus of the lateral lemniscus, and posterior colliculus. Consistent with these findings were alterations in the amplitude of the brainstem auditory evoked responses (BAER) for peaks N 3 , P 4 , N 4 , and N 5 that represented changes in auditory transmission between the anterior olivary nucleus to the medial geniculate nucleus in animals after exposure for 2 weeks to 400 ppm COS. A concentration-related decrease in cytochrome oxidase activity was detected in the posterior colliculus and parietal cortex of exposed rats as early as 3 weeks. Cytochrome oxidase activity was significantly decreased at COS concentrations that did not cause detectable lesions, suggesting that disruption of the mitochondrial respiratory chain may precede these brain lesions. Our studies demonstrate that this environmental air contaminant has the potential to cause a wide spectrum of brain lesions that are dependent on the degree

Dimethylarsinic acid: Results of chronic toxicity/oncogenicity studies in F344 rats and in B6C3F1 mice

International Nuclear Information System (INIS)

Arnold, Lora L.; Eldan, Michal; Nyska, Abraham; Gemert, Marcia van; Cohen, Samuel M.

2006-01-01

Dimethylarsinic acid (DMA V , cacodylic acid), a foliar herbicide, was administered in the diet to B6C3F1 mice (at dose levels of 0, 8, 40, 200, and 500 ppm) and to F344 rats (at dose levels of 0, 2, 10, 40, and 100 ppm) for 2 years, according to US EPA guidelines. In mice, there were no treatment-related tumors observed at any site. Treatment-related progressive glomerulonephropathy and nephrocalcinosis were observed in the kidneys in both sexes. The incidence of vacuolation of the epithelium in the urinary bladder was increased in both sexes, but was not associated with cytotoxicity, necrosis or hyperplasia. Based on non-neoplastic lesions found in the urinary bladder, the NOEL for mice was assessed to be 40 ppm in males and 8 ppm in females. In rats, treatment-related mortality occurred early in the study in five males in the 100 ppm group and in one male in the 40 ppm group. Papillomas and carcinomas with degeneration of the urothelium, necrosis and urothelial cell hyperplasia, were found in the urinary bladders of both sexes. In male rats, one papilloma was found in each of the 10 and 40 ppm groups; one urothelial cell carcinoma was found in the 2 ppm group and two in the 100 ppm group. Four papillomas and six urothelial cell carcinomas were found in the female 100 ppm group. Non-neoplastic treatment-related kidney lesions were confined to the 40 and 100 ppm levels and included necrosis, pyelonephritis, medullary nephrocalcinosis and tubular cystic dilation, hyperplasia of the epithelial lining of the papilla, and pelvic urothelial cell hyperplasia. All of these kidney changes appear to be related to an increase in the aging nephropathy of the rat. Dose-related increases in the height of the thyroid follicular epithelium were also noted in males and females, however, such changes reflect an adaptive response of the thyroid to decreased levels of circulating thyroid hormone, rather than an adverse effect. Based on the kidney and bladder lesions, the NOEL for

Lack of adverse health effects following 30-weeks of dietary exposure to acrylamide at low doses in male F344 rats

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Jayadev Raju

Full Text Available Understanding the health hazards following exposure to food-borne acrylamide, especially at low levels typified by human diets, is an ongoing food safety issue. We recently published results from a study that aimed to understand the effects of acrylamide short-term exposure at doses known to cause tumors in rodents, demonstrating that a number of key toxicological end points were altered by acrylamide exposure. Additionally, we reported that at much lower doses for 30 weeks of exposure, dietary acrylamide was ‘not a complete carcinogen’ to the colon in an organ-specific rodent carcinogenesis study but acted as a co-carcinogen along with azoxymethane (AOM, a colon-specific carcinogen. Here, we present toxicological data from a sub-set of this long-term exposure study from animals that received saline (instead of AOM. Briefly, male F344 rats were randomized to receive acrylamide at 0.5, 1.0 and 2.0 mg/kg diet (∼0.02, 0.04, and 0.09 mg/kg BW/day, respectively or no acrylamide (control, for 30 weeks; all rats were then euthanized and their tissues harvested and processed for toxicological evaluation. We report that at the doses tested, acrylamide did not cause any changes in general well-being, body weight or food intake. Similarly, acrylamide did not cause any biologically relevant change in parameters associated with immunophenotyping, serum biochemistry or hematology. Histopathology assessment of tissues showed no changes except in the testis, where non-specific mild lesions were observed in all the groups, inclusive of the controls. No neuropathological effects of acrylamide were observed in the brain and nerve tissues. Together, these results suggest that acrylamide administered to rats through the diet at low doses for 30 weeks did not cause any toxicologically relevant changes. Given that the doses of acrylamide in the current study are low and are comparable to human dietary exposure, this null-effect study provides data that

Epistatic effects contribute to variation in BMD in Fischer 344 x Lewis F2 rats.

Science.gov (United States)

Koller, Daniel L; Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2008-01-01

To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs. The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F(2) progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an alpha level of 0.01. Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture.

Physical limits to autofluorescence signals in vivo recordings in the rat olfactory bulb: a Monte Carlo study

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L'Heureux, B.; Gurden, H.; Pinot, L.; Mastrippolito, R.; Lefebvre, F.; Lanièce, P.; Pain, F.

2007-07-01

Understanding the cellular mechanisms of energy supply to neurons following physiological activation is still challenging and has strong implications to the interpretation of clinical functional images based on metabolic signals such as Blood Oxygen Level Dependent Magnetic Resonance Imaging or 18F-Fluorodexoy-Glucose Positron Emission Tomography. Intrinsic Optical Signal Imaging provides with high spatio temporal resolution in vivo imaging in the anaesthetized rat. In that context, intrinsic signals are mainly related to changes in the optical absorption of haemoglobin depending on its oxygenation state. This technique has been validated for imaging of the rat olfactory bulb, providing with maps of the actived olfactory glomeruli, the functional modules involved in the first step of olfactory coding. A complementary approach would be autofluorescence imaging relying on the fluorescence properties of endogenous Flavin Adenine Dinucleotide (FAD) or Nicotinamide Adenine Dinucleotide (NADH) both involved in intracellular metabolic pathways. The purpose of the present study was to investigate the feasibility of in vivo autofluorescence imaging in the rat olfactory bulb. We performed standard Monte Carlo simulations of photons scattering and absorption at the excitation and emission wavelengths of FAD and NADH fluorescence. Characterization of the fluorescence distribution in the glomerulus, effect of hemoglobin absorption at the excitation and absorption wavelengths as well as the effect of the blurring due to photon scattering and the depth of focus of the optical apparatus have been studied. Finally, optimal experimental parameters are proposed to achieve in vivo validation of the technique in the rat olfactory bulb.

NTP Toxicology and Carcinogenesis Studies of Dimethyl Methylphosphonate (CAS No. 756-79-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Science.gov (United States)

1987-11-01

Dimethyl methylphosphonate (98% pure) is one of four chemicals nominated by the U.S. Army for toxicology and carcinogenesis studies because it was being considered for use to simulate the physical and spectroscopic (but not the biologic) properties of anticholinesterase (nerve) agents. Dimethyl methylphosphonate is also used as a flame retardant, a preignition additive for gasoline, an antifoam agent, a plasticizer and stabilizer, a textile conditioner and antistatic agent, and an additive for solvents and low-temperature hydraulic fluids. The United States produces 0.2-2 million pounds (91,000-910,000 kg) of per year. Gavage was chosen as the route of administration for all four candidate "simulants" to mimic potential exposure. Experimental Design: Dimethyl methylphosphonate was administered in corn oil by gavage to male and female F344/N rats and B6C3F1 mice in single-administration, 15-day, and 13-week studies to obtain toxicity data, to establish dose levels for the 2-year studies, and to identify target tissues. Additional studies were also performed to determine toxicity to the reproductive system of male F344/N rats and B6C3F1 mice and to study the potential for genetic damage in bacteria, mammalian cells, and Drosophila. Single-Administration Studies: In the single-administration studies, dimethyl methylphosphonate was given to rats and mice at doses up to 6,810 mg/kg body weight. No compound-related deaths were seen in male or female rats or male mice; two high dose female mice died. Rats exhibited inactivity, unsteady gait, and prostration after dosing; mice were inactive after dosing. Fifteen-Day Studies: Rats and mice received doses of 0, 1,250, 2,500, 5,000, 10,000, or 15,000 mg/kg dimethyl methylphosphonate per day. Compound-related deaths occurred in the three highest dose groups of rats and the two highest dose groups of mice. Rats receiving doses of 2,500 mg/kg or higher were inactive and at 5,000 or 10,000 mg/kg had an unsteady gait after dosing

Epistatic Effects Contribute to Variation in BMD in Fischer 344 × Lewis F2 Rats

Science.gov (United States)

Koller, Daniel L; Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2008-01-01

To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs. Introduction The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F2 progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Materials and Methods Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an α level of 0.01. Results and Conclusions Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture. PMID:17907919

Modulation of aflatoxin toxicity and biomarkers by lycopene in F344 rats

International Nuclear Information System (INIS)

Tang, Lili; Guan Hongxia; Ding Xiaolin; Wang Jiasheng

2007-01-01

Modulation by lycopene of aflatoxin B 1 (AFB 1 )-induced toxic effects, metabolism, and metabolic activations was studied in young F344 rats. Animals were pretreated orally with either corn oil (control group) or lycopene [100 mg/kg body weight (b.w.), intervention group] 5 days/week for 2 weeks. Control animals were then treated daily with AFB 1 (250 μg/kg b.w) alone. Intervention animals were administered lycopene (100 mg/kg b.w.) at 1 h following a daily treatment with AFB 1 (250 μg/kg b.w.). Pretreatment and intervention with lycopene significantly reduced the toxic effect caused by AFB 1 and greatly modulated AFB 1 metabolism and metabolic activation. Urinary excretion of AFB 1 phase 1 metabolites, AFM 1 , AFQ 1 , and AFP 1 , was significantly decreased in lycopene-treated animals. Formation of serum AFB 1 -albumin adducts was also significantly reduced. The rate of reduction was from approximately 30% on day 1 (p 1 -DNA adducts in liver compared to control animals, with the highest reduction (52.7%) occurring on day 3 (p 1 -N 7 -guanine excreted in urine were also significantly decreased. Urinary excretion of the phase 2 detoxification metabolite, AFB 1 -mecapturic acid, was significantly increased in lycopene-intervened animals. AFB 1 -induced urinary excretion of 8-hydroxydeoxyguanosine was also reduced to 50% on day 7 after lycopene intervention. Collectively, these results suggest that inhibition of phase 1 metabolism and metabolic activation, as well as induction of phase 2 detoxification enzyme activity are the potential mechanisms for the chemopreventive effects of lycopene

NTP Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Science.gov (United States)

1986-04-01

Benzene ranks 16th in production volume for chemicals produced in the United States, with approximately 9.9 billion pounds being produced in 1984, 9.1 billion pounds in 1983, and 7.8 billion pounds in 1982. This simplest aromatic chemical in used in the synthesis of styrene (polystyrene plastics and synthetic rubber), phenol (phenolic resins), cyclohexane (nylon), aniline, maleic anhydride (polyester resins), alkylbenzenes (detergents), chlorobenzenes, and other products used in the production of drugs, dyes, insecticides, and plastics. Benzene, along with other light, high-octane aromatic hydrocarbons, such as toluene and xylenes, is a component of motor gasoline. Benzene is also used as a solvent, but for most applications, it has been replaced by less hazardous solvents. During the 17-week studies, groups of 10 or 15 male and female F344/N rats and B6C3F1 mice were gavaged 5 days per week with benzene in corn oil (5 ml/kg) at doses of 0 to 600 mg/kg. No benzene-related deaths occurred; in rats that received benzene, final mean body weights were 14%-22% lower compared with vehicle controls and in mice, slight dose-related reductions were observed (less than 10% differences). Doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Two-year toxicology and carcinogenesis studies of benzene (greater than 99.7% pure) were conducted in groups of 50 F344/N rats and 50 B6C3F1 mice of each sex and for each dose. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil (5 ml/kg) were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten additional animals in each of the 16 groups were killed at 12 months and necropsies were performed. Hematologic

Neuropeptide Y enhances olfactory mucosa responses to odorant in hungry rats.

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Negroni, Julia; Meunier, Nicolas; Monnerie, Régine; Salesse, Roland; Baly, Christine; Caillol, Monique; Congar, Patrice

2012-01-01

Neuropeptide Y (NPY) plays an important role in regulating appetite and hunger in vertebrates. In the hypothalamus, NPY stimulates food intake under the control of the nutritional status. Previous studies have shown the presence of NPY and receptors in rodent olfactory system, and suggested a neuroproliferative role. Interestingly, NPY was also shown to directly modulate olfactory responses evoked by a food-related odorant in hungry axolotls. We have recently demonstrated that another nutritional cue, insulin, modulates the odorant responses of the rat olfactory mucosa (OM). Therefore, the aim of the present study was to investigate the potential effect of NPY on rat OM responses to odorants, in relation to the animal's nutritional state. We measured the potential NPY modulation of OM responses to odorant, using electro-olfactogram (EOG) recordings, in fed and fasted adult rats. NPY application significantly and transiently increased EOG amplitudes in fasted but not in fed rats. The effects of specific NPY-receptor agonists were similarly quantified, showing that NPY operated mainly through Y1 receptors. These receptors appeared as heterogeneously expressed by olfactory neurons in the OM, and western blot analysis showed that they were overexpressed in fasted rats. These data provide the first evidence that NPY modulates the initial events of odorant detection in the rat OM. Because this modulation depends on the nutritional status of the animal, and is ascribed to NPY, the most potent orexigenic peptide in the central nervous system, it evidences a strong supplementary physiological link between olfaction and nutritional processes.

Pulmonary retention and tissue distribution of 239Pu nitrate in F344 rats and syrian hamsters inhaling carbon tetrachloride

International Nuclear Information System (INIS)

Benson, J.M.; Barr, E.B.; Lundgren, D.L.; Nikula, K.J.

1994-01-01

Carbon tetrachloride (CCl 4 ) has been used extensively in the nuclear weapons industry, so it is possible that nuclear plant workers have been exposed to CCl 4 and plutonium compounds. Potential for future exposure exists during open-quotes cleanupclose quotes operations at weapon production sites such as the Hanford, Washington, and Rocky Flats, Colorado, facilities. The current Threshold Limit Value for CCl 4 is 5 ppm; however, concentrations of CCl 4 occurring in the nuclear weapons facilities over the past 40-50 y are unknown and may have exceeded this value. The pilot study described in this report is designed to determine whether subchronic inhalation of CCl 4 by CDF register (F-344)/CrlBR rats and Syrian golden hamsters, at concentrations expected to produce some histologic changes in liver, alters the hepatic retention and toxic effects of inhaled 239 Pu nitrate 239 Pu(NO 3 ) 4

Olfactory bulb glomerular NMDA receptors mediate olfactory nerve potentiation and odor preference learning in the neonate rat.

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Rebecca Lethbridge

Full Text Available Rat pup odor preference learning follows pairing of bulbar beta-adrenoceptor activation with olfactory input. We hypothesize that NMDA receptor (NMDAR-mediated olfactory input to mitral cells is enhanced during training, such that increased calcium facilitates and shapes the critical cAMP pattern. Here, we demonstrate, in vitro, that olfactory nerve stimulation, at sniffing frequencies, paired with beta-adrenoceptor activation, potentiates olfactory nerve-evoked mitral cell firing. This potentiation is blocked by a NMDAR antagonist and by increased inhibition. Glomerular disinhibition also induces NMDAR-sensitive potentiation. In vivo, in parallel, behavioral learning is prevented by glomerular infusion of an NMDAR antagonist or a GABA(A receptor agonist. A glomerular GABA(A receptor antagonist paired with odor can induce NMDAR-dependent learning. The NMDA GluN1 subunit is phosphorylated in odor-specific glomeruli within 5 min of training suggesting early activation, and enhanced calcium entry, during acquisition. The GluN1 subunit is down-regulated 3 h after learning; and at 24 h post-training the GluN2B subunit is down-regulated. These events may assist memory stability. Ex vivo experiments using bulbs from trained rat pups reveal an increase in the AMPA/NMDA EPSC ratio post-training, consistent with an increase in AMPA receptor insertion and/or the decrease in NMDAR subunits. These results support a model of a cAMP/NMDA interaction in generating rat pup odor preference learning.

A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats.

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Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Mizuta, Yasuko; Yoshida, Midori; Nishikawa, Akiyoshi; Ogawa, Kumiko

2014-04-01

3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

Modulation of olfactory sensitivity and glucose sensing by the feeding state in obese Zucker rats.

Directory of Open Access Journals (Sweden)

Pascaline eAimé

2014-09-01

Full Text Available The Zucker fa/fa rat has been widely used as an animal model to study obesity, since it recapitulates most of its behavioral and metabolic dysfunctions, such as hyperphagia, hyperglycemia and insulin resistance. Although it is well established that olfaction is under nutritional and hormonal influences, little is known about the impact of metabolic dysfunctions on olfactory performances and glucose-sensing in the olfactory system of the obese Zucker rat. In the present study, using a behavioral paradigm based on a conditioned olfactory aversion, we have shown that both obese and lean Zucker rats have a better olfactory sensitivity when they are fasted than when they are satiated. Interestingly, the obese Zucker rats displayed a higher olfactory sensitivity than their lean controls. By investigating the molecular mechanisms involved in glucose-sensing in the olfactory system, we demonstrated that sodium-coupled glucose transporters 1 (SGLT1 and insulin dependent glucose transporters 4 (GLUT4 are both expressed in the olfactory bulb (OB. By comparing the expression of GLUT4 and SGLT1 in OB of obese and lean Zucker rats, we found that only SGLT1 is regulated in genotype-dependent manner. Next, we used glucose oxidase biosensors to simultaneously measure in vivo the extracellular fluid glucose concentrations ([Gluc]ECF in the OB and the cortex. Under metabolic steady state, we have determined that the OB contained twice the amount of glucose found in the cortex. In both regions, the [Gluc]ECF was 2 fold higher in obese rats compared to their lean controls. Under induced dynamic glycemia conditions, insulin injection produced a greater decrease of [Gluc]ECF in the OB than in the cortex. Glucose injection did not affect OB [Gluc]ECF in Zucker fa/fa rats. In conclusion, these results emphasize the importance of glucose for the OB network function and provide strong arguments towards establishing the OB glucose-sensing as a key factor for sensory

Olfactory stimulation modulates the blood glucose level in rats.

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Tsuji, Tadataka; Tanaka, Susumu; Bakhshishayan, Sanam; Kogo, Mikihiko; Yamamoto, Takashi

2018-01-01

In both humans and animals, chemosensory stimuli, including odors and tastes, induce a variety of physiologic and mental responses related to energy homeostasis, such as glucose kinetics. The present study examined the importance of olfactory function in glucose kinetics following ingestion behavior in a simplified experimental scenario. We applied a conventional glucose tolerance test to rats with and without olfactory function and analyzed subsequent blood glucose (BG) curves in detail. The loss of olfactory input due to experimental damage to the olfactory mucosa induced a marked decrease in the area under the BG curve. Exposure to grapefruit odor and its main component, limonene, both of which activate the sympathetic nerves, before glucose loading also greatly depressed the BG curve. Pre-loading exposure to lavender odor, a parasympathetic activator, stabilized the BG level. These results suggest that olfactory function is important for proper glucose kinetics after glucose intake and that certain fragrances could be utilized as tools for controlling BG levels.

Subchronic toxicity evaluation of anthraquinone in Fischer 344 rats.

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Dodd, Darol E; Layko, Debra K; Cantwell, Katherine E; Willson, Gabrielle A; Thomas, Russell S

2013-01-01

Female F344 rats were exposed to anthraquinone (AQ) by dietary feed at concentrations of 0, 50, 150, 469, 938, 1875, or 3750 ppm for 2 or 13 weeks. End points evaluated included clinical observations, body weights, serum chemistry, blood AQ, gross pathology, organ weights, and select tissue histopathology. Mean body weight and food consumption were 5% to 10% lower than control values in rats of the ≥938 ppm group during study weeks 2 through 13. Occasional decreases in body weight means were also observed in rats of the 150 and 469 ppm groups. Increases in liver, kidney, and spleen weights were observed in rats exposed to AQ diet concentrations ≥150 ppm for 13 weeks. Urinary bladder weights were increased at ≥469 ppm. Liver and spleen weights were also increased following 2 weeks of exposure. Liver weight increases were clearly dependent on AQ concentration. At 2 weeks, decreases in serum aspartate aminotransferase (AST), blood urea nitrogen, and creatinine concentrations were observed in higher AQ exposure groups, and AST was decreased at 13 weeks (≥1875 ppm). Microscopic alterations were observed in the liver (mild centrilobular hypertrophy), spleen (mild hematopoietic cell proliferation and pigmentation), and kidneys (minimal hyaline droplets) of rats exposed to AQ for 13 weeks. Blood AQ concentrations ranged from 0.75 to 14.8 µg/mL in rats of the 150 to 3750 ppm groups, respectively, and were similar in value following either 2 weeks or 13 weeks of exposure. A no observed adverse effect level of 469 ppm AQ (31.3 mg/kg/d) was selected based on the absence of liver histopathology.

Toxicology and carcinogenesis studies of p,p'-dichlorophenyl sulfone (CAS No. 80-07-9) in F344/N rats and B6C3F1 mice (feed studies).

Science.gov (United States)

2001-09-01

p,pN-Dichlorodiphenyl sulfone is used as a starting material in the production of polysulfones and polyethersulfones and as a component in reactive dyes in the textile industry; it is also a by-product of pesticide production. p,pN-Dichlorodiphenyl sulfone was nominated for study by the National Cancer Institute because of its history of high production and use, the prospect of increased production and use, and the absence of adequate toxicity testing. Male and female F344/N rats and B6C3F1 mice were exposed top,pN-dichlorodiphenyl sulfone (greater than 99% pure)in feed for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium,cultured Chinese hamster ovary cells, and mouse bone marrow. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 2, 6, 19, 65, or 200 mgp,pN-dichlorodiphenyl sulfone/kg body weight) for 14 weeks. All rats survived until the end of the study. Mean body weights of groups exposed to 300 ppm or greater were significantly less than those of the controls. Liver weights of groups exposed to 100 ppm or greater and kidney weights of 1,000 and 3,000 ppm male rats were significantly greater than those of the controls. Centrilobular hepatocyte hypertrophy of the liver was observed in most male rats exposed to 100 ppm or greater and in all female rats exposed to 300 ppm or greater, and the severities were increased in 300 ppm males and 1,000 and 3,000 ppm males and females. The incidences of nephropathy in 1,000 and 3,000 ppm female rats were significantly increased. Dose-related increases in severity of nephropathy were observed in male rats. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 30, 100, 300, 1,000, or 3,000 ppm p,pN-dichlorodiphenyl sulfone (equivalent to average daily doses of approximately 3.5, 15, 50

The role of urinary pH in o-phenylphenol-induced cytotoxicity and chromosomal damage in the bladders of F344 rats.

Science.gov (United States)

Balakrishnan, S; Hasegawa, L; Eastmond, D A

2016-04-01

o-Phenylphenol (OPP) is a widely used fungicide and antibacterial agent that at high doses has been shown to cause bladder cancer in male F344 rats. The mechanisms underlying OPP-induced bladder carcinogenicity remain unclear but it has been proposed that a non-enzymatic pH-dependent autoxidation of phenylhydroquinone (PHQ), a primary metabolite of OPP, may be a key step in OPP-induced rat bladder carcinogenesis. To investigate this mechanism and to provide insights into the potential human health relevance of OPP-induced cancer, a series of in vitro and in vivo experiments were conducted. In human lymphoblastoid TK-6 cells and rat bladder epithelial NBT-II cells, strong increases in cytotoxicity were seen at a constant concentration of PHQ by increasing the buffer pH as well as by increasing concentrations of PHQ at a constant pH. In in vivo studies, male rats were administered OPP (4,000 and 8,000 ppm) in a diet supplemented with either 1% ammonium chloride or 3% sodium bicarbonate to produce acidic and alkaline urinary pH, respectively. Significant increases in cell proliferation as detected by 5-bromo-2'-deoxyuridine incorporation and micronucleus formation were seen in the bladder cells of OPP-treated rats with neutral or alkaline urinary pH but not in animals with the acidified urine. The results from these in vitro and in vivo studies provide support for the autoxidation hypothesis of bioactivation, and provide additional evidence that urinary pH can significantly influence the genotoxicity and carcinogenicity of this important agent. © 2016 Wiley Periodicals, Inc.

Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and B6C3F1 mice following 2-year inhalation exposure

International Nuclear Information System (INIS)

Stout, Matthew D.; Herbert, Ronald A.; Kissling, Grace E.; Suarez, Fernando; Roycroft, Joseph H.; Chhabra, Rajendra S.; Bucher, John R.

2008-01-01

Methyl isobutyl ketone (MIBK) is primarily used as a denaturant for rubbing alcohol, as a solvent and in the manufacture of methyl amyl alcohol. Inhalation of vapors is the most likely route of exposure in the work place. In order to evaluate the potential of MIBK to induce toxic and carcinogenic effects following chronic exposure, groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to MIBK at concentrations of 0, 450, 900, or 1800 ppm by inhalation, 6 h/day, 5 days per week for 2 years. Survival was decreased in male rats at 1800 ppm. Body weight gains were decreased in male rats at 900 and 1800 ppm and in female mice at 1800 ppm. The primary targets of MIBK toxicity and carcinogenicity were the kidney in rats and the liver in mice. In male rats, there was increased mineralization of the renal papilla at all exposure concentrations. The incidence of chronic progressive nephropathy (CPN) was increased at 1800 ppm and the severity was increased in all exposed groups. There were also increases in renal tubule hyperplasia at all exposure concentrations, and in adenoma and adenoma or carcinoma (combined) at 1800 ppm; these lesions are thought to represent a continuum in the progression of proliferative lesions in renal tubule epithelium. These increases may have resulted from the increased severity of CPN, either through α2μ-globulin-dependent or -independent mechanisms. An increase in mononuclear cell leukemia at 1800 ppm was an uncertain finding. Adrenal medulla hyperplasia was increased at 1800 ppm, and there was a positive trend for increases in benign or malignant pheochromocytomas (combined). In female rats, there were increases in the incidence of CPN in all exposure concentrations and in the severity at 1800 ppm, indicating that CPN was increased by mechanisms in addition to those related to α2μ-globulin. There were renal mesenchymal tumors, which have not been observed in historical control animals, in two female rats at 1800 ppm. The

The Fischer 344 rat as a model of presbycusis

Czech Academy of Sciences Publication Activity Database

Syka, Josef

2010-01-01

Roč. 264, 1-2 (2010), s. 70-78 ISSN 0378-5955 R&D Projects: GA ČR GA309/07/1336; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50390703 Keywords : Rat * Fischer 344 * Presbycusis Subject RIV: FH - Neurology Impact factor: 2.428, year: 2010

NTP technical report on the toxicity studies of Castor Oil (CAS No. 8001-79-4) in F344/N Rats and B6C3F1 Mice (Dosed Feed Studies).

Science.gov (United States)

Irwin, R

1992-03-01

Castor oil is a natural oil derived from the seeds of the castor bean, Ricinus communis. It is comprised largely of triglycerides with a high ricinolin content. Toxicity studies with castor oil were performed by incorporating the material at concentrations as high as 10% in diets given to F344/N rats and B6C3F1 mice of both sexes for 13 weeks. Genetic toxicity studies also were performed and were negative for mutation induction in Salmonella typhimurium, for induction of sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, and for induction of micronuclei in the peripheral blood erythrocytes of mice evaluated at the end of the 13-week studies. Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice (10 per sex and dose). There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of estrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies. Synonyms: Ricinus Oil, oil of Palma Christi, tangantangan oil, phorboyl, Neoloid.

Effect of long-term caloric restriction on brain monoamines in aging male and female Fischer 344 rats.

Science.gov (United States)

Kolta, M G; Holson, R; Duffy, P; Hart, R W

1989-05-01

The present study examines the changes in central monoamines and their metabolites in aged male and female rats after long-term caloric restriction. Fischer 344 rats of both sexes (n = 5-10/group) were maintained on one of two dietary regimens: ad libitum NIH 31 diet or 60% by weight of the ad lib. intake (restricted), supplemented with vitamins and minerals. Animals received these diets from the age of 14 weeks until killed at 22.25 months of age. Caudate nucleus (CN), hypothalamus (HYPO), olfactory bulb (OB) and nucleus accumbens (NA) were assayed for content of norepinephrine (NE), dopamine (DA) and its metabolites (dihydroxyphenylacetic acid, DOPAC, and homovanillic acid, HVA) and serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) using HPLC/EC. Relative to the ad lib. group, restricted rats of both sex showed significant decreases in NE content in CN, HYPO and OB. DA and 5-HT content were decreased significantly in the CN and HYPO. No significant changes were found in the levels of DA metabolites in all brain regions studied. While the 5-HIAA level was significantly reduced in the HYPO and NA of the female restricted rats, it was increased several-fold in the OB of the male restricted animals. These preliminary results suggest that long-term caloric restriction alters brain monoamine concentrations, an effect which may in turn modify the normal rate of aging.

Expression of rat class I major histocompatibility complex (MHC) alloantigens and hepatocytes and hepatoma cells

International Nuclear Information System (INIS)

Hunt, J.M.; Desai, P.A.; Chakraborty, S.

1986-01-01

Altered expression of Class I MHC alloantigens has been reported for murine tumors, and may be associated with the tumorigenic phenotype of tumor cells. To characterize MHC Class I alloantigen expression on a chemically-induced transplantable rat hepatoma cell line, 17X, derived from a (WF x F344) F 1 rat, polyvalent anti-F344 and anti-WF rat alloantisera were first used to immunoprecipitate the rat RT1.A Class I MHC alloantigens expressed on primary (WF x F344) F 1 hepatocyptes in short-term monolayer cultures. Two-dimensional isoelectric focusing and SDS-PAGE of immunoprecipitates from 35 S-methionine-labeled (WF x F344) F 1 hepatocytes clearly resolved the RT1.A/sup u/ (WF) and RT1.A/sup LvI/ (F344) parental alloantigens. Identical radiolabeling and immunoprecipitation failed to detect either parental alloantigen on the 17X hepatoma cells. However, indirect immunofluorescence and immunoblot analyses demonstrated the presence of parental alloantigens on the 17X cells. Immunization of F344 rats but not of WF rats with 17X cells resulted in antibodies cytotoxic for normal (WF X F344) F 1 spleen cells in the presence of complement. These findings indicate that a combination of detection techniques will be necessary to characterize altered alloantigen expression on rat hepatoma cells

Diet-induced obesity, exogenous leptin-, and MADB106 tumor cell challenge affect tissue leukocyte distribution and serum levels of cytokines in F344 rats.

Science.gov (United States)

Behrendt, Patrick; Buchenauer, Tobias; Horn, Rüdiger; Brabant, Georg; Jacobs, Roland; Bode, Felix; Stephan, Michael; Nave, Heike

2010-08-01

The adipocyte-derived catabolic protein leptin alters cell-mediated immunity and cytokine crosstalk. This may provide new insights into the altered immune response, seen in obese individuals. Therefore, we determined the tissue distribution of immune cells in diet-induced obese (dio) and normal weight F344 rats challenged with MADB106 tumor cells or leptin. Immune cell distribution in blood (by FACS analysis) and tissues (NK cells in spleen and liver, immunohistologically) as well as pro-inflammatory cytokines (IL-6, TNF-α; by flow cytometry) were investigated in 28 normal weight and 28 dio rats (n = 4-6/group). Pro-inflammatory cytokines were increased 3-fold for IL-6 and 7-fold for TNF-α in obese animals. Higher numbers of blood monocytes and NK cells were found in obese as compared to normal weight animals. In dio rats challenged with leptin and MADB106 tumor cells, monocyte numbers were decreased as compared to the obese control animals. Immunohistochemistry revealed an altered NK cell distribution in a compartment-, treatment-, and bodyweight-specific manner. In conclusion, our data reveal a distinct distribution pattern of monocytes and NK cells in dio rats as compared to normal weight littermates and an additional modulatory effect of a leptin- and MADB106 tumor cell challenge.

Disposition and metabolism of aniline in Fischer 344 rats and C57BL/6 X C3H F1 mice

International Nuclear Information System (INIS)

McCarthy, D.J.; Waud, W.R.; Struck, R.F.; Hill, D.L.

1985-01-01

We examined the metabolism and disposition of aniline, which induces spleen hemangiosarcomas in rats but no tumors in mice, in normal and predosed Fischer 344 rats, and C57BL/6 X C3H F1 mice administered low (50 and 100 mg/kg, respectively) or high (250 and 500 mg/kg, respectively) doses. Of 11 tissues examined, the highest levels of binding of [ 14 C]aniline to DNA were in the kidney, large intestine, and spleen of high-dose rats that had received prior dosing; these tissues had covalent binding indices of 14.2, 4.3, and 3.7 mumol/mol nucleotides/dose, respectively. Protein and RNA were the major macromolecular targets for binding of radioactivity from [ 14 C]aniline. Relative to controls, most tissues from predosed mice (low dose and high dose) showed less binding to protein and RNA; but for most tissues from predosed rats administered 50-mg/kg doses of [ 14 C]aniline, there was more extensive binding. Also relative to controls, binding of radioactivity in the spleen of predosed rats given [ 14 C]aniline (50 mg/kg) was 148% greater for protein and 302% greater for RNA. For rats administered 250 mg of [ 14 C]aniline per kg, however, there were no outstanding differences in binding to RNA and protein between normal and predosed animals. The profiles of urinary metabolites produced by rats and mice were not appreciably different in animals predosed with aniline. For rats, however, the profiles were different for the low and high doses, suggesting that the main metabolic pathway was saturated at the higher dose. p-Acetamidophenyl sulfate represented over 70% of the total radioactivity recovered from the urine of rats dosed with 50 mg of aniline per kg but only 30% in the urine of those dosed with 250 mg/kg. The urine of the high-dose rats contained greater percentages of p-aminophenyl sulfate, p-acetamidophenyl glucuronide, and unconjugated metabolites

Toxicokinetics of 14C-saligenin cyclic-o-tolyl phosphate (SCOTP) in male F-344 rats

International Nuclear Information System (INIS)

Chapin, R.E.; Burka, L.T.

1990-01-01

SCOTP has been proposed as the active metabolite of tri-o-cresyl phosphate (TOCP), a neurotoxic organophosphate. TOCP is also toxic to the testis and SCOTP mimics some of this toxicity. SCOTP is reactive and may not be sufficiently stable to be made elsewhere and transported by blood to the testis. SCOTP's stability in vivo and its uptake by the testes has now been made measured. Male F-344 rats treated iv with 1 mg of 14C-SCOTP/kg were killed at intervals ranging from 5 to 60 min. Blood and selected tissues were rapidly removed at sacrifice, extracted with acetonitrile and analyzed by HPLC. Total radioactivity in these tissues was also determined. The half-life of SCOTP in blood was 8.0 ± 1.1 min. Testes, along with brain and muscle, had lower concentrations of 14C-SCOTP derived radioactivity than blood. Liver and kidney had higher concentrations of radioactivity than blood. HPLC analysis of liver, kidney, testes and blood extracts showed that 2.8, 48, 11 and 18%, respectively, of the radioactivity present at 5 min was SCOTP. The amount of SCOTP declined rapidly, and at 30 min SCOTP could be detected only in kidney. From these results it appears that SCOTP, although reactive, has sufficient stability to be transported from organ to organ. There is no evidence of active uptake of SCOTP from blood by the testes

Role of UDP-Glucuronosyltransferase (UGT) 2B2 in Metabolism of Triiodothyronine: Effect of Microsomal Enzyme Inducers in Sprague Dawley and UGT2B2-Deficient Fischer 344 Rats

Science.gov (United States)

Richardson, Terrilyn A.; Klaassen, Curtis D.

2010-01-01

Microsomal enzyme inducers (MEI) that increase UDP-glucuronosyltransferases (UGTs) can impact thyroid hormone homeostasis in rodents. Increased glucuronidation can result in reduction of serum thyroid hormone and a concomitant increase in thyroid-stimulating hormone (TSH). UGT2B2 is thought to glucuronidate triiodothyronine (T3). The purposes of this study were to determine the role of UGT2B2 in T3 glucuronidation and whether increased T3 glucuronidation mediates the increased TSH observed after MEI treatment. Sprague Dawley (SD) and UGT2B2-deficient Fischer 344 (F344) rats were fed a control diet or diet containing pregnenolone-16α-carbonitrile (PCN; 800 ppm), 3-methylcholanthrene (3-MC; 200 ppm), or Aroclor 1254 (PCB; 100 ppm) for 7 days. Serum thyroxine (T4), T3, and TSH concentrations, hepatic androsterone/T4/T3 glucuronidation, and thyroid follicular cell proliferation were determined. In both SD and F344 rats, MEI treatments decreased serum T4, whereas serum T3 was maintained (except with PCB treatment). Hepatic T4 glucuronidation increased significantly after MEI in both rat strains. Compared with the other MEI, only PCN treatment significantly increased T3 glucuronidation (281 and 497%) in both SD and UGT2B2-deficient F344 rats, respectively, and increased both serum TSH and thyroid follicular cell proliferation. These data demonstrate an association among increases in T3 glucuronidation, TSH, and follicular cell proliferation after PCN treatment, suggesting that T3 is glucuronidated by other PCN-inducible UGTs in addition to UGT2B2. These data also suggest that PCN (rather than 3-MC or PCB) promotes thyroid tumors through excessive TSH stimulation of the thyroid gland. PMID:20421340

Polycyclic aromatic hydrocarbons modulate cell proliferation in rat hepatic epithelial stem-like WB-F344 cells

International Nuclear Information System (INIS)

Chramostova, Katerina; Vondracek, Jan; Sindlerova, Lenka; Vojtesek, Borivoj; Kozubik, Alois; Machala, Miroslav

2004-01-01

Although many polycyclic aromatic hydrocarbons (PAHs) are recognized as potent mutagens and carcinogens, relatively little is known about their role in the tumor promotion. It is known that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce release of rat hepatic oval epithelial cells from contact inhibition by a mechanism possibly involving the aryl hydrocarbon receptor (AhR) activation. Many PAHs are AhR ligands and are known to act as transient inducers of AhR-mediated activity. In this study, effects of 19 selected PAHs on proliferation of confluent rat liver epithelial WB-F344 cells were investigated. Non-mutagens that are weak activators or nonactivators of AhR-mediated activity had no effect on cell proliferation. Relatively strong or moderate AhR ligands with low mutagenic potencies, such as benzofluoranthenes, benz[a]anthracene, and chrysene, were found to increase cell numbers, which corresponded to an increased percentage of cells entering S-phase. Strong mutagens, including benzo[a]pyrene and dibenzo[a,l]pyrene, increased a percentage of cells in S-phase without inducing a concomitant increase in cell numbers. The treatment with mutagenic PAHs was associated with an increased DNA synthesis and induction of cell death, which corresponded with the activation of p53 tumor suppressor. Apoptosis was blocked by pifithrin-α, the chemical inhibitor of p53. Both weakly and strongly mutagenic PAHs known as AhR ligands were found to induce significant increase of cytochrome P4501A activity, suggesting a presence of functional AhR. The results of the present study seem to suggest that a release from contact inhibition could be a part of tumor promoting effects of AhR-activating PAHs; however, the genotoxic effects of some PAHs associated with p53 activation might interfere with this process

Covalent interactions of 1,2,3-trichloropropane with hepatic macromolecules: studies in the male F-344 rat.

Science.gov (United States)

Weber, G L; Sipes, I G

1990-07-01

Preliminary investigations into the role of biotransformation in 1,2,3-trichloropropane (TCP)-induced tumor formation have been undertaken. Male F-344 rats were administered 30 mg/kg [14C]TCP (100 microCi/kg) ip and killed 4 hr later. The extent of covalent binding to hepatic protein, DNA, and RNA was 418, 244, and 432 pmol [14C]TCP equivalents/mg, respectively. An in vivo covalent binding time course showed no significant change in [14C]TCP equivalents bound to hepatic DNA (1-48 hr), while binding to protein was maximal by 4 hr and decreased significantly by 48 hr. The binding of TCP-associated radioactivity to hepatic protein and DNA was shown to be cumulative for two and three doses when given 24 hr apart. Pretreatment of animals with phenobarbital caused a decrease while pretreatment with SKF 525-A caused an increase in covalent binding of [14C]TCP equivalents to protein and DNA. Pretreatment of rats with beta-naphthoflavone did not alter the covalent binding of [14C]TCP equivalents to protein or DNA. However, glutathione depletion with L-buthionine-(R,S)-sulfoximine increased binding to protein by 342% while it decreased binding to DNA by 56%. Intraperitoneal administration of TCP also depleted hepatic GSH by 41 and 61% 2 hr after doses of 30 and 100 mg/kg. The in vivo binding data suggest a dual role for GSH in the bioactivation of TCP. It may, in part, be that GSH is involved in the bioactivation and covalent binding of TCP to hepatic DNA. However, it also appears to detoxify a reactive intermediate(s) that binds to protein.

Induction of glutathione S-transferase placental form positive foci in liver and epithelial hyperplasia in urinary bladder, but no tumor development in male Fischer 344 rats treated with monomethylarsonic acid for 104 weeks

International Nuclear Information System (INIS)

Shen Jun; Wanibuchi, Hideki; Salim, Elsayed I.; Wei Min; Doi, Kenichiro; Yoshida, Kaoru; Endo, Ginji; Morimura,; Fukushima, Shoji

2003-01-01

The carcinogenicity of monomethylarsonic acid (MMA(V)), a major metabolite of inorganic arsenics in human and experimental animals, was investigated in male Fischer 344 rats. A total of 129 rats at 10 weeks of age were randomly divided into three groups and received drinking water containing MMA(V) at doses of 0 (Control), 50, and 200 ppm ad libitum for 104 weeks. No significant differences were found between the control and the MMA(V)-treated groups regarding clinical signs, mortality, hematological, and serum biochemistry findings. Quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci in liver revealed a significant increase of numbers and areas in the 200 ppm MMA(V)-treated group. In the urinary bladder MMA(V) induced simple hyperplasia and significantly elevated the proliferating cell nuclear antigen (PCNA)-positive index in the urothelium. A variety of tumors developed in rats of all groups, including the controls, but all were histologically similar to those known to occur spontaneously in F344 rats and there were no significant differences among the groups. Thus, it could be concluded that, under the present experimental conditions, MMA(V) induced lesions in the liver and urinary bladder, but did not cause tumor development in male F344 rats even after 2 years exposure

Eicosapentenoic Acid Attenuates Allograft Rejection in an HLA-B27/EGFP Transgenic Rat Cardiac Transplantation Model.

Science.gov (United States)

Liu, Zhong; Hatayama, Naoyuki; Xie, Lin; Kato, Ken; Zhu, Ping; Ochiya, Takahiro; Nagahara, Yukitoshi; Hu, Xiang; Li, Xiao-Kang

2012-01-01

The development of an animal model bearing definite antigens is important to facilitate the evaluation and modulation of specific allo-antigen responses after transplantation. In the present study, heterotopic cardiac transplantation was performed from F344/EGFPTg and F344/HLA-B27Tg rats to F344 rats. The F344 recipients accepted the F344/EGFPTg transplants, whereas they rejected the cardiac tissue from the F344/HLA-B27Tg rats by 39.4 ± 6.5 days, due to high production of anti-HLA-B27 IgM- and IgG-specific antibodies. In addition, immunization of F344 rats with skin grafts from F344/HLA-B27Tg rats resulted in robust production of anti- HLA-B27 IgM and IgG antibodies and accelerated the rejection of a secondary cardiac allograft (7.4 ± 1.9 days). Of interest, the F344 recipients rejected cardiac grafts from double transgenic F344/HLA-B27&EGFPTg rats within 9.0 ± 3.2 days, and this was associated with a significant increase in the infiltration of lymphocytes by day 7, suggesting a role for cellular immune rejection. Eicosapentenoic acid (EPA), one of the ω-3 polyunsaturated fatty acids in fish oil, could attenuate the production of anti-HLA IgG antibodies and B-cell proliferation, significantly prolonging double transgenic F344HLA-B27&EGFPTg to F344 rat cardiac allograft survival (36.1 ± 13.6 days). Moreover, the mRNA expression in the grafts was assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), revealing an increase in the expression of the HO-1, IL-10, TGF-β, IDO, and Foxp3 genes in the EPA-treated group. Hence, our data indicate that HLA-B27 and/or GFP transgenic proteins are useful for establishing a unique animal transplantation model to clarify the mechanism underlying the allogeneic cellular and humoral immune response, in which the transplant antigens are specifically presented. Furthermore, we also demonstrated that EPA was effective in the treatment of rat cardiac allograft rejection and may allow the development of

The olfactory deficit and fMRI in the Alzheimer's disease

International Nuclear Information System (INIS)

Yin Jianzhong; Wang Jianli; Yang Qingxian; Qi Ji

2008-01-01

Olfactory deficit is a common symptom occurring at the early stage of Alzheimer's disease, the purpose of this review is to summarize MRI research on olfactory deficit in the Alzheimer's disease and potential clinical relevance of fMRI in this area. (authors)

Collagen changes in the cochlea of aged Fischer 344 rats

Czech Academy of Sciences Publication Activity Database

Buckiová, Daniela; Popelář, Jiří; Syka, Josef

2006-01-01

Roč. 41, - (2006), s. 296-302 ISSN 0531-5565 R&D Projects: GA ČR GA309/04/1074; GA MZd NR8113; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50390512 Keywords : Presbycusis * Rat * Fischer 344 strain Subject RIV: FH - Neurology Impact factor: 2.930, year: 2006

The Natural History of Pneumonic Tularemia in Female Fischer 344 Rats after Inhalational Exposure to Aerosolized Francisella tularensis Subspecies tularensis Strain SCHU S4.

Science.gov (United States)

Hutt, Julie A; Lovchik, Julie A; Dekonenko, Alexander; Hahn, Andrew C; Wu, Terry H

2017-02-01

The inbred Fischer 344 rat is being evaluated for testing novel vaccines and therapeutics against pneumonic tularemia. Although primary pneumonic tularemia in humans typically occurs by inhalation of aerosolized bacteria, the rat model has relied on intratracheal inoculation of organisms because of safety and equipment issues. We now report the natural history of pneumonic tularemia in female Fischer 344 rats after nose-only inhalational exposure to lethal doses of aerosolized Francisella tularensis subspecies tularensis, strain SCHU S4. Our results are consistent with initial uptake of aerosolized SCHU S4 from the nasal cavity, lungs, and possibly the gastrointestinal tract. Bacteremia with hematogenous dissemination was first detected 2 days after exposure. Shortly thereafter, the infected rats exhibited fever, tachypnea, and hypertension that persisted for 24 to 36 hours and then rapidly decreased as animals succumbed to infection between days 5 and 8 after exposure. Tachycardia was observed briefly, but only after the core body temperature and blood pressure began to decrease as the animals were near death. Initial neutrophilic and histiocytic inflammation in affected tissues became progressively more fibrinous and necrotizing over time. At death, as many as 10 10 colony-forming units were found in the lungs, spleen, and liver. Death was attributed to sepsis and disseminated intravascular coagulation. Overall, the pathogenesis of pneumonic tularemia in the female F344 rat model appears to replicate the disease in humans. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Fos Protein Expression in Olfactory-Related Brain Areas after Learning and after Reactivation of a Slowly Acquired Olfactory Discrimination Task in the Rat

Science.gov (United States)

Roullet, Florence; Lienard, Fabienne; Datiche, Frederique; Cattarelli, Martine

2005-01-01

Fos protein immunodetection was used to investigate the neuronal activation elicited in some olfactory-related areas after either learning of an olfactory discrimination task or its reactivation 10 d later. Trained rats (T) progressively acquired the association between one odor of a pair and water-reward in a four-arm maze. Two groups of…

Aging influences multiple indices of oxidative stress in the heart of the Fischer 344/NNia x Brown Norway/BiNia rat.

Science.gov (United States)

Asano, Shinichi; Rice, Kevin M; Kakarla, Sunil; Katta, Anjaiah; Desai, Devashish H; Walker, Ernest M; Wehner, Paulette; Blough, Eric R

2007-01-01

We report the influence of aging on multiple markers of oxidative-nitrosative stress in the heart of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSd x Brown Norway/BiNia (F344/NXBN) rats. Compared to adult (6-month) hearts, indices of oxidative (superoxide anion [O2*-], 4-hydroxy-2-nonenal [4-HNE]) and nitrosative (protein nitrotyrosylation) stress were 34.1 +/- 28.1%, 186 +/- 28.1% and 94 +/- 5.8% higher, respectively, in 36-month hearts and these findings were highly correlated with increases in left ventricular wall thickness (r > 0.669; r > 0.710 and P lead to age-associated alterations in cardiac oxidative stress.

Rat strains differ in susceptibility to Ureaplasma parvum-induced urinary tract infection and struvite stone formation.

Science.gov (United States)

Reyes, Leticia; Reinhard, Mary; O'donell, L J; Stevens, Janet; Brown, Mary B

2006-12-01

Individuals with struvite uroliths are susceptible to recurrent urinary tract infections (UTI), sepsis, and renal disease. Unfortunately, little is known about the host-specific factors that predispose to this disease. In order to develop a rodent model that can address this problem, we inoculated female Fischer 344 (F344), Lewis (LEW), Sprague-Dawley (SD), and Wistar (WIS) rats with a host-adapted strain of Ureaplasma parvum. Animals were necropsied at 2 weeks postinoculation; 100% of F344, 42% of SD, 10% of LEW, and 10% of WIS rats remained infected. Severe bladder lesions and struvite calculi were seen in 64% of F344 rats; in other rat strains, bladder lesions were mild or absent. F344 rats with struvite uroliths had the highest urinary levels of proinflammatory cytokines, such as GRO/KC, interleukin-1alpha (IL-1alpha), and IL-1beta. F344 rats without struvite stones at necropsy had milder bladder lesions and significantly lower urinary levels of proinflammatory cytokines but a more prominent inflammatory response than did other rat strains. Based on our results, struvite stone formation is linked to a robust inflammatory response that does not resolve UTI but instead promotes damage to surrounding tissues.

Multi-Shell Hybrid Diffusion Imaging (HYDI) at 7 Tesla in TgF344-AD Transgenic Alzheimer Rats.

Science.gov (United States)

Daianu, Madelaine; Jacobs, Russell E; Weitz, Tara M; Town, Terrence C; Thompson, Paul M

2015-01-01

Diffusion weighted imaging (DWI) is widely used to study microstructural characteristics of the brain. Diffusion tensor imaging (DTI) and high-angular resolution imaging (HARDI) are frequently used in radiology and neuroscience research but can be limited in describing the signal behavior in composite nerve fiber structures. Here, we developed and assessed the benefit of a comprehensive diffusion encoding scheme, known as hybrid diffusion imaging (HYDI), composed of 300 DWI volumes acquired at 7-Tesla with diffusion weightings at b = 1000, 3000, 4000, 8000 and 12000 s/mm2 and applied it in transgenic Alzheimer rats (line TgF344-AD) that model the full clinico-pathological spectrum of the human disease. We studied and visualized the effects of the multiple concentric "shells" when computing three distinct anisotropy maps-fractional anisotropy (FA), generalized fractional anisotropy (GFA) and normalized quantitative anisotropy (NQA). We tested the added value of the multi-shell q-space sampling scheme, when reconstructing neural pathways using mathematical frameworks from DTI and q-ball imaging (QBI). We show a range of properties of HYDI, including lower apparent anisotropy when using high b-value shells in DTI-based reconstructions, and increases in apparent anisotropy in QBI-based reconstructions. Regardless of the reconstruction scheme, HYDI improves FA-, GFA- and NQA-aided tractography. HYDI may be valuable in human connectome projects and clinical research, as well as magnetic resonance research in experimental animals.

The effect of age on digoxin pharmacokinetics in Fischer-344 rats

International Nuclear Information System (INIS)

Evans, R.L.; Owens, S.M.; Ruch, S.; Kennedy, R.H.; Seifen, E.

1990-01-01

Digoxin protein binding and pharmacokinetics were studied in 4-, 14-, and 25-month-old male Fischer-344 rats to determine if there were age-dependent changes in digoxin disposition. Serum protein binding did not differ among age groups. The average percentage unbound digoxin for all animals was 61.3 ± 5.3% (means ± SD, n = 15). For pharmacokinetic studies, [ 3 H]digoxin and 1 mg/kg unlabeled digoxin were administered as an intravenous bolus dose to animals from each age group. The [ 3 H]digoxin terminal elimination half-life was 2.0, 2.3, and 2.5 hr, respectively. The steady-state volume of distribution in the three age groups was 1.51, 1.49, and 1.27 liters/kg, respectively. Total body clearance for the three age groups was 14.2, 12.1, and 7.5 ml/min/kg, respectively. Analysis of variance of these data followed by Duncan's multiple range test indicated a significant decrease in clearance in the aged rats (25-month-old, p less than 0.05). This age-dependent decrease in clearance suggested that digoxin pharmacokinetics could be a significant factor in age-related alterations in digoxin cardiotoxicity in the rat, as it is in humans, and that the Fischer-344 rat could be a useful model for studies of digoxin pharmacokinetic changes with age

O modelo experimental de carcinogênese gástrica induzido por n-methyl-n-nitrosourea em ratos F344 e camundongos C3H é válido para os ratos Wistar? Experimental model of gastric carcinogenesis with N-methyl-N-nitrosourea for F344 rats and C3H mices is valid for Wistar rats?

Directory of Open Access Journals (Sweden)

Lissandro Tarso

2011-03-01

Full Text Available INTRODUÇÃO: O N-metil-N-nitrosourea (MNU tem ação cancerígena direta, induzindo tumores em várias espécies em uma variedade de órgãos, incluindo o estômago de ratos. Tratamento do MNU na água de beber por 25-42 semanas, seletivamente, induz carcinoma gástrico glandular de ratos F344 e camundongos C3H. OBJETIVO: Estabelecer um modelo experimental para indução seletiva de câncer no estômago glandular de ratos Wistar com MNU. MÉTODOS: Um total de 48 ratos Wistar machos com oito semanas, foram utilizados no presente estudo. MNU (Sigma-Aldrich foi dissolvido em DMSO e liberada água potável ad libitum por um período variando de 16 a 70 semanas. Após 16 semanas, quatro ratos foram selecionados aleatoriamente e mortos. Depois, de seis em seis semanas, quatro animais também foram mortos até 70 semanas. RESULTADOS: A taxa de sobrevivência foi superior a 90%. Ocorreu a indução de dois adenocarcinomas, um carcinoma espinocelular e um sarcoma. A incidência de adenocarcinoma gástrico foi de 4,5% (0,5 a 15. CONCLUSÕES: O modelo experimental de carcinogênese gástrica em ratos Wistar, utilizando MNU dissolvido na água, não mostrou viabilidade prática neste estudo, devido à baixa taxa de adenocarcinoma gástrico que ocorreu.BACKGROUND: The N-methyl-N-nitrosourea (MNU is a direct acting carcinogen, inducing tumors in several species in a variety of organs, including stomach of rats. Treatment of MNU in the drinking water for 25-42 weeks selectively induced glandular gastric carcinoma in F344 rats and C3H mice. AIM: To establish an experimental model for selective MNU induction of glandular stomach cancer in Wistar rats. METHODS: A total of 48 males eight-week-old Wistar rats were used in the present study. MNU (Sigma-Aldrich was dissolved in DMSO and provided as the drinking water ad libitum for a period ranging from 16 to 70 weeks. After 16 weeks, four rats were randomly selected and killed. After every six weeks four animals

NTP Toxicology and Carcinogenesis Studies of Xylenes (Mixed) (60% m-Xylene, 14% p-Xylene, 9% o-Xylene, and 17% Ethylbenzene) (CAS No. 1330-20-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Science.gov (United States)

1986-12-01

The technical grade of xylenes (mixed) (hereafter termed xylenes) contains the three isomeric forms and ethylbenzene (percentage composition shown above). The annual production for 1985 was approximately 7.4 x 108 gallons. Xylenes is used as a solvent and a cleaning agent and as a degreaser and is a constituent of aviation and automobile fuels. Xylenes is also used in the production of benzoic acid, phthalate anhydride, and isophthalic and terephthalic acids as well as their dimethyl esters. Toxicology and carcinogenesis studies of xylenes were conducted in laboratory animals because a large number of workers are exposed and because the long- term effects of exposure to xylenes were not known. Exposure for the present studies was by gavage in corn oil. In single-administration studies, groups of five F344/N rats and B6C3F1 mice of each sex received 500, 1,000, 2,000, 4,000, or 6,000 mg/kg. Administration of xylenes caused deaths at 6,000 mg/kg in rats and mice of each sex and at 4,000 mg/kg in male rats. In rats, clinical signs observed within 24 hours of dosing at 4,000 mg/kg included prostration, muscular incoordination, and loss of hind limb movement; these effects continued through the second week of observation. Tremors, prone position, and slowed breathing were recorded for mice on day 3, but all mice appeared normal by the end of the 2- week observation period. In 14- day studies, groups of five rats of each sex were administered 0, 125, 250, 500, 1,000, or 2,000 mg/kg, and groups of five mice of each sex received 0, 250, 500, 1,000, 2,000, or 4,000 mg/kg. Chemical- related mortality occurred only at 2,000 mg/kg in rats and at 4,000 mg/kg in mice. Rats and mice exhibited shallow breathing and prostration within 48 hours following dosing at 2,000 mg/kg. These signs persisted until day 12 for rats, but no clinical signs were noted during the second week for mice. In 13- week studies, groups of 10 rats of each sex received 0, 62.5, 125, 250, 500, or 1,000 mg

Gene expression changes induced by ochratoxin A in renal and hepatic tissues of male F344 rat after oral repeated administration

International Nuclear Information System (INIS)

Arbillaga, Leire; Vettorazzi, Ariane; Gil, Ana G; Delft, Joost van; Garcia-Jalon, Jose Antonio; Lopez de Cerain, Adela

2008-01-01

Ochratoxin A (OTA), a naturally occurring mycotoxin, is nephrotoxic in all animal species tested and is considered a potent renal carcinogen, particularly in male rats. Its mechanism of toxicity is still unknown, although oxidative stress appears to be a plausible mechanism. Therefore, the objective of this study was to identify the biological pathways that are modulated in vivo by OTA in male F344 rats in order to gain further insight into its mechanism of renal toxicity. Rats were gavaged daily with OTA (500 μg/kg bw) and gene expression profiles in target and non-target organs were analyzed after 7 and 21 days administration. As was expected, a time-dependent increase of OTA concentrations was found in plasma, kidney and liver, with the concentrations found in both tissues being quite similar. However, histopathological examinations only revealed changes in kidney; signs of nephrotoxicity involving single cell necrosis and karyomegalic nuclei were observed in the treated rats. The number of differentially expressed genes in kidney was much higher than in liver (541 versus 11 at both time points). Several similarities were observed with other in vivo gene expression data. However, great differences were found with previous in vitro gene expression data, with the exception of DNA damage response which was not observed at mRNA level in any of our study conditions. Down-regulation was the predominant effect. Oxidative stress response pathway and genes involved in metabolism and transport were inhibited at both time points. RGN (regucalcin) - a gene implicated in calcium homeostasis - was strongly inhibited at both time points and genes implicated in cell survival and proliferation were up-regulated at day 21. Moreover, translation factors and annexin genes were up-regulated at both time points. Apart from oxidative stress, alterations of the calcium homeostasis and cytoskeleton structure may be present at the first events of OTA toxicity

Rat Strains Differ in Susceptibility to Ureaplasma parvum-Induced Urinary Tract Infection and Struvite Stone Formation▿

Science.gov (United States)

Reyes, Leticia; Reinhard, Mary; O'Donell, L. J.; Stevens, Janet; Brown, Mary B.

2006-01-01

Individuals with struvite uroliths are susceptible to recurrent urinary tract infections (UTI), sepsis, and renal disease. Unfortunately, little is known about the host-specific factors that predispose to this disease. In order to develop a rodent model that can address this problem, we inoculated female Fischer 344 (F344), Lewis (LEW), Sprague-Dawley (SD), and Wistar (WIS) rats with a host-adapted strain of Ureaplasma parvum. Animals were necropsied at 2 weeks postinoculation; 100% of F344, 42% of SD, 10% of LEW, and 10% of WIS rats remained infected. Severe bladder lesions and struvite calculi were seen in 64% of F344 rats; in other rat strains, bladder lesions were mild or absent. F344 rats with struvite uroliths had the highest urinary levels of proinflammatory cytokines, such as GRO/KC, interleukin-1α (IL-1α), and IL-1β. F344 rats without struvite stones at necropsy had milder bladder lesions and significantly lower urinary levels of proinflammatory cytokines but a more prominent inflammatory response than did other rat strains. Based on our results, struvite stone formation is linked to a robust inflammatory response that does not resolve UTI but instead promotes damage to surrounding tissues. PMID:16982825

Could Cells from Your Nose Fix Your Heart? Transplantation of Olfactory Stem Cells in a Rat Model of Cardiac Infarction

Directory of Open Access Journals (Sweden)

Cameron McDonald

2010-01-01

Full Text Available This study examines the hypothesis that multipotent olfactory mucosal stem cells could provide a basis for the development of autologous cell transplant therapy for the treatment of heart attack. In humans, these cells are easily obtained by simple biopsy. Neural stem cells from the olfactory mucosa are multipotent, with the capacity to differentiate into developmental fates other than neurons and glia, with evidence of cardiomyocyte differentiation in vitro and after transplantation into the chick embryo. Olfactory stem cells were grown from rat olfactory mucosa. These cells are propagated as neurosphere cultures, similar to other neural stem cells. Olfactory neurospheres were grown in vitro, dissociated into single cell suspensions, and transplanted into the infarcted hearts of congeneic rats. Transplanted cells were genetically engineered to express green fluorescent protein (GFP in order to allow them to be identified after transplantation. Functional assessment was attempted using echocardiography in three groups of rats: control, unoperated; infarct only; infarcted and transplanted. Transplantation of neurosphere-derived cells from adult rat olfactory mucosa appeared to restore heart rate with other trends towards improvement in other measures of ventricular function indicated. Importantly, donor-derived cells engrafted in the transplanted cardiac ventricle and expressed cardiac contractile proteins.

Multi-Shell Hybrid Diffusion Imaging (HYDI at 7 Tesla in TgF344-AD Transgenic Alzheimer Rats.

Directory of Open Access Journals (Sweden)

Madelaine Daianu

Full Text Available Diffusion weighted imaging (DWI is widely used to study microstructural characteristics of the brain. Diffusion tensor imaging (DTI and high-angular resolution imaging (HARDI are frequently used in radiology and neuroscience research but can be limited in describing the signal behavior in composite nerve fiber structures. Here, we developed and assessed the benefit of a comprehensive diffusion encoding scheme, known as hybrid diffusion imaging (HYDI, composed of 300 DWI volumes acquired at 7-Tesla with diffusion weightings at b = 1000, 3000, 4000, 8000 and 12000 s/mm2 and applied it in transgenic Alzheimer rats (line TgF344-AD that model the full clinico-pathological spectrum of the human disease. We studied and visualized the effects of the multiple concentric "shells" when computing three distinct anisotropy maps-fractional anisotropy (FA, generalized fractional anisotropy (GFA and normalized quantitative anisotropy (NQA. We tested the added value of the multi-shell q-space sampling scheme, when reconstructing neural pathways using mathematical frameworks from DTI and q-ball imaging (QBI. We show a range of properties of HYDI, including lower apparent anisotropy when using high b-value shells in DTI-based reconstructions, and increases in apparent anisotropy in QBI-based reconstructions. Regardless of the reconstruction scheme, HYDI improves FA-, GFA- and NQA-aided tractography. HYDI may be valuable in human connectome projects and clinical research, as well as magnetic resonance research in experimental animals.

Prediction of Endocrine System Affectation in Fisher 344 Rats by Food Intake Exposed with Malathion, Applying Naïve Bayes Classifier and Genetic Algorithms.

Science.gov (United States)

Mora, Juan David Sandino; Hurtado, Darío Amaya; Sandoval, Olga Lucía Ramos

2016-01-01

Reported cases of uncontrolled use of pesticides and its produced effects by direct or indirect exposition, represent a high risk for human health. Therefore, in this paper, it is shown the results of the development and execution of an algorithm that predicts the possible effects in endocrine system in Fisher 344 (F344) rats, occasioned by ingestion of malathion. It was referred to ToxRefDB database in which different case studies in F344 rats exposed to malathion were collected. The experimental data were processed using Naïve Bayes (NB) machine learning classifier, which was subsequently optimized using genetic algorithms (GAs). The model was executed in an application with a graphical user interface programmed in C#. There was a tendency to suffer bigger alterations, increasing levels in the parathyroid gland in dosages between 4 and 5 mg/kg/day, in contrast to the thyroid gland for doses between 739 and 868 mg/kg/day. It was showed a greater resistance for females to contract effects on the endocrine system by the ingestion of malathion. Females were more susceptible to suffer alterations in the pituitary gland with exposure times between 3 and 6 months. The prediction model based on NB classifiers allowed to analyze all the possible combinations of the studied variables and improving its accuracy using GAs. Excepting the pituitary gland, females demonstrated better resistance to contract effects by increasing levels on the rest of endocrine system glands.

NTP Toxicology and Carcinogenesis Studies of 3,3'-Dimethoxybenzidine Dihydrochloride (CAS No. 20325-40-0) in F344/N Rats (Drinking Water Studies).

Science.gov (United States)

1990-01-01

3,3'-Dimethoxybenzidine dihydrochloride is an off-white powder with a melting point of 274 degrees C. 3,3'-Dimethoxybenzidine is used principally as an intermediate in the production of commercial bisazobiphenyl dyes for coloring textiles, paper, plastic, rubber, and leather. In the synthesis of the bisazobiphenyl dyes, the amine groups of 3,3'-dimethoxybenzidine are chemically linked with other aromatic amines. A small quantity of 3,3'-dimethoxybenzidine is also used as an intermediate in the production of o-dianisidine diisocyanate, which is used in isocyanate-based adhesive systems and as a component of polyurethane elastomers. 3,3'-Dimethoxybenzidine dihydrochloride was evaluated in toxicity and carcinogenicity studies as part of the National Toxicology Program's Benzidine Dye Initiative. This Initiative was designed to evaluate the representative benzidine congeners and benzidine congener-derived and benzidine-derived dyes. 3,3'-Dimethoxybenzidine dihydrochloride was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. NTP Toxicology and Carcinogenesis studies were conducted by administering 3,3'-dimethoxybenzidine dihydrochloride (greater than 97.5% pure) in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, 9 months, or 21-months. The 21-month studies were intended to last 24 months but were terminated early because of rapidly declining survival due to neoplasia. Studies were performed only in rats because similar studies are being performed in mice at the National Center for Toxicology Research. Genetic toxicology studies were conducted with Salmonella typhimurium, Chinese hamster over (CHO) cells, and Drosophila melanogaster. Fourteen-Day Studies: All rats receiving drinking water concentrations up to 4,500 ppm lived to the end of the studies. Rats that received water containing 4,500 ppm 3

Behavioural inflexibility in a comorbid rat model of striatal ischemic injury and mutant hAPP overexpression.

Science.gov (United States)

Levit, Alexander; Regis, Aaron M; Garabon, Jessica R; Oh, Seung-Hun; Desai, Sagar J; Rajakumar, Nagalingam; Hachinski, Vladimir; Agca, Yuksel; Agca, Cansu; Whitehead, Shawn N; Allman, Brian L

2017-08-30

Alzheimer disease (AD) and stroke coexist and interact; yet how they interact is not sufficiently understood. Both AD and basal ganglia stroke can impair behavioural flexibility, which can be reliably modeled in rats using an established operant based set-shifting test. Transgenic Fischer 344-APP21 rats (TgF344) overexpress pathogenic human amyloid precursor protein (hAPP) but do not spontaneously develop overt pathology, hence TgF344 rats can be used to model the effect of vascular injury in the prodromal stages of Alzheimer disease. We demonstrate that the injection of endothelin-1 (ET1) into the dorsal striatum of TgF344 rats (Tg-ET1) produced an exacerbation of behavioural inflexibility with a behavioural phenotype that was distinct from saline-injected wildtype & TgF344 rats as well as ET1-injected wildtype rats (Wt-ET1). In addition to profiling the types of errors made, interpolative modeling using logistic exposure-response regression provided an informative analysis of the timing and efficiency of behavioural flexibility. During set-shifting, Tg-ET1 committed fewer perseverative errors than Wt-ET1. However, Tg-ET1 committed significantly more regressive errors and had a less efficient strategy change than all other groups. Thus, behavioural flexibility was more vulnerable to striatal ischemic injury in TgF344 rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Chronically reinforced, operant olfactory conditioning increases the number of newborn GABAergic olfactory periglomerular neurons in the adult rat.

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Tapia-Rodríguez, Miguel; Esquivelzeta-Rabell, José F; Gutiérrez-Ospina, Gabriel

2012-12-01

The mammalian brain preserves the ability to replace olfactory periglomerular cells (PGC) throughout life. Even though we have detailed a great deal the mechanisms underlying stem and amplifying cells maintenance and proliferation, as well as those modulating migration and differentiation, our knowledge on PGC phenotypic plasticity is at best fragmented and controversial. Here we explored whether chronically reinforced olfactory conditioning influences the phenotype of newborn PGC. Accordingly, olfactory conditioned rats showed increased numbers of GAD 65/67 positive PGC. Because such phenotypic change was not accompanied neither by increments in the total number of PGC, or periglomerular cell nuclei labeled with bromodeoxyuridine, nor by reductions in the number of tyrosine hydroxylase (TH), calbindin (CB) or calretinin (CR) immunoreactive PGC, we speculate that increments in the number of GABAergic PGC occur at the expense of other PGC phenotypes. In any event, these results support that adult newborn PGC phenotype may be subjected to phenotypic plasticity influenced by sensory stimulation. Copyright © 2012 Elsevier B.V. All rights reserved.

Aging cochleas in the F344 rat: morphological and functional changes

Czech Academy of Sciences Publication Activity Database

Buckiová, Daniela; Popelář, Jiří; Syka, Josef

2007-01-01

Roč. 42, č. 7 (2007), s. 629-638 ISSN 0531-5565 R&D Projects: GA ČR GA309/04/1074; GA MZd NR8113; GA MŠk(CZ) LC554 Institutional research plan: CEZ:AV0Z50390512 Keywords : Presbycusis * Fischer 344 strain * Long Evans strain Subject RIV: DN - Health Impact of the Environment Quality Impact factor: 2.879, year: 2007

A functional study of the rat olfactory bulb through autoradiography with 14C-2-deoxyglucose

International Nuclear Information System (INIS)

Verrier, Marie; Leveteau, Jean; Giachetti, Ismene; MacLeod, Patrick

1978-01-01

The autoradiographic methods has been used in the rat to map active regions in the olfactory bulb after a pulse of 14 C-2-deoxyglucose with electrical stimulation of the lateral olfactory tract. The highest optical densities were found at the external plexiform, mural, internal plexiform and granular layers: the lowest was found in the glomerular layer [fr

Toxicokinetics of α-thujone following intravenous and gavage administration of α-thujone or α- and β-thujone mixture in male and female F344/N rats and B6C3F1 mice

International Nuclear Information System (INIS)

Waidyanatha, Suramya; Johnson, Jerry D.; Hong, S. Peter; Robinson, Veronica Godfrey; Gibbs, Seth; Graves, Steven W.; Hooth, Michelle J.; Smith, Cynthia S.

2013-01-01

Plants containing thujone have widespread use and hence have significant human exposure. α-Thujone caused seizures in rodents following gavage administration. We investigated the toxicokinetics of α-thujone in male and female F344/N rats and B6C3F1 mice following intravenous and gavage administration of α-thujone or a mixture of α- and β-thujone (which will be referred to as α,β-thujone). Absorption of α-thujone following gavage administration was rapid without any dose-, species-, sex- or test article-related effect. Absolute bioavailability of α-thujone following administration of α-thujone or α,β-thujone was generally higher in rats than in mice. In rats, females had higher bioavailability than males following administration of either test article although a sex difference was not observed in mice. C max and AUC ∞ increased greater than proportional to the dose in female rats following administration of α-thujone and in male and female mice following administration of α,β-thujone suggesting possible saturation of elimination kinetics with increasing dose. Dose-adjusted AUC ∞ for male and female rats was 5- to 15-fold and 3- to 24-fold higher than mice counterparts following administration of α-thujone and α,β-thujone, respectively (p-value < 0.0001 for all comparisons). Following both intravenous and gavage administration, α-thujone was distributed to the brains of rats and mice with females, in general, having higher brain:plasma ratios than males. These data are in support of the observed toxicity of α-thujone and α,β-thujone where females were more sensitive than males of both species to α-thujone-induced neurotoxicity. In general there was no difference in toxicokinetics between test articles when normalized to α-thujone concentration. - Highlights: • Absorption of α-thujone following gavage administration was rapid in rats and mice. • Rats undergo higher exposure to α-thujone than mice. • α-Thujone brain:plasma ratios

Toxicokinetics of α-thujone following intravenous and gavage administration of α-thujone or α- and β-thujone mixture in male and female F344/N rats and B6C3F1 mice

Energy Technology Data Exchange (ETDEWEB)

Waidyanatha, Suramya, E-mail: waidyanathas@niehs.nih.gov [Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Johnson, Jerry D.; Hong, S. Peter [Battelle Memorial Institute, Columbus, OH 43201 (United States); Robinson, Veronica Godfrey [Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Gibbs, Seth; Graves, Steven W. [Battelle Memorial Institute, Columbus, OH 43201 (United States); Hooth, Michelle J.; Smith, Cynthia S. [Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States)

2013-09-01

Plants containing thujone have widespread use and hence have significant human exposure. α-Thujone caused seizures in rodents following gavage administration. We investigated the toxicokinetics of α-thujone in male and female F344/N rats and B6C3F1 mice following intravenous and gavage administration of α-thujone or a mixture of α- and β-thujone (which will be referred to as α,β-thujone). Absorption of α-thujone following gavage administration was rapid without any dose-, species-, sex- or test article-related effect. Absolute bioavailability of α-thujone following administration of α-thujone or α,β-thujone was generally higher in rats than in mice. In rats, females had higher bioavailability than males following administration of either test article although a sex difference was not observed in mice. C{sub max} and AUC{sub ∞} increased greater than proportional to the dose in female rats following administration of α-thujone and in male and female mice following administration of α,β-thujone suggesting possible saturation of elimination kinetics with increasing dose. Dose-adjusted AUC{sub ∞} for male and female rats was 5- to 15-fold and 3- to 24-fold higher than mice counterparts following administration of α-thujone and α,β-thujone, respectively (p-value < 0.0001 for all comparisons). Following both intravenous and gavage administration, α-thujone was distributed to the brains of rats and mice with females, in general, having higher brain:plasma ratios than males. These data are in support of the observed toxicity of α-thujone and α,β-thujone where females were more sensitive than males of both species to α-thujone-induced neurotoxicity. In general there was no difference in toxicokinetics between test articles when normalized to α-thujone concentration. - Highlights: • Absorption of α-thujone following gavage administration was rapid in rats and mice. • Rats undergo higher exposure to α-thujone than mice. • α-Thujone brain

Involvement of emotion in olfactory responses. A fMRI study

International Nuclear Information System (INIS)

Uno, Tominori; Wang, L.; Miwakeichi, Fumikazu; Tonoike, Mitsuo; Kaneda, Teruo

2010-01-01

We investigated the olfactory 'Kansei' information processing for two kinds of smells by measuring the brain activities associated with olfactory responses in humans. In this study, the brain activities related to discrimination and recognition of odors were examined using functional magnetic resonance imaging (fMRI). In experiment 1, odor stimuli (lemon-like and banana-like) were presented using a block design in a blinded manner, and the kind of fruits was identified by its odor. The frontal and temporal lobe, inferior parietal lobule, cingulate gyrus, amygdaloid body and parahippocampal gyrus were primarily activated by each odor based on conjunction analysis. In experiment 2, as a result of performing an oddball experiment using the odors of experiment 1, the active areas were mainly found in the temporal lobe, superior and inferior parietal lobule, insula, thalamus, supramarginal gyrus, uncus and parahippocampal gyrus. Moreover, these regions overlapped with the emotional circuit. These experimental results suggest that common brain activities accompany the discrimination and cognition associated with odor stimuli, which may underlie the olfactory responses relevant to the higher brain function and emotions associated with olfactory function. (author)

MicroRNA expression profiles in chronic epilepsy rats and neuroprotection from seizures by targeting miR-344a

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Liu XX

2017-07-01

Full Text Available Xixia Liu,1,2 Yuhan Liao,1 Xiuxiu Wang,1 Donghua Zou,1 Chun Luo,1 Chongdong Jian,1 Yuan Wu1 1Department of Neurology, First Affiliated Hospital of Guangxi Medical University, 2Department of Rehabilitation, People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China Abstract: MicroRNA (miRNA is believed to play a crucial role in the cause and treatment of epilepsy by controlling gene expression. However, it is still unclear how miRNA profiles change after multiple prolonged seizures and aggravation of brain injury in chronic epilepsy (CE. To investigate the role of miRNA in epilepsy, we utilized the CE rat models with pentylenetetrazol (PTZ and miRNA profiles in the hippocampus. miRNA profiles were characterized using miRNA microarray analysis and were compared with the rats in the sham group, which received 0.9% physiological saline treatment at the same dose. Four up-regulated miRNAs (miR-139–3p, -770–5p, -127–5p, -331–3p and 5 down-regulated miRNAs (miR-802–5p, -380–5p, -183–5p, -547–5p, -344a/-344a–5p were found in the CE rats (fold change >1.5, P<0.05. Three of the dysregulated miRNAs were validated by quantitative real-time polymerase chain reaction, which revealed an outcome consistent with the initial results of the miRNA microarray analyses. Then, miR-344a agomir was intracerebroventricularly injected and followed by PTZ induction of CE models to investigate the effect of miR-344a in chronic neocortical epileptogenesis. After miRNA-344a agomir and scramble treatment, results showed a restoration of seizure behavior and a reduction in neuron damage in the cortex in miRNA-334a agomir treated rats. These data suggest that miRNA-344a might have a small modulatory effect on seizure-induced apoptosis signaling pathways in the cortex. Keywords: microRNA, chronic epilepsy, miR-344a, epigenetics, apoptosis

Effect of chronic alcohol ingestion on the progression of periodontitis induced in Fisher-344 rats

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Éder Ricardo Biasoli

2009-01-01

Full Text Available Objective: Understand the effect of chronic alcohol on the progression of periodontitis induced in Fischer-344 rats.Methods: For the study, 22 Fischer-344 rats, two months old were used, divided into groups: alcohol (n=8, ligature (n=7 and control (n=7. On the first day, the animals in the alcohol group were exposed to ingestion of a water solution containing 20% alcohol (size/size, up to day 90. After thirty days from the beginning of the experiment, the animals in the alcohol group and the ligature group were submitted to the placement of a silk thread around the right maxillary second molar. Nothing was performed on the left side, serving as control. All the groups were submitted to euthanasia 60 days after ligature placement. To assess the destruction of periodontitis, a radiographic exam was used to measure the destruction of bone height. Results: The results of the study showed that on the side in which periodontitis was induced, the group that ingested alcohol suffered an increase in destruction, with statistical differences when compared with the ligature and control groups and increased bone destruction in the ligature group when compared to control. Conclusion: Within the limitations of the study, it was concluded that chronic alcohol consumption by Fischer-344 rats led to greater progression of induced periodontitis.

Dimethylarsinic acid in drinking water changed the morphology but not the expression of DNA repair genes of bladder transitional epithelium in F344 rats

Science.gov (United States)

Inorganic arsenic increases urinary bladder transitional cell carcinoma in humans. In laboratory animals, it is dimethylarsinic acid [DMA(V)], a major arsenic metabolite in the urine of inorganic arsenic-exposed people, that increases transitional cell carcinoma, namely in F344 r...

[Blockade of the pheromonal effects in rat by central deafferentation of the accessory olfactory system].

Science.gov (United States)

Sánchez-Criado, J E

1979-06-01

Female rats reared without sex odours from male rats have a five day stral cycle. With exposure to male odour the estral cycle is shortened from five to four days. This pheromonal effect is blocked on deafferenting the vomeronasal system by electrolytically damaging both accessory olfactory bulbs.

Aversive properties of negative incentive shifts in Fischer 344 and Lewis rats

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Brewer, Adam; Johnson, Patrick; Stein, Jeff; Schlund, Michael; Williams, Dean C.

2018-01-01

Research on incentive contrast highlights that reward value is not absolute but rather is based upon comparisons we make to rewards we have received and expect to receive. Both human and nonhuman studies on incentive contrast show that shifting from a larger more-valued reward to a smaller less-valued reward is associated with long periods of nonresponding—a negative contrast effect. In this investigation, we used two different genetic rat strains, Fischer 344 and Lewis rats that putatively differ in their sensitivity to aversive stimulation, to assess the aversive properties of large-to-small reward shifts (negative incentive shifts). Additionally, we examined the extent to which increasing cost (fixed-ratio requirements) modulates negative contrast effects. In the presence of a cue that signaled the upcoming reward magnitude, lever pressing was reinforced with one of two different magnitudes of food (large or small). This design created two contrast shifts (small-to-large, large-to-small) and two shifts used as control conditions (small-to-small, large-to-large). Results showed a significant interaction between rat strain and cost requirements only during the negative incentive shift with the emotionally reactive Fischer 344 rats exhibiting significantly longer response latencies with increasing cost, highlighting greater negative contrast. These findings are more consistent with emotionality accounts of negative contrast and results of neurophysiological research that suggests shifting from a large to a small reward is aversive. Findings also highlight how subjective reward value and motivation is a product of gene-environment interactions. PMID:27864048

Age-related changes in cochlear and brainstem auditory functions in Fischer 344 rats

Czech Academy of Sciences Publication Activity Database

Popelář, Jiří; Groh, Daniel; Pelánová, Jana; Canlon, B.; Syka, Josef

2006-01-01

Roč. 27, č. 3 (2006), s. 490-500 ISSN 0197-4580 R&D Projects: GA ČR GA309/04/1074; GA MZd NR8113 Institutional research plan: CEZ:AV0Z50390512 Keywords : Fischer 344 rats * Hearing threshold * Otoacoustic emissions Subject RIV: FH - Neurology Impact factor: 5.599, year: 2006

Sexual odor preference and dopamine release in the nucleus accumbens by estrous olfactory cues in sexually naïve and experienced male rats.

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Fujiwara, Masaya; Chiba, Atsuhiko

2018-03-01

Sexual behavior is a natural reward that activates mesolimbic dopaminergic system. Microdialysis studies have shown that extracellular level of dopamine (DA) in the nucleus accumbens (NAcc) significantly increases during copulation in male rats. The NAcc DA level is also known to be increased during the presentation of a sexually receptive female before mating. This rise in DA was probably associated with sexual motivation elicited by incentive stimuli from the receptive female. These microdialysis studies, however, did not thoroughly investigated if olfactory stimuli from estrous females could significantly increase the extracellular DA in the NAcc of male rats. The present study was designed to examine systematically the relationship between the expression of preference for the olfactory stimuli from estrous females and the effects of these stimuli on the extracellular DA levels in the NAcc measured by in vivo microdialysis in male Long-Evans (LE) rats. We used two types of olfactory stimuli, either airborne odors (volatile stimuli) or soiled bedding (volatile plus nonvolatile stimuli). The sexually experienced male rats, which experienced six ejaculations, significantly preferred both of these olfactory stimuli from estrous females as opposed to males. Exposure to these female olfactory stimuli gradually increased extracellular DA in the NAcc, which reached significantly higher level above baseline during the period following the removal of the stimuli although not during the 15-min stimulus presentation period. The sexually naïve male rats, on the other hand, showed neither preference for olfactory stimuli from estrous females nor increase in the NAcc DA after exposure to these stimuli. These data suggest that in male LE rats olfactory stimuli from estrous females in and of themselves can be conditional cues that induce both incentive motivation and a significant increase in the NAcc DA probably as a result of being associated with sexual reward through

Oral carcinogenicity study with nickel sulfate hexahydrate in Fischer 344 rats

International Nuclear Information System (INIS)

Heim, Katherine E.; Bates, Hudson K.; Rush, Rusty E.; Oller, Adriana R.

2007-01-01

Until now, existing data on the oral carcinogenicity of nickel substances have been inconclusive. Yet, the assessment of oral carcinogenicity of nickel has serious scientific and regulatory implications. In the present study, nickel sulfate hexahydrate was administered daily to Fischer 344 rats by oral gavage for 2 years (104 weeks) at exposure levels of 10, 30 and 50 mg NiSO 4 ·6H 2 O/kg. This treatment produced a statistically significant reduction in body weight of male and female rats, compared to controls, in an exposure-related fashion at 30 and 50 mg/kg/day. An exposure-dependent increase in mortality was observed in female rats. However, the overall study survival rate (males and females) was at least 25 animals per group (compliant with OECD guidelines) in the treated animals. Daily oral administration of nickel sulfate hexahydrate did not produce an exposure-related increase in any common tumor type or an increase in any rare tumors. One tumor type was statistically increased in a nickel sulfate-treated group compared to the study controls (keratoacanthoma in the 10 mg NiSO 4 ·6H 2 O/kg/day males), but there was no exposure-response relationship for this common tumor type. This study achieved sufficient toxicity to reach the Maximum Tolerated Dose (MTD) while maintaining a sufficiently high survival rate to allow evaluation for carcinogenicity. The present study indicated that nickel sulfate hexahydrate does not have the potential to cause carcinogenicity by the oral route of exposure in the Fischer 344 rat. Data from this and other studies demonstrate that inhalation is the only route of exposure that might cause concern for cancer in association with nickel exposures

The influence of early life interventions on olfactory memory related to palatable food, and on oxidative stress parameters and Na+/K+-ATPase activity in the hippocampus and olfactory bulb of female adult rats.

Science.gov (United States)

Noschang, Cristie; Krolow, Rachel; Arcego, Danusa M; Laureano, Daniela; Fitarelli, Luiza D; Huffell, Ana Paula; Ferreira, Andréa G K; da Cunha, Aline A; Machado, Fernanda Rossato; Wyse, Angela T S; Dalmaz, Carla

2012-08-01

The effects of neonatal handling and the absence of ovarian hormones on the olfactory memory related to a palatable food in adulthood were investigated. Oxidative stress parameters and Na+/K+-ATPase activity in the hippocampus and olfactory bulb of adult pre-puberty ovariectomized female rats handled or not in the neonatal period were also evaluated. Litters were non-handled or handled (10 min/day, days 1-10 after birth). Females from each litter were divided into: OVX (subjected to ovariectomy), sham, and intact. When adults, olfactory memory related to a palatable food (chocolate) was evaluate using the hole-board olfactory task. Additionally, oxidative stress parameters and Na+/K+-ATPase activity were measured in the hippocampus and olfactory bulb. No difference between groups was observed considering olfactory memory evaluation. Neonatal handled rats presented an increase in Na+/K+-ATPase activity in the hippocampus and in the olfactory bulb, compared to non-handled ones. Considering the surgical procedure, there was a decrease in Na+/K+-ATPase and catalase activities in sham and OVX groups, compared to intact animals in the olfactory bulb. We concluded that olfactory memory related to a palatable food in adulthood was not affected by neonatal handling or by pre-puberty surgery, with or without removal of ovaries. The difference observed between groups in catalase and Na+/K+-ATPase activity does not seem to be related to the olfactory memory. Additionally, the increase in Na+/K+-ATPase activity (an enzyme that maintains the neurochemical gradient necessary for neuronal excitability) induced by neonatal handling may be related to neuroplastic changes in the hippocampus and olfactory bulb.

Reliability in the Location of Hindlimb Motor Representations in Fischer-344 Rats

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Frost, Shawn B.; Iliakova, Maria; Dunham, Caleb; Barbay, Scott; Arnold, Paul; Nudo, Randolph J.

2014-01-01

Object The purpose of the present study was to determine the feasibility of using a common laboratory rat strain for locating cortical motor representations of the hindlimb reliably. Methods Intracortical Microstimulation (ICMS) techniques were used to derive detailed maps of the hindlimb motor representations in six adult Fischer-344 rats. Results The organization of the hindlimb movement representation, while variable across individuals in topographic detail, displayed several commonalities. The hindlimb representation was positioned posterior to the forelimb motor representation and postero-lateral to the motor trunk representation. The areal extent of the hindlimb representation across the cortical surface averaged 2.00 +/− 0.50 mm2. Superimposing individual maps revealed an overlapping area measuring 0.35 mm2, indicating that the location of the hindlimb representation can be predicted reliably based on stereotactic coordinates. Across the sample of rats, the hindlimb representation was found 1.25–3.75 mm posterior to Bregma, with an average center location ~ 2.6 mm posterior to Bregma. Likewise, the hindlimb representation was found 1–3.25 mm lateral to the midline, with an average center location ~ 2 mm lateral to midline. Conclusions The location of the cortical hindlimb motor representation in Fischer-344 rats can be reliably located based on its stereotactic position posterior to Bregma and lateral to the longitudinal skull suture at midline. The ability to accurately predict the cortical localization of functional hindlimb territories in a rodent model is important, as such animal models are being used increasingly in the development of brain-computer interfaces for restoration of function after spinal cord injury. PMID:23725395

NTP Toxicology and Carcinogenesis of 1,2,3-Trichloropropane (CAS No. 96-18-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Science.gov (United States)

1993-08-01

1,2,3-Trichloropropane is a colorless liquid used as a paint and varnish remover, solvent, and degreasing agent, and as a crosslinking agent in the synthesis of polysulfides and hexafluoropropylene. 1,2,3-Trichloropropane may be found as an impurity in certain nematocides and soil fumigants and as a contaminant of drinking and ground water. Studies on the toxic and carcinogenic effects of 1,2,3-trichloropropane were initiated because of the close structural relationship of this chemical to other short-chain halogenated compounds that were demonstrated to be carcinogenic in experimental animals, and because of the potential for human exposure. Toxicology and carcinogenicity studies were conducted by administering 1,2,3-trichloropropane (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3FI mice for 17 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium strains, mouse lymphoma cells, and Chinese hamster ovary cells. 17-Week Studies: Groups of 20 male and 20 female rats received 1,2,3-trichloropropane in corn oil by gavage at doses of 8, 16, 32, 63, 125, or 250 mg/kg body weight 5 days per week for up to 17 weeks; 30 male and 30 female rats received corn oil alone and served as controls. Animals were evaluated at 8 or 17 weeks. All rats in the 250 mg/kg groups died by week 5. One male and four female rats in the 125 mg/kg groups died during the study. The mean body weight gains and final mean body weights of males receiving 63 mg/kg and of males and females receiving 125 mg/kg were lower than those of the controls. Hematocrit values, hemoglobin concentrations, and erythrocyte counts decreased with dose in males and females. Serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase activities were significantly increased in some female rats receiving 125 mg/kg. Serum pseudocholinesterase activity decreased with dose in females. Increases in kidney and liver weights were related

DNA adduct formation in B6C3F1 mice and Fischer-344 rats exposed to 1,2,3-trichloropropane.

Science.gov (United States)

La, D K; Lilly, P D; Anderegg, R J; Swenberg, J A

1995-06-01

1,2,3-Trichloropropane (TCP) is a multispecies, multisite carcinogen which has been found to be an environmental contaminant. In this study, we have characterized and measured DNA adducts formed in vivo following exposure to TCP. [14C]TCP was administered to male B6C3F1 mice and Fischer-344 rats by gavage at doses used in the NTP carcinogenesis bioassay. Both target and nontarget organs were examined for the formation of DNA adducts. Adducts were hydrolyzed from DNA by neutral thermal or mild acid hydrolysis, isolated by HPLC, and detected and quantitated by measurement of radioactivity. The HPLC elution profile of radioactivity suggested that one major DNA adduct was formed. To characterize this adduct, larger yields were induced in rats by intraperitoneal administration of TCP (300 mg/kg). The DNA adduct was isolated by HPLC based on coelution with the radiolabeled adduct, and compared to previously identified adducts. The isolated adduct coeluted with S-[1-(hydroxymethyl)-2-(N7-guanyl)-ethyl]glutathione, an adduct derived from the structurally related carcinogen 1,2-dibromo-3-chloropropane (DBCP). Analysis by electrospray mass spectrometry suggested that the TCP-induced adduct and the DBCP-derived adduct were identical. The 14C-labeled DNA adduct was distributed widely among the organs examined. Adduct levels varied depending on species, organ, and dose. In rat organs, adduct concentrations for the low dose ranged from 0.8 to 6.6 mumol per mol guanine and from 7.1 to 47.6 mumol per mol guanine for the high dose. In the mouse, adduct yields ranged from 0.32 to 28.1 mumol per mol guanine for the low dose and from 12.2 to 208.1 mumol per mol guanine for the high dose. The relationship between DNA adduct formation and organ-specific tumorigenesis was unclear. Although relatively high concentrations of DNA adducts were detected in target organs, several nontarget sites also contained high adduct levels. Our data suggest that factors in addition to adduct formation

Effect of dietary galacto-oligosaccharides on azoxymethane-induced aberrant crypt foci and colorectal cancer in Fischer 344 rats

NARCIS (Netherlands)

Wijnands, M.V.W.; Schoterman, H.C.; Bruijntjes, J.P.; Hollanders, V.M.H.; Woutersen, R.A.

2001-01-01

The aim of the present study was to investigate the effects of galacto-oligosaccharides (GOS, Elix'or) on the development of aberrant crypt foci (ACF) and colorectal tumours in rats treated with azoxymethane (AOM). Two groups of 102 male Fischer 344 rats were injected twice with AOM to induce

Lung clearance and disposition of 63Ni in F344/N rats after intratracheal instillation of nickel sulfate solutions

International Nuclear Information System (INIS)

Medinsky, M.A.; Benson, J.M.; Hobbs, C.H.

1987-01-01

Epidemiology studies have indicated increased incidences of respiratory tract and renal cancer in nickel refinery workers. Since the most likely route of exposure to nickel in the workplace is via the respiratory tract, the objectives of the experiments described here were to determine the retention pattern of Ni in the lungs, identify the target organs for Ni absorbed from the respiratory tract, and determine rates for excretion of Ni. Male and female F344 rats were given 17, 190, or 1800 nmoles Ni (as a nickel sulfate solution) in saline, containing trace amounts of 63 Ni, by intratracheal instillation. Urine and feces were collected, and rats were necropsied at predetermined times up to 96 hr after instillation. At all times, lungs, trachea, larynx, kidney, and urinary bladder contained the highest concentrations of Ni as determined by liquid scintillation spectrometry. Urine was the major route for excretion of Ni, accounting for 50% of the dose after instillation of 17 or 190 nmoles Ni, and 80% of the dose after instillation of 1800 nmoles Ni. The half-time for urinary excretion of Ni increased from 4.6 hr at the highest dose to 23 hr at the lowest dose used. Fecal excretion accounted for 30% (17- and 190-nmole doses) or 13% (1800 nmoles) of the initial dose. Of the Ni remaining in the body at the end of 96 hr, over 50% was in the lungs. The long-term half-time for clearance of Ni from the lungs ranged from 21 hr at the highest dose to 36 hr at the lowest dose instilled. As the amount of instilled Ni decreased, the fraction of the instilled Ni associated with the long-term clearance component increased (from 24% at the highest dose to 40% at the lowest dose). Results suggest that, over the range of doses studied, both pulmonary clearance of Ni and routes for excretion of Ni were dependent on the instilled dose

Reliability in the location of hindlimb motor representations in Fischer-344 rats: laboratory investigation.

Science.gov (United States)

Frost, Shawn B; Iliakova, Maria; Dunham, Caleb; Barbay, Scott; Arnold, Paul; Nudo, Randolph J

2013-08-01

The purpose of the present study was to determine the feasibility of using a common laboratory rat strain for reliably locating cortical motor representations of the hindlimb. Intracortical microstimulation techniques were used to derive detailed maps of the hindlimb motor representations in 6 adult Fischer-344 rats. The organization of the hindlimb movement representation, while variable across individual rats in topographic detail, displayed several commonalities. The hindlimb representation was positioned posterior to the forelimb motor representation and posterolateral to the motor trunk representation. The areal extent of the hindlimb representation across the cortical surface averaged 2.00 ± 0.50 mm(2). Superimposing individual maps revealed an overlapping area measuring 0.35 mm(2), indicating that the location of the hindlimb representation can be predicted reliably based on stereotactic coordinates. Across the sample of rats, the hindlimb representation was found 1.25-3.75 mm posterior to the bregma, with an average center location approximately 2.6 mm posterior to the bregma. Likewise, the hindlimb representation was found 1-3.25 mm lateral to the midline, with an average center location approximately 2 mm lateral to the midline. The location of the cortical hindlimb motor representation in Fischer-344 rats can be reliably located based on its stereotactic position posterior to the bregma and lateral to the longitudinal skull suture at midline. The ability to accurately predict the cortical localization of functional hindlimb territories in a rodent model is important, as such animal models are being increasingly used in the development of brain-computer interfaces for restoration of function after spinal cord injury.

δ- and γ-tocopherols, but not α-tocopherol, inhibit colon carcinogenesis in azoxymethane-treated F344 rats.

Science.gov (United States)

Guan, Fei; Li, Guangxun; Liu, Anna B; Lee, Mao-Jung; Yang, Zhihong; Chen, Yu-Kuo; Lin, Yong; Shih, Weichung; Yang, Chung S

2012-04-01

The cancer preventive activity of vitamin E has been extensively discussed, but the activities of specific forms of tocopherols have not received sufficient attention. Herein, we compared the activities of δ-tocopherol (δ-T), γ-T, and α-T in a colon carcinogenesis model. Male F344 rats, seven weeks old, were given two weekly subcutaneous injections of azoxymethane (AOM) each at a dose of 15 mg/kg body weight. Starting 1 week before the AOM injection, the animals were maintained on a modified AIN76A diet, or the same diet containing 0.2% of δ-T, γ-T, α-T, or a γ-T-rich mixture of tocopherols (γ-TmT), until the termination of the experiment at 8 weeks after the second AOM injection. δ-T treatment showed the strongest inhibitory effect, decreasing the numbers of aberrant crypt foci by 62%. γ-T and γ-TmT were also effective, but α-T was not. Immunohistochemical analysis showed that δ-T and γ-T treatments reduced the levels of 4-hydroxynonenal and nitrotyrosine and the expression of cyclin D1 in the colon, preserved the expression of PPAR-γ, and decreased the serum levels of prostaglandin E2 and 8-isoprostane. Supplementation with 0.2% δ-T, γ-T, or α-T increased the respective levels of tocopherols and their side-chain degradation metabolites in the serum and colon tissues. Rather high concentrations of δ-T and γ-T and their metabolites were found in colon tissues. Our study provides the first evidence for the much higher cancer preventive activity of δ-T and γ-T than α-T in a chemically induced colon carcinogenesis model. It further suggests that δ-T is more effective than γ-T. 2012 AACR

Toxicity of inhaled 239PuO2 in Fischer 344 rats

International Nuclear Information System (INIS)

Redman, H.C.; Boecker, B.B.; Muggenburg, B.A.; Griffith, W.C.; Guilmette, R.A.; Mewhinney, J.A.; Scott, B.R.

1979-01-01

Studies on the biological effects of inhaled particles of 239 PuO 2 have been initiated in the Fischer 344 rat. To obtain information on the importance of homogeneity or nonhomogeneity of radiation dose to the lung, young adult (84 +- 7 days) animals have been exposed to monodisperse aerosols (sigma/sub g/ 239 PuO 2 of 1.0 and 2.8 μm aerodynamic diameter (AD). To determine the effects of age at exposure, aged rats (600 to 660 days) have been exposed to monodisperse aerosols of 239 PuO 2 of 1.0 μm aerodynamic diameter. To date, 480 young adult rats have been exposed to 239 PuO 2 : 240 rats to 1.0 μm AD particles and 240 rats to 2.85 μm AD particles. The projected exposure level ranged from 0.012 to 0.115 μCi/kg body weight. One hundred sixty rats were sham-exposed and maintained as controls. Also, 240 aged rats have been exposed to date to 1.0 μm AD particles of 239 PuO 2 . The projected activity level ranged from 0.012 to 0.115 μCi/kg body weight. Eighty rats were sham-exposed and maintained as controls. In addition, a serial sacrifice study to determine radiation-dose pattern in rats resulting from the inhalation of these monodisperse aerosols of 239 PuO 2 has been initiated in the young adult rat

Genetic susceptibility to mammary carcinogenesis in rats

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Kamiya, Kenji; Nitta, Yumiko [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine

1999-06-01

The Copenhagen (COP) rat strain has previously been shown to be genetically resistant to chemical induction of breast cancer, while Wistar/Furth (WF) and Fischer 344 (F344) animals are relatively susceptible. We have compared the carcinogenic response of these three strains of rats to N-methyl-N-nitrosourea (MNU) with that to {sup 60}Co gamma rays. High incidences of mammary carcinomas were induced by MNU in the F344 and WF rats (100%), whereas the COP strain proved resistant (11.8%). In contrast, radiation-induced mammary carcinomas in COP rats developed in a similar incidence (37.0%) to those in the F344 (22.6%) and WF (26.9%) strains. The low incidence of papillary carcinomas in MNU-treated COP rats appeared to be directly related to the COP genetic resistance controlled by the Mcs genes. Ionizing radiation did, however, induce papillary carcinomas in all the three strains of rats. These carcinomas were more differentiated than MNU-induced cancers with regard to the two mammary differentiation markers, rat milk fat globule membrane (R-MFGM) and {alpha}-smooth muscle actin ({alpha}-SMA). Furthermore, ionizing radiation but not MNU induced mammary adenomas in all three strains, especially in COP rats. Such adenomas had differentiation marker profiles similar to these of carcinomas induced by {sup 60}Co gamma rays. When transplanted into syngenic hosts, growth of adenomas was 17 {beta}-estradiol (E{sub 2})-dependent and they progressed to carcinomas. Furthermore, one microcarcinoma was observed to develop from adenoma tissue in a radiation-exposed COP rat. The findings suggest that radiation and chemical carcinogens are likely to induce mammary cancers through different pathways or from different cell populations. The induction of relatively high incidences of mammary carcinomas and adenomas by radiation in COP rats may correlate with the genetically modulated and highly differentiated physiological status of their mammary glands. (author)

[Oxidative metabolism of main and accessory olfactory bulbs, limpic system and hypothalamus during the estral cycle of the rat (author's transl)].

Science.gov (United States)

Sánchez-Criado, J E

1979-06-01

The in vitro oxidative metabolism of hypothalamus, olfactory and limbic systems from female rats in the estrous cycle have been measured. The accessory olfactory bulb becomes most active during diestrous when the hypothalamus reaches its lowest values.

Olfactory bulb as an alternative in neurotransplantation

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Руслан Романович Новиков

2015-05-01

Full Text Available The article examines the ethical and legal aspects of transplantation of embryonic neural tissue, structure of the rat olfactory bulb. It is given substantiation for its use as a possible alternative version of the embryonic neural tissue at damage in the cerebral hemispheres in the experiment.Materials and methods. Detailed description of the fault model of the cerebral hemispheres of the brain of rats, olfactory bulb biopsy procedure, cultivation of olfactory bulb suspension and fetal neural tissue, comparison of the functional aspects of transplantation of the olfactory bulb and the embryonic neural tissue.Results. The obtained data are similar to structure of olfactory bulb and fetal tissues during culturing. Recovery in the motor areas varies by the time factor and less intense in the group of the olfactory bulb and the group without tissue transplantation.Conclusions. Comparative analysis of the effectiveness of transplantation of embryonic neural tissue and olfactory bulb in the injured brain allows us to speak about the positive results of these groups to the difference in the duration of the recovery process

The olfactory bulb theta rhythm follows all frequencies of diaphragmatic respiration in the freely behaving rat

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Daniel eRojas-Líbano

2014-06-01

Full Text Available Sensory-motor relationships are part of the normal operation of sensory systems. Sensing occurs in the context of active sensor movement, which in turn influences sensory processing. We address such a process in the rat olfactory system. Through recordings of the diaphragm electromyogram (EMG, we monitored the motor output of the respiratory circuit involved in sniffing behavior, simultaneously with the local field potential (LFP of the olfactory bulb (OB in rats moving freely in a familiar environment, where they display a wide range of respiratory frequencies. We show that the OB LFP represents the sniff cycle with high reliability at every sniff frequency and can therefore be used to study the neural representation of motor drive in a sensory cortex.

Feasibility of Diffusion Tensor Imaging for Assessing Functional Recovery in Rats with Olfactory Ensheathing Cell Transplantation After Contusive Spinal Cord Injury (SCI).

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Gu, Mengchao; Gao, Zhengchao; Li, Xiaohui; Zhao, Feng; Guo, Lei; Liu, Jiantao; He, Xijing

2017-06-17

BACKGROUND Olfactory ensheathing cell transplantation is a promising treatment for spinal cord injury. Diffusion tensor imaging has been applied to assess various kinds of spinal cord injury. However, it has rarely been used to evaluate the beneficial effects of olfactory ensheathing cell transplantation. This study aimed to explore the feasibility of diffusion tensor imaging in the evaluation of functional recovery in rats with olfactory ensheathing cell transplantation after contusive spinal cord injury. MATERIAL AND METHODS Immunofluorescence staining was performed to determine the purity of olfactory ensheathing cells. Rats received cell transplantation at week 1 after injury. Basso, Beattie, and Bresnahan score was used to assess the functional recovery. Magnetic resonance imaging was applied weekly, including diffusion tensor imaging. Diffusion tensor tractography was reconstructed to visualize the repair process. RESULTS The results showed that olfactory ensheathing cell transplantation increased the functional and histological recovery and restrained the secondary injury process after the initial spinal cord injury. The fractional anisotropy values in rats with cell transplantation were significantly higher than those in the control group, while the apparent diffusion coefficient values were significantly lower. Basso, Beattie, and Bresnahan score was positively and linearly correlated with fractional anisotropy value, and it was negatively and linearly correlated with apparent diffusion coefficient value. CONCLUSIONS These findings suggest that diffusion tensor imaging parameters are sensitive biomarker indices for olfactory ensheathing cell transplantation interventions, and diffusion tensor imaging scan can reflect the functional recovery promoted by the olfactory ensheathing cell transplantation after contusive spinal cord injury.

Neural circuits containing olfactory neurons are involved in prepulse inhibition of the startle reflex in rats

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Haichen eNiu

2015-03-01

Full Text Available Many neuropsychiatric disorders, such as schizophrenia, have been associated with abnormalities in the function of the olfactory system and prepulse inhibition (PPI of the startle reflex. However, whether these two abnormalities are related is unclear. The present study was designed to determine whether inhibiting olfactory sensory input via the infusion of zinc sulfate (ZnE, 0.17 M, 0.5 ml into the olfactory naris disrupts PPI. Furthermore, lidocaine/MK801 was bilaterally microinjected into the olfactory bulb (OB to examine whether the blockade of olfactory sensory input impairs PPI. To identify the neural projections that connect the olfaction- and PPI-related areas of the CNS, trans-synaptic retrograde tracing using a recombinant pseudorabies virus (PRV was performed. Our results demonstrated that blocking olfactory sensory input altered olfaction-related behavior. At the functional level, we demonstrated that the inhibition of olfactory sensory input impaired PPI of the startle response subsequent to a decrease in c-fos expression in relevant brain regions. Furthermore, the results of a similar and more robust experiment indicated that blocking olfactory sensory input via the microinjection of lidocaine/MK801 into the OB impaired PPI. At the circuit level, based on trans-synaptic retrograde tracing using PRV, we demonstrated that a large portion of the labeled neurons in several regions of the olfactory cortices connected to the pedunculopontine tegmental nucleus (PPTg. Thus, these data suggest that the olfactory system participates in the regulation of PPI and plays a role in the effect of PPI on the startle response in rats.

Cortical Metabolic Arrangement During Olfactory Processing: Proposal for a 18F FDG PET/CT Methodological Approach

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Micarelli, Alessandro; Pagani, Marco; Chiaravalloti, Agostino; Bruno, Ernesto; Pavone, Isabella; Candidi, Matteo; Danieli, Roberta; Schillaci, Orazio; Alessandrini, Marco

2014-01-01

Abstract The aim of this article is to investigate the cortical metabolic arrangements in olfactory processing by using 18F fluorodeoxyglucose (FDG) positron emission tomography/computed tomography. Twenty-six normosmic individuals (14 women and 12 men; mean age 46.7 ± 10 years) were exposed to a neutral olfactory condition (NC) and, after 1 month, to a pure olfactory condition (OC) in a relatively ecological environment, that is, outside the scanner. All the subjects were injected with 185–210 megabecquerel of 18F FDG during both stimulations. Statistical parametric mapping version 2 was used in order to assess differences between NC and OC. As a result, we found a significant higher glucose consumption during OC in the cuneus, lingual, and parahippocampal gyri, mainly in the left hemisphere. During NC, our results show a relative higher glucose metabolism in the left superior, inferior, middle, medial frontal, and orbital gyri as well as in the anterior cingulate cortex. The present investigation, performed with a widely available functional imaging clinical tool, may help to better understand the neural responses associated to olfactory processing in healthy individuals and in patients with olfactory disorders by acquiring data in an ecologic, noise-free, and resting condition in which possible cerebral activations related to unwanted attentional processes might be avoided. PMID:25340494

Cortical activity during olfactory stimulation in multiple chemical sensitivity: a 18F-FDG PET/CT study

International Nuclear Information System (INIS)

Chiaravalloti, Agostino; Di Pietro, Barbara; Pagani, Marco; Micarelli, Alessandro; Alessandrini, Marco; Genovesi, Giuseppe; Schillaci, Orazio

2015-01-01

To investigate the differences in brain glucose consumption during olfactory stimulation between subjects affected by multiple chemical sensitivity (MCS) and a group of healthy individuals. Two 18 F-FDG PET/CT scans were performed in 26 subjects (6 men and 20 women; mean age 46.7 ± 11 years) with a clinical diagnosis of MCS and in 11 healthy controls (6 women and 5 men; mean age 45.7 ± 11 years), the first scan after a neutral olfactory stimulation (NS) and the second after a pure olfactory stimulation (OS). Differences in 18 F-FDG uptake were analysed by statistical parametric mapping (SPM2). In controls OS led to an increase in glucose consumption in BA 18 and 19 and a reduction in glucose metabolism in BA 10, 11, 32 and 47. In MCS subjects, OS led to an increase in glucose consumption in BA 20, 23, 18 and 37 and a reduction in glucose metabolism in BA 8, 9 and 10. The results of our study suggest that cortical activity in subjects with MCS differs from that in healthy individuals during olfactory stimulation. (orig.)

Cortical activity during olfactory stimulation in multiple chemical sensitivity: a (18)F-FDG PET/CT study.

Science.gov (United States)

Chiaravalloti, Agostino; Pagani, Marco; Micarelli, Alessandro; Di Pietro, Barbara; Genovesi, Giuseppe; Alessandrini, Marco; Schillaci, Orazio

2015-04-01

To investigate the differences in brain glucose consumption during olfactory stimulation between subjects affected by multiple chemical sensitivity (MCS) and a group of healthy individuals. Two (18)F-FDG PET/CT scans were performed in 26 subjects (6 men and 20 women; mean age 46.7 ± 11 years) with a clinical diagnosis of MCS and in 11 healthy controls (6 women and 5 men; mean age 45.7 ± 11 years), the first scan after a neutral olfactory stimulation (NS) and the second after a pure olfactory stimulation (OS). Differences in (18)F-FDG uptake were analysed by statistical parametric mapping (SPM2). In controls OS led to an increase in glucose consumption in BA 18 and 19 and a reduction in glucose metabolism in BA 10, 11, 32 and 47. In MCS subjects, OS led to an increase in glucose consumption in BA 20, 23, 18 and 37 and a reduction in glucose metabolism in BA 8, 9 and 10. The results of our study suggest that cortical activity in subjects with MCS differs from that in healthy individuals during olfactory stimulation.

A Single Bout of Fasting (24 h) Reduces Basal Cytokine Expression and Minimally Impacts the Sterile Inflammatory Response in the White Adipose Tissue of Normal Weight F344 Rats.

Science.gov (United States)

Speaker, Kristin J; Paton, Madeline M; Cox, Stewart S; Fleshner, Monika

2016-01-01

Sterile inflammation occurs when inflammatory proteins are increased in blood and tissues by nonpathogenic states and is a double-edged sword depending on its cause (stress, injury, or disease), duration (transient versus chronic), and inflammatory milieu. Short-term fasting can exert a host of health benefits through unknown mechanisms. The following experiment tested if a 24 h fast would modulate basal and stress-evoked sterile inflammation in plasma and adipose. Adult male F344 rats were either randomized to ad libitum access to food or fasted for 24 h prior to 0 (control), 10, or 100, 1.5 mA-5 s intermittent, inescapable tail shocks (IS). Glucose, nonesterified free fatty acids (NEFAs), insulin, leptin, and corticosterone were measured in plasma and tumor necrosis factor- (TNF-) α , interleukin- (IL-) 1 β , IL-6, and IL-10 in plasma, and subcutaneous, intraperitoneal, and visceral compartments of white adipose tissue (WAT). In control rats, a 24 h fast reduced all measured basal cytokines in plasma and visceral WAT, IL-1 β and IL-6 in subcutaneous WAT, and IL-6 in intraperitoneal WAT. In stressed rats (IS), fasting reduced visceral WAT TNF- α , subcutaneous WAT IL-1 β , and plasma insulin and leptin. Short-term fasting may thus prove to be a useful dietary strategy for reducing peripheral inflammatory states associated with visceral obesity and chronic stress.

A comparison of Lewis and Fischer rat strains on autoshaping (sign-tracking), discrimination reversal learning and negative auto-maintenance.

Science.gov (United States)

Kearns, David N; Gomez-Serrano, Maria A; Weiss, Stanley J; Riley, Anthony L

2006-05-15

Lewis (LEW) and Fischer (F344) rat strains differ on a number of physiological characteristics, such as hypothalamic-pituitary-adrenal (HPA) axis activity, as well as on behavioral tasks, including those that measure impulsivity and drug reward. Since autoshaping, the phenomenon where animals approach and contact reward-paired conditioned stimuli, has been linked to HPA axis functioning, impulsivity and drug taking, the present study compared LEW and F344 rats on the rate of acquisition and performance of the autoshaping response. Rats were trained on an autoshaping procedure where insertions of one retractable lever (CS(+)) were paired response-independently with food, while insertions of another lever (CS(-)) were not paired with food. LEW rats acquired the autoshaping response more rapidly and also performed the autoshaping response at a higher rate than F344 rats. No differences between the strains were observed when rats were trained on a discrimination reversal where the CS(+) and CS(-) levers were reversed or during a negative auto-maintenance phase where CS(+) lever contacts cancelled food delivery. Potential physiological mechanisms that might mediate the present results, including strain differences in HPA axis and monoamine neurotransmitter activity, are discussed. The finding that LEW (as compared to F344 rats) more readily acquire autoshaping and perform more responses is consistent with research indicating that LEW rats behave more impulsively and more readily self-administer drugs of abuse.

Dicty_cDB: SLJ344 [Dicty_cDB

Lifescience Database Archive (English)

Full Text Available SL (Link to library) SLJ344 (Link to dictyBase) - - - Contig-U16255-1 SLJ344P (Link... to Original site) SLJ344F 253 SLJ344Z 273 SLJ344P 526 - - Show SLJ344 Library SL (Link to library) Clone ID SLJ344 (Link to dict...yBase) Atlas ID - NBRP ID - dictyBase ID - Link to Contig Contig-U16255-1 Original site URL http://dict...Amino Acid sequence GTSGGTPGSCDKVNCPNGYICTIVNQLAVCVSPSSSSSSSSSTTGSHTTTGGSTTGSHTT TGGSTTGSHTTTGGSTTGSHTTTG---...li tilffniqrlykkkkkkkkkknkp*tklkin*kk Frame B: GTSGGTPGSCDKVNCPNGYICTIVNQLAVCVSPSSSSSSSSSTTGSHTTTGGSTTGSHTT

A physiological increase of insulin in the olfactory bulb decreases detection of a learned aversive odor and abolishes food odor-induced sniffing behavior in rats.

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Pascaline Aimé

Full Text Available Insulin is involved in multiple regulatory mechanisms, including body weight and food intake, and plays a critical role in metabolic disorders such as obesity and diabetes. An increasing body of evidence indicates that insulin is also involved in the modulation of olfactory function. The olfactory bulb (OB contains the highest level of insulin and insulin receptors (IRs in the brain. However, a role for insulin in odor detection and sniffing behavior remains to be elucidated. Using a behavioral paradigm based on conditioned olfactory aversion (COA to isoamyl-acetate odor, we demonstrated that an intracerebroventricular (ICV injection of 14 mU insulin acutely decreased olfactory detection of fasted rats to the level observed in satiated animals. In addition, whereas fasted animals demonstrated an increase in respiratory frequency upon food odor detection, this effect was absent in fasted animals receiving a 14 mU insulin ICV injection as well as in satiated animals. In parallel, we showed that the OB and plasma insulin levels were increased in satiated rats compared to fasted rats, and that a 14 mU insulin ICV injection elevated the OB insulin level of fasted rats to that of satiated rats. We further quantified insulin receptors (IRs distribution and showed that IRs are preferentially expressed in the caudal and lateral parts of the main OB, with the highest labeling found in the mitral cells, the main OB projection neurons. Together, these data suggest that insulin acts on the OB network to modulate olfactory processing and demonstrate that olfactory function is under the control of signals involved in energy homeostasis regulation and feeding behaviors.

Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

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Tanaka, Takuji, E-mail: tmntt08@gmail.com [Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Shimizu, Masahito; Kochi, Takahiro; Shirakami, Yohei [Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Mori, Takayuki [Department of Pharmacy, Ogaki Municipal Hospital, 4-86 Minaminokawa-cho, Ogaki 503-8502 (Japan); Watanabe, Naoki [Department of Diagnostic Pathology (DDP) & Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, 7-1 Kashima-Cho, Gifu 500-8513 (Japan); Naiki, Takafumi [Department of Clinical Laboratory, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu 500-8513 (Japan); Moriwaki, Hisataka [Department of Internal Medicine/Gastroenterology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan); Yoshimi, Kazuto; Serikawa, Tadao; Kuramoto, Takashi [The Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501 (Japan)

2014-07-21

Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation.

Apc-Mutant Kyoto Apc Delta (KAD) Rats Are Susceptible to 4-NQO-Induced Tongue Carcinogenesis

International Nuclear Information System (INIS)

Tanaka, Takuji; Shimizu, Masahito; Kochi, Takahiro; Shirakami, Yohei; Mori, Takayuki; Watanabe, Naoki; Naiki, Takafumi; Moriwaki, Hisataka; Yoshimi, Kazuto; Serikawa, Tadao; Kuramoto, Takashi

2014-01-01

Despite widening interest in the possible association between infection/inflammation and cancer development, knowledge of this issue in relation to oral cancer remains inadequate. This study aimed to determine the susceptibility of Apc-mutant Kyoto Apc Delta (KAD) rats, which are vulnerable to developing inflammation-associated colorectal carcinogenesis, to 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in order to clarify the role of inflammation in oral cancer. KAD (20 males and 22 females) and F344/NS1c (22 males and 23 females) rats received drinking water with or without 4-NQO (20 ppm) for eight weeks. Histopathological and immunohistochemical analyses of the tongue were performed at week 20. Additionally, the mRNA expression of inflammatory cytokines in the tongue mucosa was determined at week 8. Tongue squamous cell carcinoma (SCC) developed in the KAD and F344/NS1c rats that received 4-NQO. Regardless of gender, the incidence and multiplicity of tongue SCC were greater in the KAD rats than in the F344/NS1c rats. In addition, the multiplicity of tongue SCC in the female KAD rats was significantly greater than that observed in the male KAD (p < 0.01) and female F344/NS1c rats (p < 0.05). The levels of inflammation and the mRNA expression of inflammatory cytokines in the tongue in the 4-NQO-treated female KAD rats were the highest among the rats given 4-NQO. These results show that KAD rats, particularly females, are susceptible to 4-NQO-induced tongue carcinogenesis, suggesting the utility of models employing KAD rats for investigating the pathobiology of oral (tongue) carcinogenesis associated with inflammation

Sniffing and Oxytocin: Effects on Olfactory Memories.

Science.gov (United States)

Stoop, Ron

2016-05-04

In this issue of Neuron, Oettl et al. (2016) show how oxytocin can boost processing of olfactory information in female rats by a top-downregulation from the anterior olfactory nucleus onto the main olfactory bulb. As a result, interactions with juvenile conspecifics receive more attention and are longer memorized. Copyright © 2016 Elsevier Inc. All rights reserved.

Decline of prefrontal cortical-mediated executive functions but attenuated delay discounting in aged Fischer 344 × brown Norway hybrid rats.

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Hernandez, Caesar M; Vetere, Lauren M; Orsini, Caitlin A; McQuail, Joseph A; Maurer, Andrew P; Burke, Sara N; Setlow, Barry; Bizon, Jennifer L

2017-12-01

Despite the fact that prefrontal cortex (PFC) function declines with age, aged individuals generally show an enhanced ability to delay gratification, as evident by less discounting of delayed rewards in intertemporal choice tasks. The present study was designed to evaluate relationships between 2 aspects of PFC-dependent cognition (working memory and cognitive flexibility) and intertemporal choice in young (6 months) and aged (24 months) Fischer 344 × brown Norway F1 hybrid rats. Rats were also evaluated for motivation to earn rewards using a progressive ratio task. As previously reported, aged rats showed attenuated discounting of delayed rewards, impaired working memory, and impaired cognitive flexibility compared with young. Among aged rats, greater choice of delayed reward was associated with preserved working memory, impaired cognitive flexibility, and less motivation to work for food. These relationships suggest that age-related changes in PFC and incentive motivation contribute to variance in intertemporal choice within the aged population. Cognitive impairments mediated by PFC are unlikely, however, to fully account for the enhanced ability to delay gratification that accompanies aging. Copyright © 2017 Elsevier Inc. All rights reserved.

Opposite effects depending on learning and memory demands in dorsomedial prefrontal cortex lesioned rats performing an olfactory task.

Science.gov (United States)

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

1997-01-01

In this study, the functional properties of the dorsomedial prefrontal cortex (dmPFC) of the rat were examined in two olfactory tasks. In a successive cue olfactory discrimination task, dmPFC lesioned animals improved performance across sessions more rapidly than operated control animals. In an olfactory task using fixed interval training, animals with similar lesions were impaired. Both effects, although opposite, can be explained by a temporal processing deficit. The present results seem to indicate that the dmPFC is required for timing, classified as part of non-declarative memory. As reference memory improved in the lesioned animals, the finding is that the dmPFC supports non-declarative memory and thus interacts with declarative memory in the long-term formation of the associations between a particular stimulus (olfactory cue) and particular responses.

Cortical activity during olfactory stimulation in multiple chemical sensitivity: a {sup 18}F-FDG PET/CT study

Energy Technology Data Exchange (ETDEWEB)

Chiaravalloti, Agostino; Di Pietro, Barbara [University Tor Vergata, Department of Biomedicine and Prevention, Rome (Italy); Pagani, Marco [Institute of Cognitive Sciences and Technologies, CNR, Rome (Italy); Department of Nuclear Medicine Karolinska Hospital Stockholm, Stockholm (Sweden); Micarelli, Alessandro; Alessandrini, Marco [University Tor Vergata, Department of Medical Science and Translational Medicine, Rome (Italy); Genovesi, Giuseppe [University La Sapienza, Department of Experimental Medicine, Rome (Italy); University La Sapienza, Regional Center for Diagnosis, Treatment and Prevention of MCS, Rome (Italy); Schillaci, Orazio [University Tor Vergata, Department of Biomedicine and Prevention, Rome (Italy); IRCCS Neuromed, Pozzilli (Italy)

2015-04-01

To investigate the differences in brain glucose consumption during olfactory stimulation between subjects affected by multiple chemical sensitivity (MCS) and a group of healthy individuals. Two {sup 18}F-FDG PET/CT scans were performed in 26 subjects (6 men and 20 women; mean age 46.7 ± 11 years) with a clinical diagnosis of MCS and in 11 healthy controls (6 women and 5 men; mean age 45.7 ± 11 years), the first scan after a neutral olfactory stimulation (NS) and the second after a pure olfactory stimulation (OS). Differences in {sup 18}F-FDG uptake were analysed by statistical parametric mapping (SPM2). In controls OS led to an increase in glucose consumption in BA 18 and 19 and a reduction in glucose metabolism in BA 10, 11, 32 and 47. In MCS subjects, OS led to an increase in glucose consumption in BA 20, 23, 18 and 37 and a reduction in glucose metabolism in BA 8, 9 and 10. The results of our study suggest that cortical activity in subjects with MCS differs from that in healthy individuals during olfactory stimulation. (orig.)

Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes

Science.gov (United States)

Bogdani, Marika; Henschel, Angela M.; Kansra, Sanjay; Fuller, Jessica M.; Geoffrey, Rhonda; Jia, Shuang; Kaldunski, Mary L.; Pavletich, Scott; Prosser, Simon; Chen, Yi-Guang; Lernmark, Åke; Hessner, Martin J.

2014-01-01

Islet-level oxidative stress has been proposed as a trigger for type 1 diabetes (T1D), and release of cytokines by infiltrating immune cells further elevates reactive oxygen species (ROS), exacerbating β cell duress. To identify genes/mechanisms involved with diabeto-genesis at the β cell level, gene expression profiling and targeted follow-up studies were used to investigate islet activity in the biobreeding (BB) rat. Forty-day-old spontaneously diabetic lymphopenic BB DRlyp/lyp rats (before T cell insulitis) as well as nondiabetic BB DR+/+ rats, nondiabetic but lymphopenic F344lyp/lyp rats, and healthy Fischer (F344) rats were examined. Gene expression profiles of BB rat islets were highly distinct from F344 islets and under-expressed numerous genes involved in ROS metabolism, including glutathione S-transferase (GST) family members (Gstm2, Gstm4, Gstm7, Gstt1, Gstp1, and Gstk1), superoxide dismutases (Sod2 and Sod3), peroxidases, and peroxiredoxins. This pattern of under-expression was not observed in brain, liver, or muscle. Compared with F344 rats, BB rat pancreata exhibited lower GST protein levels, while plasma GST activity was found significantly lower in BB rats. Systemic administration of the antioxidant N-acetyl cysteine to DRlyp/lyp rats altered abundances of peripheral eosinophils, reduced severity of insulitis, and significantly delayed but did not prevent diabetes onset. We find evidence of β cell dysfunction in BB rats independent of T1D progression, which includes lower expression of genes related to antioxidative defense mechanisms during the pre-onset period that may contribute to overall T1D susceptibility. PMID:23111281

Stress Alters the Discriminative Stimulus and Response Rate Effects of Cocaine Differentially in Lewis and Fischer Inbred Rats

Directory of Open Access Journals (Sweden)

Therese A. Kosten

2012-03-01

Full Text Available Stress enhances the behavioral effects of cocaine, perhaps via hypothalamic-pituitary-adrenal (HPA axis activity. Yet, compared to Fischer 344 (F344 rats, Lewis rats have hyporesponsive HPA axis function and more readily acquire cocaine self-administration. We hypothesized that stress would differentially affect cocaine behaviors in these strains. The effects of three stressors on the discriminative stimulus and response rate effects of cocaine were investigated. Rats of both strains were trained to discriminate cocaine (10 mg/kg from saline using a two-lever, food-reinforced (FR10 procedure. Immediately prior to cumulative dose (1, 3, 10 mg/kg cocaine test sessions, rats were restrained for 15-min, had 15-min of footshock in a distinct context, or were placed in the shock-paired context. Another set of F344 and Lewis rats were tested similarly except they received vehicle injections to test if stress substituted for cocaine. Most vehicle-tested rats failed to respond after stressor exposures. Among cocaine-tested rats, restraint stress enhanced cocaine’s discriminative stimulus effects in F344 rats. Shock and shock-context increased response rates in Lewis rats. Stress-induced increases in corticosterone levels showed strain differences but did not correlate with behavior. These data suggest that the behavioral effects of cocaine can be differentially affected by stress in a strain-selective manner.

Suppression of Neuroinflammatory and Apoptotic Signaling Cascade by Curcumin Alone and in Combination with Piperine in Rat Model of Olfactory Bulbectomy Induced Depression

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Rinwa, Puneet; Kumar, Anil; Garg, Sukant

2013-01-01

Objectives Bilateral destruction of the olfactory bulbs is known to cause behavioral changes analogous to symptoms of depression. Curcumin, a traditional Indian spice is currently being investigated in different psychiatric problems including depression. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study is an attempt to elucidate the neuroprotective mechanism of curcumin and its co-administration with piperine against olfactory bulbectomy induced depression in rats. Methods Rats undergone olfactory bulbs ablations were analyzed after post-surgical rehabilitation period of 2 weeks. Animals were then treated with different doses of curcumin (100, 200 and 400 mg/kg; p.o.), piperine (20 mg/kg; p.o.) and their combination daily for another 2 weeks. Imipramine (10 mg/kg; i.p.) served as a standard control. Various behavioral tests like forced swim test (FST), open field behaviour and sucrose preference test (SPT) were performed, followed by estimation of biochemical, mitochondrial, molecular and histopathological parameters in rat brain. Results Ablation of olfactory bulbs caused depression-like symptoms as evidenced by increased immobility time in FST, hyperactivity in open field arena, and anhedonic like response in SPT along with alterations in mitochondrial enzyme complexes, increased serum corticosterone levels and oxidative damage. These deficits were integrated with increased inflammatory cytokines (TNF-α) and apoptotic factor (caspase-3) levels along with a marked reduction in neurogenesis factor (BDNF) in the brain of olfactory bulbectomized (OBX) rats. Curcumin treatment significantly and dose-dependently restored all these behavioral, biochemical, mitochondrial, molecular and histopathological alterations associated with OBX induced depression. Further, co-administration of piperine with curcumin significantly potentiated their neuroprotective effects as compared to their

Suppression of neuroinflammatory and apoptotic signaling cascade by curcumin alone and in combination with piperine in rat model of olfactory bulbectomy induced depression.

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Puneet Rinwa

Full Text Available OBJECTIVES: Bilateral destruction of the olfactory bulbs is known to cause behavioral changes analogous to symptoms of depression. Curcumin, a traditional Indian spice is currently being investigated in different psychiatric problems including depression. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study is an attempt to elucidate the neuroprotective mechanism of curcumin and its co-administration with piperine against olfactory bulbectomy induced depression in rats. METHODS: Rats undergone olfactory bulbs ablations were analyzed after post-surgical rehabilitation period of 2 weeks. Animals were then treated with different doses of curcumin (100, 200 and 400 mg/kg; p.o., piperine (20 mg/kg; p.o. and their combination daily for another 2 weeks. Imipramine (10 mg/kg; i.p. served as a standard control. Various behavioral tests like forced swim test (FST, open field behaviour and sucrose preference test (SPT were performed, followed by estimation of biochemical, mitochondrial, molecular and histopathological parameters in rat brain. RESULTS: Ablation of olfactory bulbs caused depression-like symptoms as evidenced by increased immobility time in FST, hyperactivity in open field arena, and anhedonic like response in SPT along with alterations in mitochondrial enzyme complexes, increased serum corticosterone levels and oxidative damage. These deficits were integrated with increased inflammatory cytokines (TNF-α and apoptotic factor (caspase-3 levels along with a marked reduction in neurogenesis factor (BDNF in the brain of olfactory bulbectomized (OBX rats. Curcumin treatment significantly and dose-dependently restored all these behavioral, biochemical, mitochondrial, molecular and histopathological alterations associated with OBX induced depression. Further, co-administration of piperine with curcumin significantly potentiated their neuroprotective effects as

Grape Powder Improves Age-Related Decline in Mitochondrial and Kidney Functions in Fischer 344 Rats

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Indira Pokkunuri

2016-01-01

Full Text Available We examined the effects and mechanism of grape powder- (GP- mediated improvement, if any, on aging kidney function. Adult (3-month and aged (21-month Fischer 344 rats were treated without (controls and with GP (1.5% in drinking water and kidney parameters were measured. Control aged rats showed higher levels of proteinuria and urinary kidney injury molecule-1 (KIM-1, which decreased with GP treatment in these rats. Renal protein carbonyls (protein oxidation and gp91phox-NADPH oxidase levels were high in control aged rats, suggesting oxidative stress burden in these rats. GP treatment in aged rats restored these parameters to the levels of adult rats. Moreover, glomerular filtration rate and sodium excretion were low in control aged rats suggesting compromised kidney function, which improved with GP treatment in aged rats. Interestingly, low renal mitochondrial respiration and ATP levels in control aged rats were associated with reduced levels of mitochondrial biogenesis marker MtTFA. Also, Nrf2 proteins levels were reduced in control aged rats. GP treatment increased levels of MtTFA and Nrf2 in aged rats. These results suggest that GP by potentially regulating Nrf2 improves aging mitochondrial and kidney functions.

Toxicology and carcinogenesis studies of dipropylene glycol in rats and mice.

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Hooth, Michelle J; Herbert, Ronald A; Haseman, Joseph K; Orzech, Denise P; Johnson, Jerry D; Bucher, John R

2004-11-15

Dipropylene glycol (DPG) is a component of many commercial products such as antifreeze, air fresheners, cosmetic products, solvents, and plastics. Male and female F344/N rats and B6C3F1 mice were exposed to DPG in the drinking water for 2 weeks, 3 months, or 2 years. In the 2-week and 3-month studies, rats and mice were exposed to 0, 5000, 10,000, 20,000, 40,000, or 80,000 ppm DPG. There was no mortality in the 2-week studies. In the 3-month rat study, all animals survived to the end of the study. Liver weights of rats exposed to 10,000 ppm or greater and kidney weights of rats exposed to 40,000 and 80,000 ppm were greater than those of the controls. The incidences of liver and kidney lesions were significantly increased in males exposed to 20,000 ppm or greater and females exposed to 80,000 ppm. Focal olfactory epithelial degeneration was present in all rats exposed to 80,000 ppm. In males, the incidences of testicular atrophy, epididymal hypospermia, and preputial gland atrophy were significantly increased in the 80,000 ppm group. In the 3-month mouse study, three males and one female exposed to 80,000 ppm died. Liver weights were increased, as was the incidence of centrilobular hypertrophy in males exposed to 40,000 ppm and males and females exposed to 80,000 ppm. In the 2-year studies, exposure groups were 0, 2500 (rats only), 10,000, 20,000 (mice only) or 40,000 ppm DPG. Survival of male rats exposed to 40,000 ppm and mean body weights of males and females exposed to 40,000 ppm were significantly less than controls. In male rats, exposure to DPG resulted in increased incidences and severities of nephropathy and secondary lesions in the parathyroid and forestomach. Increased incidences of focal histiocytic and focal granulomatous inflammation of the liver were also observed. In male and female rats, there were increased incidences of bile duct hyperplasia and changes in the olfactory epithelium of the nose. In mice, survival of males and females was similar to

Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors.

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Prediger, Rui D S; Batista, Luciano C; Takahashi, Reinaldo N

2005-06-01

Caffeine, a non-selective adenosine receptor antagonist, has been suggested as a potential drug to counteract age-related cognitive decline since critical changes in adenosinergic neurotransmission occur with aging. In the present study, olfactory discrimination and short-term social memory of 3, 6, 12 and 18 month-old rats were assessed with the olfactory discrimination and social recognition tasks, respectively. The actions of caffeine (3.0, 10.0 and 30.0 mg/kg, i.p.), the A1 receptor antagonist DPCPX (1.0 and 3.0 mg/kg, i.p.) and the A2A receptor antagonist ZM241385 (0.5 and 1.0 mg/kg, i.p.) in relation to age-related effects on olfactory functions were also studied. The 12 and 18 month-old rats exhibited significantly impaired performance in both models, demonstrating deficits in their odor discrimination and in their ability to recognize a juvenile rat after a short period of time. Acute treatment with caffeine or ZM241385, but not with DPCPX, reversed these age-related olfactory deficits. The present results suggest the participation of adenosine receptors in the control of olfactory functions and confirm the potential of caffeine for the treatment of aged-related cognitive decline.

Locoregional injection of F-18 radiopharmaceuticals suppresses tumor xenograft growth in rats

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Wong, C -L [The Univ. of Texas M.D. Anderson Cancer Center, Texas (United States)

2004-07-01

The energetic positrons (0.633 Mev) from F-18 dissipate kinetic energies before annihilation to produce two 0.511 Mev photons which also contribute to the radiation absorbed dose to the surroundings. In living organism, the contribution from the positron itself to the surrounding tissues (up to 2 mm) is larger than from the 2 photons. Apoptosis has been reported in rat tumors after systemic injection of F-18 FDG although no growth retardation was noted. This study is designed to exploit the pharmacokinetic advantages of locoregional injection of positron emitters in the suppression of tumor growth in rats. Methods: Groups of Fisher 344 adult female rats were inoculated with rat mammary tumors (100,000 cells) intramuscularly (IM) in the thigh. Locoregional injection with F-18 NaF or F-18 FDG was accomplished in days 3 or 7 with single doses of increasing strengths (0.2 to 3 mCi). Tumor growth rates were noted and compared to control (sham injection with saline). The locoregional distribution and clearance of F-18 were estimated from serial tomograms using a Concord MicroPET (R4) after intramuscular injection of 0.1-0.2 mCi of F-18 NaF or F-18 FDG in groups of triplicate rats. Results: A dose-related pattern of tumor suppression is noted with F-18 FDG, whether treatment occurs in day 3 or 7 after inoculation. Additional experiment of injection of 5 mci of F-18 FDG at day 14 also suppressed the growth of a well-formed tumor. Tumor suppression by F-18 NaF is less obvious and only occurs with high dose (2 mCi). MicroPET images demonstrate that F-18 FDG is retained in the injection site while F-18 NaF dissipates rapidly. Conclusion: Locoregional injection of positron-emitters may be sufficient to suppress tumor growth. The mechanism is likely related to the pharmacokinetic profile of the compound within the tissue. Discussion: Locoregional application of radionuclides may provide feasible alternatives to slow tumor growth or prevent tumor recurrence. The use of

[New data on olfactory control of estral receptivity of female rats].

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Satli, M A; Aron, C

1976-03-01

Olfactory bulb deprivation increased sexual receptivity in 4-day cyclic female rats on the late afternoon of prooestrus (6-7, p.m.). The proportion of receptive females was higher in bulbectomized (B) than in sham operated (SH) animals. On the contrary the same proportion of B and SH females mated in the evening of prooestrus (10. 30-11. 30 p.m.). An increased lordosis quotient was observed in the B females at either of these two stages of the cycle.

Specific olfactory receptor populations projecting to identified glomeruli in the rat olfactory bulb.

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Jastreboff, P J; Pedersen, P E; Greer, C A; Stewart, W B; Kauer, J S; Benson, T E; Shepherd, G M

1984-08-01

A critical gap exists in our knowledge of the topographical relationship between the olfactory epithelium and olfactory bulb. The present report describes the application to this problem of a method involving horseradish peroxidase conjugated to wheat germ agglutinin. This material was iontophoretically delivered to circumscribed glomeruli in the olfactory bulb and the characteristics and distribution of retrogradely labeled receptor cells were assessed. After discrete injections into small glomerular groups in the caudomedial bulb, topographically defined populations of receptor cells were labeled. Labeled receptor cell somata appeared at several levels within the epithelium. The receptor cell apical dendrites followed a tight helical course towards the surface of the epithelium. The data thus far demonstrate that functional units within the olfactory system may include not only glomeruli as previously suggested but, in addition, a corresponding matrix of receptor cells possessing functional and topographical specificity.

Impact of Single or Repeated Dose Intranasal Zinc-free Insulin in Young and Aged F344 Rats on Cognition, Signaling, and Brain Metabolism.

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Anderson, Katie L; Frazier, Hilaree N; Maimaiti, Shaniya; Bakshi, Vikas V; Majeed, Zana R; Brewer, Lawrence D; Porter, Nada M; Lin, Ai-Ling; Thibault, Olivier

2017-02-01

Novel therapies have turned to delivering compounds to the brain using nasal sprays, bypassing the blood brain barrier, and enriching treatment options for brain aging and/or Alzheimer's disease. We conducted a series of in vivo experiments to test the impact of intranasal Apidra, a zinc-free insulin formulation, on the brain of young and aged F344 rats. Both single acute and repeated daily doses were compared to test the hypothesis that insulin could improve memory recall in aged memory-deficient animals. We quantified insulin signaling in different brain regions and at different times following delivery. We measured cerebral blood flow (CBF) using MRI and also characterized several brain metabolite levels using MR spectroscopy. We show that neither acute nor chronic Apidra improved memory or recall in young or aged animals. Within 2 hours of a single dose, increased insulin signaling was seen in ventral areas of the aged brains only. Although chronic Apidra was able to offset reduced CBF with aging, it also caused significant reductions in markers of neuronal integrity. Our data suggest that this zinc-free insulin formulation may actually hasten cognitive decline with age when used chronically. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Altered susceptibility of an obese rat model to 13-week subchronic toxicity induced by 3-monochloropropane-1,2-diol.

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Toyoda, Takeshi; Cho, Young-Man; Akagi, Jun-Ichi; Mizuta, Yasuko; Matsushita, Kohei; Nishikawa, Akiyoshi; Imaida, Katsumi; Ogawa, Kumiko

2017-01-01

3-Monochloropropane-1,2-diol (3-MCPD) is a heat-induced food contaminant that has been shown to be a nongenotoxic renal carcinogen. Although the toxicity of 3-MCPD has been widely investigated for decades, there is a further concern that 3-MCPD might exert more potent toxicity in high-risk population with underlying diseases such as hyperlipidemia associated with obesity. In the present study, we performed a 13-week subchronic toxicity study for 3-MCPD using an obesity rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 9, 28.5, 90, 285, or 900 ppm 3-MCPD in drinking water for 13 weeks. 3-MCPD treatment decreased body weight gain, increased relative kidney weights, induced anemia, and induced epithelial cell necrosis in epididymal ducts in all 3 strains. The degrees of epididymal damage were higher in F344 and lean rats than in fatty rats, while renal toxicity was most potent in F344 rats and comparable in lean and fatty rats. In contrast, the hematology data indicated that anemia was worse in fatty rats than in F344 and lean rats, and a significant decrease in hematopoietic cells in the bone marrow was observed only in fatty rats. The no-observed-adverse-effect level was estimated to be 28.5 ppm in all 3 strains for 3-MCPD. These results suggested that obese Zucker rats may be more susceptible to 3-MCPD-dependent toxicity in the hematopoietic tissues than their lean counterparts.

A Single Bout of Fasting (24 h Reduces Basal Cytokine Expression and Minimally Impacts the Sterile Inflammatory Response in the White Adipose Tissue of Normal Weight F344 Rats

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Kristin J. Speaker

2016-01-01

Full Text Available Sterile inflammation occurs when inflammatory proteins are increased in blood and tissues by nonpathogenic states and is a double-edged sword depending on its cause (stress, injury, or disease, duration (transient versus chronic, and inflammatory milieu. Short-term fasting can exert a host of health benefits through unknown mechanisms. The following experiment tested if a 24 h fast would modulate basal and stress-evoked sterile inflammation in plasma and adipose. Adult male F344 rats were either randomized to ad libitum access to food or fasted for 24 h prior to 0 (control, 10, or 100, 1.5 mA-5 s intermittent, inescapable tail shocks (IS. Glucose, nonesterified free fatty acids (NEFAs, insulin, leptin, and corticosterone were measured in plasma and tumor necrosis factor- (TNF- α, interleukin- (IL- 1β, IL-6, and IL-10 in plasma, and subcutaneous, intraperitoneal, and visceral compartments of white adipose tissue (WAT. In control rats, a 24 h fast reduced all measured basal cytokines in plasma and visceral WAT, IL-1β and IL-6 in subcutaneous WAT, and IL-6 in intraperitoneal WAT. In stressed rats (IS, fasting reduced visceral WAT TNF-α, subcutaneous WAT IL-1β, and plasma insulin and leptin. Short-term fasting may thus prove to be a useful dietary strategy for reducing peripheral inflammatory states associated with visceral obesity and chronic stress.

Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats

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Junlin eZhang

2013-05-01

Full Text Available Manipulation of serotonin (5HT during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM. Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8-21. After animals reach adulthood (>90 days, OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs, these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD.

Vaginocervical stimulation enhances social recognition memory in rats via oxytocin release in the olfactory bulb.

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Larrazolo-López, A; Kendrick, K M; Aburto-Arciniega, M; Arriaga-Avila, V; Morimoto, S; Frias, M; Guevara-Guzmán, R

2008-03-27

The ability of vaginocervical stimulation (VCS) to promote olfactory social recognition memory at different stages of the ovarian cycle was investigated in female rats. A juvenile social recognition paradigm was used and memory retention tested at 30 and 300 min after an adult was exposed to a juvenile during three 4-min trials. Results showed that an intact social recognition memory was present at 30 min in animals with or without VCS and at all stages of the estrus cycle. However, whereas no animals in any stage of the estrus cycle showed retention of the specific recognition memory at 300 min, those in the proestrus/estrus phase that received VCS 10 min before the trial started did. In vivo microdialysis studies showed that there was a significant release of oxytocin after VCS in the olfactory bulb during proestrus. There was also increased oxytocin immunoreactivity within the olfactory bulb after VCS in proestrus animals compared with diestrus ones. Furthermore, when animals received an infusion of an oxytocin antagonist directly into the olfactory bulb, or a systemic administration of alpha or beta noradrenaline-antagonists, they failed to show evidence for maintenance of a selective olfactory recognition memory at 300 min. Animals with vagus or pelvic nerve section also showed no memory retention when tested after 300 min. These results suggest that VCS releases oxytocin in the olfactory bulb to enhance the social recognition memory and that this may be due to modulatory actions on noradrenaline release. The vagus and pelvic nerves are responsible for carrying the information from the pelvic area to the CNS.

Ratos isogênicos F344 como modelo biológico de sepsis intra-abdominal

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Sueli Blanes Damy

2002-01-01

Full Text Available Com o objetivo de estudar um modelo biológico de sepsis intra-abdominal aguda para estudos experimentais, foram infectados ratos isogênicos F344, convencionais, com a bactéria Escherichia coli (E.coli, cepa ATCC 11775, sorotipo H7:O1:K1. Os animais inoculados, machos e fêmeas, apresentaram 6 horas após a inoculação por E.coli os seguintes sintomas: arqueamento do dorso, piloereção, hiperpnéia e diminuição das atividades motoras. A dose que produziu 50% de mortalidade (DL50 após 7 dias, determinada pelo método Reed & Muench, foi de 6 x 10(5 CFU/ml (analisado em 32 machos e 32 fêmeas. A maior concentração de mortalidade foi observada nas primeiras 24 horas. A disfunção hepática, comum em sepsis intra-abdominal, foi avaliada por provas enzimáticas, em 0, 24, 48 e 168 horas após a inoculação. O estudo da migração de células polimorfonucleares-neutrófilos (PMN e mononucleares-macrófagos (MN apontou um aumento significante de PMN entre o grupos de machos (z ³ 4,7; p < 0,003 e de fêmeas (z ³ 6,2; p < 0,0003 inoculados E.coli, quando comparados ao grupos controles. Quanto às células MN, não houve diferença entre os grupos inoculados e os controles, tanto para os machos (z=2,3; p = 0,0107, como para as fêmeas (z=1,8; p =0,0359. Em conclusão, estes resultados demonstram que os ratos isogênicos F344 são modelos biológicos adequados para estudos de sepsis intra-abdominal aguda.

Olfactory Fear Conditioning Induces Field Potential Potentiation in Rat Olfactory Cortex and Amygdala

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Messaoudi, Belkacem; Granjon, Lionel; Mouly, Anne-Marie; Sevelinges, Yannick; Gervais, Remi

2004-01-01

The widely used Pavlovian fear-conditioning paradigms used for studying the neurobiology of learning and memory have mainly used auditory cues as conditioned stimuli (CS). The present work assessed the neural network involved in olfactory fear conditioning, using olfactory bulb stimulation-induced field potential signal (EFP) as a marker of…

Deposition and retention of 67Ga-labelled diesel particles in Fischer-344 rats

International Nuclear Information System (INIS)

Wolff, R.K.; Sun, J.D.; Lopez, J.A.; Wolf, I.; Cheng, Y.S.; McClellan, R.O.

1981-01-01

Fischer-344 rats were exposed nose-only to 67 Ga radiolabeled diesel exhaust particles produced from a 1 cylinder engine and diluted 10:1 with filtered air. Volume median diameters of the particles were 0.14 to 0.16 μm measured using an electrical aerosol analyzer, a diffusion battery and a cascade impactor. Initial lung deposition was 7 +- 2% and 12 +- 2% in two separate experiments. Gallium-67 left the lung rapidly with a clearance half-time of about 10 days, indicating that the 67 Ga label dissociated from diesel particles

Assessment of the mutagenic potential of hexavalent chromium in the duodenum of big blue® rats.

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Thompson, Chad M; Young, Robert R; Dinesdurage, Harshini; Suh, Mina; Harris, Mark A; Rohr, Annette C; Proctor, Deborah M

2017-09-01

A cancer bioassay on hexavalent chromium Cr(VI) in drinking water reported increased incidences of duodenal tumors in B6C3F1 mice at exposures of 30-180ppm, and oral cavity tumors in F344 rats at 180ppm. A subsequent transgenic rodent (TGR) in vivo mutation assay in Big Blue® TgF344 rats found that exposure to 180ppm Cr(VI) in drinking water for 28days did not increase cII transgene mutant frequency (MF) in the oral cavity (Thompson et al., 2015). Herein, we extend our analysis to the duodenum of these same TgF344 rats. At study termination, duodenum chromium levels were below either the limit of detection or quantification in control rats, but were 24.6±3.8μg/g in Cr(VI)-treated rats. The MF in control (23.2×10 -6 ) and Cr(VI)-treated rats (22.7×10 -6 ) were nearly identical. In contrast, the MF in the duodenum of rats exposed to 1-ethyl-1-nitrosourea for six days (study days 1, 2, 3, 12, 19, 26) increased 24-fold to 557×10 -6 . These findings indicate that mutagenicity is unlikely an early initiating event in Cr(VI)-induced intestinal carcinogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's disease.

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Rorabaugh, Jacki M; Chalermpalanupap, Termpanit; Botz-Zapp, Christian A; Fu, Vanessa M; Lembeck, Natalie A; Cohen, Robert M; Weinshenker, David

2017-11-01

See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus and noradrenergic dysfunction may be a critical early step in Alzheimer’s disease progression. Yet, an accurate preclinical model of these phenotypes that includes early pretangle tau accrual in the locus coeruleus, loss of locus coeruleus innervation and deficits locus coeruleus/norepinephrine modulated behaviours, does not exist, hampering the identification of underlying mechanisms and the development of locus coeruleus-based therapies. Here, a transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) and presenilin-1 (PS1ΔE9) was characterized for histological and behavioural signs of locus coeruleus dysfunction reminiscent of mild cognitive impairment/early Alzheimer’s disease. In TgF344-AD rats, hyperphosphorylated tau was detected in the locus coeruleus prior to accrual in the medial entorhinal cortex or hippocampus, and tau pathology in the locus coeruleus was negatively correlated with noradrenergic innervation in the medial entorhinal cortex. Likewise, TgF344-AD rats displayed progressive loss of hippocampal norepinephrine levels and locus coeruleus fibres in the medial entorhinal cortex and dentate gyrus, with no frank noradrenergic cell body loss. Cultured mouse locus coeruleus neurons expressing hyperphosphorylation-prone mutant human tau had shorter neurites than control neurons, but similar cell viability, suggesting a causal link between pretangle tau accrual and altered locus coeruleus fibre morphology. TgF344-AD rats had impaired reversal learning in the Morris water maze compared to their wild-type littermates, which was rescued by chemogenetic locus coeruleus activation via designer receptors exclusively activated by designer drugs (DREADDs). Our results indicate that TgF344-AD rats uniquely meet several key criteria for a

Different importance of the volatile and non-volatile fractions of an olfactory signature for individual social recognition in rats versus mice and short-term versus long-term memory.

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Noack, Julia; Richter, Karin; Laube, Gregor; Haghgoo, Hojjat Allah; Veh, Rüdiger W; Engelmann, Mario

2010-11-01

When tested in the olfactory cued social recognition/discrimination test, rats and mice differ in their retention of a recognition memory for a previously encountered conspecific juvenile: Rats are able to recognize a given juvenile for approximately 45 min only whereas mice show not only short-term, but also long-term recognition memory (≥ 24 h). Here we modified the social recognition/social discrimination procedure to investigate the neurobiological mechanism(s) underlying the species differences. We presented a conspecific juvenile repeatedly to the experimental subjects and monitored the investigation duration as a measure for recognition. Presentation of only the volatile fraction of the juvenile olfactory signature was sufficient for both short- and long-term recognition in mice but not rats. Applying additional volatile, mono-molecular odours to the "to be recognized" juveniles failed to affect short-term memory in both species, but interfered with long-term recognition in mice. Finally immunocytochemical analysis of c-Fos as a marker for cellular activation, revealed that juvenile exposure stimulated areas involved in the processing of olfactory signals in both the main and the accessory olfactory bulb in mice. In rats, we measured an increased c-Fos synthesis almost exclusively in cells of the accessory olfactory bulb. Our data suggest that the species difference in the retention of social recognition memory is based on differences in the processing of the volatile versus non-volatile fraction of the individuals' olfactory signature. The non-volatile fraction is sufficient for retaining a short-term social memory only. Long-term social memory - as observed in mice - requires a processing of both the volatile and non-volatile fractions of the olfactory signature. Copyright © 2010 Elsevier Inc. All rights reserved.

A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss.

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Cohen, Robert M; Rezai-Zadeh, Kavon; Weitz, Tara M; Rentsendorj, Altan; Gate, David; Spivak, Inna; Bholat, Yasmin; Vasilevko, Vitaly; Glabe, Charles G; Breunig, Joshua J; Rakic, Pasko; Davtyan, Hayk; Agadjanyan, Michael G; Kepe, Vladimir; Barrio, Jorge R; Bannykh, Serguei; Szekely, Christine A; Pechnick, Robert N; Town, Terrence

2013-04-10

Alzheimer's disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The "amyloid cascade hypothesis" posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aβ peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research.

Intestinal metaplasia induced by x-irradiation in different strains of rats

International Nuclear Information System (INIS)

Watanabe, Hiromitsu; Naito, Masashi; Kawashima, Kengo; Ito, Akihiro

1985-01-01

Attempts were made to examine strain differences in the susceptibility of rats to intestinal metaplasia induced by X-irradiation. The gastric regions of 4 inbred male rats (SHR, F344, WKY, and LEW strains) in 5-week-old and 2 random bred male rats (SD, and WIS strains) were irradiated with a total dose of 20 Gy X-ray given in two equal fractions separated by three days. Upon sacrifice at 6 months after the last irradiation, the number of intestinal metaplastic crypts with positive reaction to alkaline phosphatase (ALP) appeared highest in the SHR and lowest in the WIS rats. Morphologically, the number of crypts with intestinal metaplasia in whole glandular stomachs of SHR, WIS, F344, and SD rats were higher than those in WKY and LEW rats. In the pyloric gland, it was highest in WIS rats, while in the fundic gland it was highest in SHR rats. The results show that the appearance and location of intestinal metaplasia by X-irradiation are greatly influenced by the strain of the rat. (author)

Fos and Egr1 Expression in the Rat Brain in Response to Olfactory Cue after Taste-Potentiated Odor Aversion Retrieval

Science.gov (United States)

Cattarelli, Martine; Dardou, David; Datiche, Frederique

2006-01-01

When an odor is paired with a delayed illness, rats acquire a relatively weak odor aversion. In contrast, rats develop a strong aversion to an olfactory cue paired with delayed illness if it is presented simultaneously with a gustatory cue. Such a conditioning effect has been referred to as taste-potentiated odor aversion learning (TPOA). TPOA is…

Lateralized odor preference training in rat pups reveals an enhanced network response in anterior piriform cortex to olfactory input that parallels extended memory.

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Fontaine, Christine J; Harley, Carolyn W; Yuan, Qi

2013-09-18

The present study examines synaptic plasticity in the anterior piriform cortex (aPC) using ex vivo slices from rat pups given lateralized odor preference training. In the early odor preference learning model, a brief 10 min training session yields 24 h memory, while four daily sessions yield 48 h memory. Odor preference memory can be lateralized through naris occlusion as the anterior commissure is not yet functional. AMPA receptor-mediated postsynaptic responses in the aPC to lateral olfactory tract input, shown to be enhanced at 24 h, are no longer enhanced 48 h after a single training session. Following four spaced lateralized trials, the AMPA receptor-mediated fEPSP is enhanced in the trained aPC at 48 h. Calcium imaging of aPC pyramidal cells within 48 h revealed decreased firing thresholds in the pyramidal cell network. Thus multiday odor preference training induced increased odor input responsiveness in previously weakly activated aPC cells. These results support the hypothesis that increased synaptic strength in olfactory input networks mediates odor preference memory. The increase in aPC network activation parallels behavioral memory.

The Effect of Chronic Methamphetamine Exposure on the Hippocampal and Olfactory Bulb Neuroproteomes of Rats.

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Rui Zhu

Full Text Available Nowadays, drug abuse and addiction are serious public health problems in the USA. Methamphetamine (METH is one of the most abused drugs and is known to cause brain damage after repeated exposure. In this paper, we conducted a neuroproteomic study to evaluate METH-induced brain protein dynamics, following a two-week chronic regimen of an escalating dose of METH exposure. Proteins were extracted from rat brain hippocampal and olfactory bulb tissues and subjected to liquid chromatography-mass spectrometry (LC-MS/MS analysis. Both shotgun and targeted proteomic analysis were performed. Protein quantification was initially based on comparing the spectral counts between METH exposed animals and their control counterparts. Quantitative differences were further confirmed through multiple reaction monitoring (MRM LC-MS/MS experiments. According to the quantitative results, the expression of 18 proteins (11 in the hippocampus and 7 in the olfactory bulb underwent a significant alteration as a result of exposing rats to METH. 13 of these proteins were up-regulated after METH exposure while 5 were down-regulated. The altered proteins belonging to different structural and functional families were involved in processes such as cell death, inflammation, oxidation, and apoptosis.

Toxic effects of a horseradish extract and allyl isothiocyanate in the urinary bladder after 13-week administration in drinking water to F344 rats.

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Hasumura, Mai; Imai, Toshio; Cho, Young-Man; Ueda, Makoto; Hirose, Masao; Nishikawa, Akiyoshi; Ogawa, Kumiko

2011-01-01

Subchronic toxicity of a horseradish extract (HRE), consisting mainly of a mixture of allyl isothiocyanate (AITC) and other isothiocyanates, was investigated with administration at concentrations of 0, 0.0125, 0.025 and 0.05% of HRE in drinking water for 13 weeks to male and female F344 rats. For comparison, treatment with 0.0425% of AITC was similarly performed. Body weight gain was reduced in the 0.05% HRE and AITC males as compared to the 0% controls, and the cause was considered at least partly related to decreased water consumption due to the acrid smell of the test substance and decreased food consumption. Serum biochemistry demonstrated increased urea nitrogen in 0.025 and 0.05% HRE and AITC males and 0.0125-0.05% HRE and AITC females, along with decreased total cholesterol in 0.0125-0.05% HRE females. On histopathological assessment, papillary/nodular hyperplasia of bladder mucosa was observed in 0.05% HRE and AITC males and females, in addition to simple mucosal hyperplasia found in all treated groups. Based on the above findings, no-observed-adverse-effect levels (NOAELs) were estimated to be below 0.0125% of HRE for both males and females, corresponding to 9.4 and 8.0 mg/kg body weight/day, respectively, and there appeared to be comparable toxicological properties of HRE to AITC, such as the inductive effect of significant proliferative lesions in the urinary bladder.

Identification of the Ulex europaeus agglutinin-I-binding protein as a unique glycoform of the neural cell adhesion molecule in the olfactory sensory axons of adults rats.

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Pestean, A; Krizbai, I; Böttcher, H; Párducz, A; Joó, F; Wolff, J R

1995-08-04

Histochemical localization of two lectins, Ulex europaeus agglutinin-I (UEA-I) and Tetragonolobus purpureus (TPA), was studied in the olfactory bulb of adult rats. In contrast to TPA, UEA-I detected a fucosylated glycoprotein that is only present in the surface membranes of olfactory sensory cells including the whole course of their neurites up to the final arborization in glomeruli. Immunoblotting revealed that UEA-I binds specifically to a protein of 205 kDa, while TPA stains several other glycoproteins. Affinity chromatography with the use of a UEA-I column identified the 205 kDa protein as a glycoform of neural cell adhesion molecule (N-CAM), specific for the rat olfactory sensory nerves.

Cyclin D expression in plutonium-induced lung tumors in F344 rats

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Hahn, F.F.; Kelly, G. [SouthWest Scientific Resources, Inc., Albuquerque, NM (United States)

1995-12-01

The genetic mechanisms responsible for {alpha}-radiation-induced lung cancer in rats following inhalation of {sup 239}Pu is an ongoing area of research in our laboratory. Previous studies have examined the status of the p53 gene by immunohistochemistry. Only two tumors (2/26 squamous cell carcinomas) exhibited detectable levels of p53 products. Both were the result of mutations in codons 280 and 283. More recent studies of X-ray-induced lung tumors in rats showed a similar lack of involvement of p53. In conclusion, we found that {alpha}-radiation-induced rat lung tumors have a high incidence (31 of 39) of cyclin D{sub 1} overexpression.

Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65.

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Moudgil, K D; Kim, E; Yun, O J; Chi, H H; Brahn, E; Sercarz, E E

2001-03-15

Both genetic and environmental factors are believed to be involved in the induction of autoimmune diseases. Adjuvant arthritis (AA) is inducible in susceptible rat strains by injection of Mycobacterium tuberculosis, and arthritic rats raise T cell responses to the 65-kDa mycobacterial heat-shock protein (Bhsp65). We observed that Fischer 344 (F344) rats raised in a barrier facility (BF-F344) are susceptible to AA, whereas F344 rats maintained in a conventional facility (CV-F344) show significantly reduced incidence and severity of AA, despite responding well to the arthritogenic determinant within Bhsp65. The acquisition of protection from AA can be circumvented if rats are maintained on neomycin/acidified water. Strikingly, naive unimmunized CV-F344 rats but not BF-F344 rats raised T cell responses to Bhsp65 C-terminal determinants (BCTD) (we have previously shown that BCTD are involved in regulation of acute AA in the Lewis rat); however, T cells of naive CV-F344 and BF-F344 gave a comparable level of proliferative response to a mitogen, but no response at all to an irrelevant Ag. Furthermore, adoptive transfer into naive BF-F344 rats of splenic cells of naive CV-F344 rats (restimulated with BCTD in vitro) before induction of AA resulted in a considerably reduced severity of AA. These results suggest that spontaneous (inadvertent) priming of BCTD-reactive T cells, owing to determinant mimicry between Bhsp65 and its homologues in microbial agents in the conventional environment, is involved in modulating the severity of AA in CV-F344 rats. These results have important implications in broadening understanding of the host-microbe interaction in human autoimmune diseases.

Olfactory discrimination and memory deficits in the Flinders Sensitive Line rodent model of depression.

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Cook, A; Pfeiffer, L-M; Thiele, S; Coenen, V A; Döbrössy, M D

2017-10-01

Major Depressive Disorder (MDD) is a heterogeneous psychiatric disorder with broad symptomatic manifestations. The current study examined, for the first time, olfactory memory and discrimination in the Flinders Sensitive Line (FSL) rodent model of depression. Male FSL rats and controls were trained on an Olfactory Discrimination (OD) and a Social Interaction (SI) test. On the OD test, the FSL and controls performed similarly at the shortest inter-trial interval (5min), however, with extended delay of 30min, the FSLs had a recall and odour discrimination deficit. At the longest delay (60min) both groups performed poorly. The FSL rats i.) had a deficit in olfactory discrimination suggesting impairment in olfactory memory and recall; ii.) were less likely to socialize with unfamiliar rats. The data suggests that FSL animals have an impaired olfactory information processing capacity. Copyright © 2017 Elsevier B.V. All rights reserved.

Neural correlates of taste perception in congenital olfactory impairment

DEFF Research Database (Denmark)

Gagnon, Léa; Vestergaard, Martin; Madsen, Kristoffer

2014-01-01

taste identification accuracy and its neural correlates using functional magnetic resonance imaging (fMRI) in 12 congenitally olfactory impaired individuals and 8 normosmic controls. Results showed that taste identification was worse in congenitally olfactory impaired compared to control subjects. The fMRI...

Maternal deprivation decelerates postnatal morphological lung development of F344 rats.

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Hupa, Katharina Luise; Schmiedl, Andreas; Pabst, Reinhard; Von Hörsten, Stephan; Stephan, Michael

2014-02-01

Intensive medical care at premature born infants is often associated with separation of neonates from their mothers. Here, early artificial prolonged separation of rat pups from their dams (Maternal Deprivation, MD) was used to study potential impact on morphological lung maturation. Furthermore, we investigated the influence of an endogenous deficiency of the neuropeptide-cleaving dipeptidyl peptidase IV (DPP4), since the effects of MD are known to be partly mediated via neuropeptidergic effects, hypothesizing that MD will lead to a retardation of postnatal lung development, DPP4-dependendly. We used wild type and CD26/DPP4 deficient rats. For MD, the dam was placed each day into a separate cage for 2 h, while the pups remained in the nest on their own. Morphological lung maturation and cell proliferation at the postnatal days 7, 10, 14, and 21 were determined morphometrically. Maternally deprived wild types showed a retarded postnatal lung development compared with untreated controls in both substrains. During alveolarization, an increased thickness of alveolar septa and a decreased surface of septa about 50% were found. At the end of the morphological lung maturation, the surface of the alveolar septa was decreased at about 25% and the septal thickness remained increased about 20%. The proliferation rate was also decreased about 50% on day 14. However, the MD induced effects were less pronounced in DPP4-deficient rats, due to a significant deceleration already induced by DPP4-deficiency. Thus, MD as a model for postnatal stress experience influences remarkably postnatal development of rats, which is significantly modulated by the DPP4-system. Copyright © 2013 Wiley Periodicals, Inc.

Trichloroethylene-Induced DNA Methylation Changes in Male F344 Rat Liver.

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Jiang, Yan; Chen, Jiahong; Yue, Cong; Zhang, Hang; Chen, Tao

2016-10-17

Trichloroethylene (TCE), a common environmental contaminant, causes hepatocellular carcinoma in mice but not in rats. To understand the mechanisms of the species-specific hepatocarcinogenecity of TCE, we examined the methylation status of DNA in the liver of rats exposed to TCE at 0 or 1000 mg/kg b.w. for 5 days using MeDIP-chip, bisulfite sequencing, COBRA, and LC-MS/MS. The related mRNA expression levels were measured by qPCR. Although no global DNA methylation change was detected, 806 genes were hypermethylated and 186 genes were hypomethylated. The genes with hypermethylated DNA were enriched in endocytosis, MAPK, and cAMP signaling pathways. We further confirmed the hypermethylation of Uhrf2 DNA and the hypomethylation of Hadhb DNA, which were negatively correlated with their mRNA expression levels. The transcriptional levels of Jun, Ihh, and Tet2 were significantly downregulated, whereas Cdkn1a was overexpressed. No mRNA expression change was found for Mki67, Myc, Uhrf1, and Dnmt1. In conclusion, TCE-induced DNA methylation changes in rats appear to suppress instead of promote hepatocarcinogenesis, which might play a role in the species-specific hepatocarcinogenecity of TCE.

Effects of MK-801 on vicarious trial-and-error and reversal of olfactory discrimination learning in weanling rats.

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Griesbach, G S; Hu, D; Amsel, A

1998-12-01

The effects of dizocilpine maleate (MK-801) on vicarious trial-and-error (VTE), and on simultaneous olfactory discrimination learning and its reversal, were observed in weanling rats. The term VTE was used by Tolman (The determiners of behavior at a choice point. Psychol. Rev. 1938;46:318-336), who described it as conflict-like behavior at a choice-point in simultaneous discrimination learning. It takes the form of head movements from one stimulus to the other, and has recently been proposed by Amsel (Hippocampal function in the rat: cognitive mapping or vicarious trial-and-error? Hippocampus, 1993;3:251-256) as related to hippocampal, nonspatial function during this learning. Weanling male rats received systemic MK-801 either 30 min before the onset of olfactory discrimination training and its reversal, or only before its reversal. The MK-801-treated animals needed significantly more sessions to acquire the discrimination and showed significantly fewer VTEs in the acquisition phase of learning. Impaired reversal learning was shown only when MK-801 was administered during the reversal-learning phase, itself, and not when it was administered throughout both phases.

Absence of in vivo genotoxicity of 3-monochloropropane-1,2-diol and associated fatty acid esters in a 4-week comprehensive toxicity study using F344 gpt delta rats.

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Onami, Saeko; Cho, Young-Man; Toyoda, Takeshi; Horibata, Katsuyoshi; Ishii, Yuji; Umemura, Takashi; Honma, Masamitsu; Nohmi, Takehiko; Nishikawa, Akiyoshi; Ogawa, Kumiko

2014-07-01

3-Monochloropropane-1,2-diol (3-MCPD) is regarded as a rat renal and testicular carcinogen and has been classified as a possible human carcinogen (group 2B) by International Agency for Research on Cancer. This is potentially of great importance given that esters of this compound have recently found to be generated in many foods and food ingredients as a result of food processing. There have been a few reports about their toxicity, although we have recently found that the toxicity profile of 3-MCPD esters was similar to that of 3-MCPD in a rat 13-week repeated dose study, except for the acute renal toxicity seen in 3-MCPD-treated females. In the present study, to examine in vivo genotoxicity we administered equimolar doses of 3-MCPD or 3-MCPD fatty acid esters (palmitate diester, palmitate monoester and oleate diester) to 6-week-old male F344 gpt delta rats carrying a reporter transgene for 4 weeks by intragastric administration. In vivo micronucleus, Pig-a mutation and gpt assays were performed, as well as investigations of major toxicological parameters including histopathological features. As one result, the relative kidney weights of the 3-MCPD and all three ester groups were significantly increased compared with the vehicle control group. However, the frequency of micronucleated reticulocytes and Pig-a mutant red blood cells did not differ among groups. Moreover, no changes were observed in mutant frequencies of gpt and red/gam (Spi(-)) genes in the kidney and the testis of 3-MCPD and 3-MCPD-fatty-acid-esters-treated rats. In histopathological analyses, no treatment related changes were observed, except for decrease of eosinophilic bodies in the kidneys of all treated groups. These results suggest that 3-MCPD and its fatty acid esters are not in vivo genotoxins, although they may exert renal toxicity. © The Author 2014. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e

Accumulation of [35S]taurine in peripheral layers of the olfactory bulb

International Nuclear Information System (INIS)

Quinn, M.R.; Wysocki, C.J.; Sturman, J.A.; Wen, G.Y.

1981-01-01

Accumulation of [ 35 S]taurine in the laminae of the olfactory bulb of the adult cat, rat, mouse and rabbit was examined autoradiographically. [ 35 S]Taurine was administered either i.p. or i.v. and olfactory bulbs were excised 24 h post-injection. High concentrations of [ 35 S]taurine were restricted to the olfactory nerve and glomerular layers of the olfactory bulb in all species examined. Olfactory neurons are continuously renewed and the results obtained suggest that taurine may have an important role in olfactory receptor axons. (Auth.)

Olfactory granule cell development in normal and hyperthyroid rats.

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Brunjes, P C; Schwark, H D; Greenough, W T

1982-10-01

Dendritic development was examined in olfactory bulbs of both normal 7-, 14-, 21- and 60-day-old rats and littermates treated on postnatal days 1-4 with 1 microgram/g body weight of L-thyroxine sodium. Tissue was processed via the Golgi-Cox technique and subjected to quantitative analyses of mitral and internal layer granule cell development. These populations of granule cells were selected because their pattern of late proliferation suggested potentially greater susceptibility to postnatal hormonal alterations. Although neonatal hyperthyroidism induces widespread acceleration of maturation, including precocious chemosensitivity, granule cell development was unaffected relative to littermate controls. Both normal and hyperthyroid groups exhibited an inverted U-shaped pattern of cellular development, with rapid dendritic dendritic growth and expansion occurring during the earliest ages tested, but with loss of processes and dendritic field size occurring after day 21.

Fischer 344 and Lewis rat strains as a model of genetic vulnerability to drug addiction

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Cristina eCadoni

2016-02-01

Full Text Available Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40-60 % of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis to differences in mesolimbic dopamine (DA transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neurons functionality.Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigations, results from the reviewed studies might open new vistas in

Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction.

Science.gov (United States)

Cadoni, Cristina

2016-01-01

Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40-60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant

Blocking muscarinic receptors in the olfactory bulb impairs performance on an olfactory short term memory task

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Sasha eDevore

2012-09-01

Full Text Available Cholinergic inputs to cortical processing networks have long been associated with attentional and top-down processing. Experimental and theoretical studies suggest that cholinergic inputs to the main olfactory bulb (OB can modulate both neural and behavioral odor discrimination. Previous experiments from our laboratory and others demonstrate that blockade of nicotinic receptors directly impairs olfactory discrimination, whereas blockade of muscarinic receptors only measurably impairs olfactory perception when task demands are made more challenging, such as when very low-concentration odors are used or rats are required to maintain sensory memory over long durations. To further investigate the role of muscarinic signaling in the OB, we developed an olfactory delayed match-to-sample task using a digging-based behavioral paradigm. We find that rats are able to maintain robust short-term odor memory for tens to hundreds of seconds. To investigate the role of muscarinic signaling in task performance, we bilaterally infused scopolamine into the OB. We find that high dosages of scopolamine (38 mM impair performance on the task across all delays tested, including the baseline condition with no delay, whereas lower dosages (7.6 mM and 22.8 mM had no measureable effects. These results indicate that general execution of the match-to-sample task, even with no delay, is at least partially dependent on muscarinic signaling in the OB.

Blocking muscarinic receptors in the olfactory bulb impairs performance on an olfactory short-term memory task.

Science.gov (United States)

Devore, Sasha; Manella, Laura C; Linster, Christiane

2012-01-01

Cholinergic inputs to cortical processing networks have long been associated with attentional and top-down processing. Experimental and theoretical studies suggest that cholinergic inputs to the main olfactory bulb (OB) can modulate both neural and behavioral odor discrimination. Previous experiments from our laboratory and others demonstrate that blockade of nicotinic receptors directly impairs olfactory discrimination, whereas blockade of muscarinic receptors only measurably impairs olfactory perception when task demands are made more challenging, such as when very low-concentration odors are used or rats are required to maintain sensory memory over long durations. To further investigate the role of muscarinic signaling in the OB, we developed an olfactory delayed match-to-sample task using a digging-based behavioral paradigm. We find that rats are able to maintain robust short-term odor memory for 10-100 s. To investigate the role of muscarinic signaling in task performance, we bilaterally infused scopolamine into the OB. We find that high dosages of scopolamine (38 mM) impair performance on the task across all delays tested, including the baseline condition with no delay, whereas lower dosages (7.6 mM and 22.8 mM) had no measureable effects. These results indicate that general execution of the match-to-sample task, even with no delay, is at least partially dependent on muscarinic signaling in the OB.

The effect of dietary administration of Disperse Blue 1 on the urinary system of the Fischer 344 rat.

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Burnett, C M; Squire, R A

1986-04-01

Disperse Blue 1 (containing 50% lignosulphonate dispersants) was fed to Fischer 344 rats at dietary levels of 0.01 and 0.1% for 19 months and at 1.0% for 6 months. Fischer 344 rats were also given the dye by gavage at 1 g/kg for 1-3 days or in the diet at 0.5 or 1% for 4 days, and corresponding dietary levels of the colouring without dispersant were also fed for 4 days. Bladders and kidneys were examined after the 1-4 day treatments, in animals dying or killed from month 6 to termination (19 months) in the chronic study and in those killed at wk 5, 9 and 17. At the latter three times, autoradiography following injection of tritiated thymidine showed increased DNA synthesis in the urothelium of high-dose rats, but no other increased labelling in any group. Bladder lesions were seen only at the 1.0% level, epithelial erosion with adhering dye particles being seen by day 4, calculi and hyperplasia by wk 5 and squamous metaplasia by wk 9. The calculi contained more dye in males than in females and more calcium in females. By month 6, dye particles were embedded in the bladder wall, with some evidence of histiocyte accumulation in their vicinity. Two papillomas and one carcinoma, but no leiomyosarcomas, were diagnosed. The earliest tumours, two papillomas, were detected at wk 17. Tumour incidence following surgical removal of calculus was about double that in rats not subjected to surgery and the incidence of normal bladders at month 19 was higher in the latter group. Compound-related effects in the kidneys--inflammation, pelvic epithelial hyperplasia and tubular degeneration and regeneration with interstitial fibrosis--were seen only in the high-dose group. Dye present in the tubules and renal pelvis persisted in many rats for a year after cessation of treatment.

Genomic expression analysis of rat chromosome 4 for skeletal traits at femoral neck

OpenAIRE

Alam, Imranul; Sun, Qiwei; Liu, Lixiang; Koller, Daniel L.; Liu, Yunlong; Edenberg, Howard J.; Econs, Michael J.; Foroud, Tatiana; Turner, Charles H.

2008-01-01

Hip fracture is the most devastating osteoporotic fracture type with significant morbidity and mortality. Several studies in humans and animal models identified chromosomal regions linked to hip size and bone mass. Previously, we identified that the region of 4q21-q41 on rat chromosome (Chr) 4 harbors multiple femoral neck quantitative trait loci (QTLs) in inbred Fischer 344 (F344) and Lewis (LEW) rats. The purpose of this study is to identify the candidate genes for femoral neck structure an...

Changes in the interstitial cells of Cajal and neuronal nitric oxide synthase positive neuronal cells with aging in the esophagus of F344 rats.

Science.gov (United States)

Kim, Hee Jin; Kim, Nayoung; Kim, Yong Sung; Nam, Ryoung Hee; Lee, Sun Min; Park, Ji Hyun; Choi, Daeun; Hwang, Young-Jae; Lee, Jongchan; Lee, Hye Seung; Kim, Min-Seob; Lee, Moon Young; Lee, Dong Ho

2017-01-01

The aging-associated cellular and molecular changes in esophagus have not been established, yet. Thus we evaluated histological structure, interstitial cells of Cajal (ICCs), neuronal nitric oxide synthase (nNOS)-positive cells, and contractility in the esophagus of Fischer 344 rat at different ages (6-, 31-, 74-weeks, and 2-years). The lamina propria thickness and endomysial area were calculated. The immunoreactivity of c-Kit, nNOS and protein gene product (PGP) 9.5 was counted after immunohistochemistry. Expression of c-Kit, stem cell factor (SCF), nNOS and PGP 9.5 mRNA was measured by real-time PCR, and expression of c-Kit and nNOS protein was detected by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS) were conducted. The lamina propria thickness increased (6 week vs 2 year, P = 0.005) and the endomysial area of longitudinal muscle decreased with aging (6 week vs 2 year, Pcells and c-Kit-immunoreactive areas declined with aging (6 week vs 2 year; Paging (6 week vs 2 year; P = 0.006, P = 0.001 and P = 0.006, respectively), while the change of PGP 9.5 mRNA expression was not significant. Western blot showed the significant decreases of nNOS and c-Kit protein expression with aging (6 week vs 2 year; P = 0.008 and P = 0.012, respectively). The EFS-induced esophageal contractions significantly decreased in 2-yr-old rat compared with 6-wk-old rats, however, L-NG-Nitroarginine methylester did not significantly increase the spontaneous and EFS-induced contractions in the 6-wk- and 2-yr-old rat esophagus. In conclusion, an increase of lamina propria thickness, a decrease of endomysial area, c-Kit, SCF and NOS expression with preserved total enteric neurons, and contractility in aged rat esophagus may explain the aging-associated esophageal dysmotility.

Subacute effects of inhaled Jet Fuel-A (Jet A) on airway and immune function in female rats.

Science.gov (United States)

Sweeney, Lisa M; Prues, Susan L; Reboulet, James E

2013-04-01

Two studies were conducted to assess the potential airway and immune effects following subacute (14 d) exposure of female rats to 500, 1000 or 2000 mg/m³ of Jet-A for 4 h/d. The first study used Sprague-Dawley rats; the second study included both Fischer 344 (F344) and Sprague-Dawley rats. In the first study, exposure to 2000 mg/m³ jet fuel may have caused significant upper airway inflammation on day 7 post-exposure, as indicated by elevated protein and lactate dehydrogenase in nasal lavage fluid, but any inflammation resolved by day 14 post-exposure. No significant impact on immune cell populations in the spleens was observed. The histological examination showed no evidence of infectious or toxic effect. In the second study, body weights of the F344 rats in the 2000 mg/m³ group were depressed, as compared to the controls, at the end of the exposure. Some lung lavage fluid markers were increased at 24 h after the final exposure, however, no test article-induced histological changes were observed in the lungs, nasal cavities, or any other tissue of any of the jet fuel exposed animals. Overall, these studies demonstrated limited evidence of effects of 14 d of exposure to Jet A on the airways, immune system, or any other organ or system of female Sprague-Dawley and F344 rats, with no remarkable differences between strains. The lack of identified significant airway or immune effects was in contrast to previous examinations of jet fuel for pulmonary toxicity in mice and rats and for immunotoxicity in mice.

Neurogenesis in the olfactory bulb induced by paced mating in the female rat is opioid dependent.

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Marianela Santoyo-Zedillo

Full Text Available The possibility to control the rate of sexual stimulation that the female rat receives during a mating encounter (pacing increases the number of newborn neurons that reach the granular layer of the accessory olfactory bulb (AOB. If females mate repeatedly, the increase in the number of neurons is observed in other regions of the AOB and in the main olfactory bulb (MOB. It has also been shown that paced mating induces a reward state mediated by opioids. There is also evidence that opioids modulate neurogenesis. In the present study, we evaluated whether the opioid receptor antagonist naloxone (NX could reduce the increase in neurogenesis in the AOB induced by paced mating. Ovariectomized female rats were randomly divided in 5 different groups: 1 Control (not mated treated with saline, 2 control (not mated treated with naloxone, 3 females that mated without controlling the sexual interaction (no-pacing, 4 females injected with saline before pacing the sexual interaction and 5 females injected with NX before a paced mating session. We found, as previously described, that paced mating induced a higher number of new cells in the granular layer of the AOB. The administration of NX before paced mating, blocked the increase in the number of newborn cells and prevented these cells from differentiating into neurons. These data suggest that opioid peptides play a fundamental role in the neurogenesis induced by paced mating in female rats.

Olfactory Bulb [alpha][subscript 2]-Adrenoceptor Activation Promotes Rat Pup Odor-Preference Learning via a cAMP-Independent Mechanism

Science.gov (United States)

Shakhawat, Amin MD.; Harley, Carolyn W.; Yuan, Qi

2012-01-01

In this study, three lines of evidence suggest a role for [alpha][subscript 2]-adrenoreceptors in rat pup odor-preference learning: olfactory bulb infusions of the [alpha][subscript 2]-antagonist, yohimbine, prevents learning; the [alpha][subscript 2]-agonist, clonidine, paired with odor, induces learning; and subthreshold clonidine paired with…

Functional evidence of multidrug resistance transporters (MDR in rodent olfactory epithelium.

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Adrien Molinas

Full Text Available P-glycoprotein (Pgp and multidrug resistance-associated protein (MRP1 are membrane transporter proteins which function as efflux pumps at cell membranes and are considered to exert a protective function against the entry of xenobiotics. While evidence for Pgp and MRP transporter activity is reported for olfactory tissue, their possible interaction and participation in the olfactory response has not been investigated.Functional activity of putative MDR transporters was assessed by means of the fluorometric calcein acetoxymethyl ester (calcein-AM accumulation assay on acute rat and mouse olfactory tissue slices. Calcein-AM uptake was measured as fluorescence intensity changes in the presence of Pgp or MRP specific inhibitors. Epifluorescence microscopy measured time course analysis in the olfactory epithelium revealed significant inhibitor-dependent calcein uptake in the presence of each of the selected inhibitors. Furthermore, intracellular calcein accumulation in olfactory receptor neurons was also significantly increased in the presence of either one of the Pgp or MRP inhibitors. The presence of Pgp or MRP1 encoding genes in the olfactory mucosa of rat and mouse was confirmed by RT-PCR with appropriate pairs of species-specific primers. Both transporters were expressed in both newborn and adult olfactory mucosa of both species. To assess a possible involvement of MDR transporters in the olfactory response, we examined the electrophysiological response to odorants in the presence of the selected MDR inhibitors by recording electroolfactograms (EOG. In both animal species, MRPs inhibitors induced a marked reduction of the EOG magnitude, while Pgp inhibitors had only a minor or no measurable effect.The findings suggest that both Pgp and MRP transporters are functional in the olfactory mucosa and in olfactory receptor neurons. Pgp and MRPs may be cellular constituents of olfactory receptor neurons and represent potential mechanisms for modulation

Olfactory dreams, olfactory interest, and imagery : Relationships to olfactory memory

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Arshamian, Artin

2007-01-01

Existing evidence for olfactory imagery is mixed and mainly based on reports from hallucinations and volitional imagery. Using a questionnaire, Stevenson and Case (2005) showed that olfactory dreams provided a good source for olfactory imagery studies. This study applied an extended version of the same questionnaire and examined olfactory dreams and their relation to real-life experienced odors, volitional imagery, and olfactory interest. Results showed that olfactory dreams were similar to r...

Two months make a difference in spatial orientation learning in very old hybrid Fischer 344 X Brown Norway (FBNF1) rats

NARCIS (Netherlands)

Staay, van der F.J.

2006-01-01

Age-related changes in cognitive performance may be more pronounced in the period near or exceeding the median life span. Therefore, we compared the acquisition of a Morris water escape task by two groups of very old Fischer344 × Brown Norway hybrid rats. The mean age difference between the two

What a Nostril Knows: Olfactory Nerve-Evoked AMPA Responses Increase while NMDA Responses Decrease at 24-h Post-Training for Lateralized Odor Preference Memory in Neonate Rat

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Yuan, Qi; Harley, Carolyn W.

2012-01-01

Increased AMPA signaling is proposed to mediate long-term memory. Rat neonates acquire odor preferences in a single olfactory bulb if one nostril is occluded at training. Memory testing here confirmed that only trained bulbs support increased odor preference at 24 h. Olfactory nerve field potentials were tested at 24 h in slices from trained and…

Early neurovascular dysfunction in a transgenic rat model of Alzheimer's disease.

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Joo, Illsung L; Lai, Aaron Y; Bazzigaluppi, Paolo; Koletar, Margaret M; Dorr, Adrienne; Brown, Mary E; Thomason, Lynsie A M; Sled, John G; McLaurin, JoAnne; Stefanovic, Bojana

2017-04-12

Alzheimer's disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans.

Women with a history of childhood maltreatment exhibit more activation in association areas following non-traumatic olfactory stimuli: a fMRI study.

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Ilona Croy

2010-02-01

Full Text Available The aim of this study was investigating how women with a history of childhood maltreatment (CM process non-threatening and non-trauma related olfactory stimuli. The focus on olfactory perception is based on the overlap of brain areas often proposed to be affected in CM patients and the projection areas of the olfactory system, including the amygdala, orbitofrontal cortex, insula and hippocampus.Twelve women with CM and 10 controls participated in the study. All participants were, or have been, patients in a psychosomatic clinic. Participants underwent a fMRI investigation during olfactory stimulation with a neutral (coffee and a pleasant (peach odor. Furthermore, odor threshold and odor identification (Sniffin' Sticks were tested.Both groups showed normal activation in the olfactory projection areas. However, in the CM-group we found additionally enhanced activation in multiple, mainly neocortical, areas that are part of those involved in associative networks. These include the precentral frontal lobe, inferior and middle frontal structures, posterior parietal lobe, occipital lobe, and the posterior cingulate cortex.The results indicate that in this group of patients, CM was associated with an altered processing of olfactory stimuli, but not development of a functional olfactory deficit. This complements other studies on CM insofar as we found the observed pattern of enhanced activation in associative and emotional regions even following non-traumatic olfactory cues.

Strain differences of cadmium-induced hepatotoxicity in Wistar-Imamichi and Fischer 344 rats: involvement of cadmium accumulation

International Nuclear Information System (INIS)

Shimada, Hideaki; Takamure, Yasutaka; Shimada, Akinori; Yasutake, Akira; Waalkes, Michael P.; Imamura, Yorishige

2004-01-01

We previously reported that Wistar-Imamichi (WI) rats have a strong resistance to cadmium (Cd)-induced lethality compared to other strains such as Fischer 344 (Fischer) rats. The present study was designed to establish biochemical and histological differences in Cd toxicity in WI and Fischer rats, and to clarify the mechanistic basis of these strain differences. A single Cd (4.5 mg/kg, s.c.) treatment caused a significant increase in serum alanine aminotransferase activity, indicative of hepatotoxicity, in Fischer rats, but did not in WI rats. This difference in hepatotoxic response to Cd was supported by pathological analysis. After treatment with Cd at doses of 3.0, 3.5 and 4.5 mg/kg, the hepatic and renal accumulation of Cd was significantly lower in the WI rats than in the Fischer rats, indicating a kinetic mechanism for the observed strain differences in Cd toxicity. Thus, the remarkable resistance to Cd-induced hepatotoxicity in WI rats is associated, at least in part, with a lower tissue accumulation of the metal. Hepatic and renal zinc (Zn) contents after administration were similarly lower in WI than in Fischer rats. When Zn was administered in combination with Cd to Fischer rats, it decreased Cd contents in the liver and kidney, and exhibited a significant protective effect against the toxicity of Cd. We propose the possibility that Zn transporter plays an important role in the strain difference of Cd toxicity in WI and Fischer rats

Early neurovascular dysfunction in a transgenic rat model of Alzheimer’s disease

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Joo, Illsung L.; Lai, Aaron Y.; Bazzigaluppi, Paolo; Koletar, Margaret M.; Dorr, Adrienne; Brown, Mary E.; Thomason, Lynsie A. M.; Sled, John G.; McLaurin, JoAnne; Stefanovic, Bojana

2017-01-01

Alzheimer’s disease (AD), pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration, is thought to involve early-onset neurovascular abnormalities. Hitherto studies on AD-associated neurovascular injury have used animal models that exhibit only a subset of AD-like pathologies and demonstrated some Aβ-dependent vascular dysfunction and destabilization of neuronal network. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broader repertoire of AD-like pathologies to investigate the cerebrovascular and neuronal network functioning using in situ two-photon fluorescence microscopy and laminar array recordings of local field potentials, followed by pathological analyses of vascular wall morphology, tau hyperphosphorylation, and amyloid plaques. Concomitant to widespread amyloid deposition and tau hyperphosphorylation, cerebrovascular reactivity was strongly attenuated in cortical penetrating arterioles and venules of TgF344-AD rats in comparison to those in non-transgenic littermates. Blood flow elevation to hypercapnia was abolished in TgF344-AD rats. Concomitantly, the phase-amplitude coupling of the neuronal network was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude. These results demonstrate significant neurovascular network dysfunction at an early stage of AD-like pathology. Our study identifies early markers of pathology progression and call for development of combinatorial treatment plans. PMID:28401931

Effects of dose, species, and dosing vehicle on the disposition of methacrylonitrile (MAN) in male rats

International Nuclear Information System (INIS)

Sanchez, I.M.; Ghanayem, B.I.

1991-01-01

MAN is structurally similar to known carcinogen acrylontrile (AN), with nitriles having similar industrial uses. Current studies were designed to investigate the biological fate of 2- 14 C-MAN in rats. After gavage administration of 115, 11.5 or 1.15 mg MAN/kg in water, F344 male rats were placed in glass metabolism cages and urine, expired air and feces were collected. Rats were sacrificed at various times and concentration of MAN-derived radioactivity in tissues was determined. MAN was rapidly absorbed from the GI tract and distributed to all major tissues. Sixty-70% of the low and medium doses were exhaled as 14 CO 2 in 72 hr compared to 25% of the highest dose. While 40% of the highest dose was expired as organic volatiles in 72 hr, only 9-12% of the low and accounted for 20-30% of all doses within 72 hr after dosing. Comparison of MAN disposition in Sprague-Dawley (SD) and F344 rats at 115 mg/kg revealed that SD rats excreted a greater % of the dose as 14 CO 2 and in the urine than did F344 rats. Administration of 115 mg MAN/kg to SD male rats in safflower oil resulted in increased elimination of MAN-derived radioactivity as CO 2 , volatiles, and in the urine over that observed when administered in water. These results suggest that: (1) saturation of MAN metabolism occurs at high doses: (2) MAN metabolism and disposition differ with the strain of rats studied; (3) MAN disposition may vary with the dosing vehicle used; and (4) MAN metabolism and disposition is apparently different from that reported on AN

NTP Toxicology and Carcinogenesis Studies of Barium Chloride Dihydrate (CAS No. 10326-27-9) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).

Science.gov (United States)

1994-01-01

Barium chloride dihydrate, a white crystalline granule or powder, is used in pigments, aluminum refining, leather tanning and coloring, the manufacture of magnesium metal, ceramics, glass, and paper products, as a pesticide, and in medicine as a cardiac stimulant. Toxicology and carcinogenicity studies were conducted by administering barium chloride dihydrate (99% pure) in drinking water to F344/N rats and B6C3F1 mice for 15 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse lymphoma cells. 15-DAY STUDY IN RATS: Groups of five males and five females received barium chloride dihydrate in the drinking water at concentrations of 0, 125, 250, 500, 1,000, or 2,000 ppm for 15 days, corresponding to average daily doses of 10, 15, 35, 60, or 110 mg barium/kg body weight to males and females. No chemical-related deaths, differences in final mean body weights, or clinical findings of toxicity were observed. Water consumption by male and female rats exposed to 2,000 ppm was slightly less (S16%) than controls during week 2. There were no significant differences in absolute or relative organ weights between exposed and control rats. No biologically significant differences in hematology, clinical chemistry, or neurobehavioral parameters occurred in rats. 15-DAY STUDY IN MICE: Groups of five males and five females received barium chloride dihydrate in the drinking water at concentrations of 0, 40, 80,173, 346, or 692 ppm for 15 days, corresponding to average daily doses of 5,10, 20, 40, or 70 mg barium/kg body weight to males and 5, 10, 15, 40, or 85 mg barium/kg body weight to females. No chemical-related deaths, differences in mean body weights or in water consumption, or clinical findings of toxicity were observed in mice. The relative liver weight of males receiving 692 ppm was significantly greater than that of the controls. The absolute and relative liver weights of females that

Processing of Intraoral Olfactory and Gustatory Signals in the Gustatory Cortex of Awake Rats.

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Samuelsen, Chad L; Fontanini, Alfredo

2017-01-11

The integration of gustatory and olfactory information is essential to the perception of flavor. Human neuroimaging experiments have pointed to the gustatory cortex (GC) as one of the areas involved in mediating flavor perception. Although GC's involvement in encoding the chemical identity and hedonic value of taste stimuli is well studied, it is unknown how single GC neurons process olfactory stimuli emanating from the mouth. In this study, we relied on multielectrode recordings to investigate how single GC neurons respond to intraorally delivered tastants and tasteless odorants dissolved in water and whether/how these two modalities converge in the same neurons. We found that GC neurons could either be unimodal, responding exclusively to taste (taste-only) or odor (odor-only), or bimodal, responding to both gustatory and olfactory stimuli. Odor responses were confirmed to result from retronasal olfaction: monitoring respiration revealed that exhalation preceded odor-evoked activity and reversible inactivation of olfactory receptors in the nasal epithelium significantly reduced responses to intraoral odorants but not to tastants. Analysis of bimodal neurons revealed that they encode palatability significantly better than the unimodal taste-only group. Bimodal neurons exhibited similar responses to palatable tastants and odorants dissolved in water. This result suggested that odorized water could be palatable. This interpretation was further supported with a brief access task, where rats avoided consuming aversive taste stimuli and consumed the palatable tastants and dissolved odorants. These results demonstrate the convergence of the chemosensory components of flavor onto single GC neurons and provide evidence for the integration of flavor with palatability coding. Food perception and choice depend upon the concurrent processing of olfactory and gustatory signals from the mouth. The primary gustatory cortex has been proposed to integrate chemosensory stimuli

Chronic intermittent hypoxia impairs heart rate responses to AMPA and NMDA and induces loss of glutamate receptor neurons in nucleus ambiguous of F344 rats.

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Yan, Binbin; Li, Lihua; Harden, Scott W; Gozal, David; Lin, Ying; Wead, William B; Wurster, Robert D; Cheng, Zixi Jack

2009-02-01

Chronic intermittent hypoxia (CIH), as occurs in sleep apnea, impairs baroreflex-mediated reductions in heart rate (HR) and enhances HR responses to electrical stimulation of vagal efferent. We tested the hypotheses that HR responses to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the nucleus ambiguous (NA) are reduced in CIH-exposed rats and that this impairment is associated with degeneration of glutamate receptor (GluR)-immunoreactive NA neurons. Fischer 344 rats (3-4 mo) were exposed to room air (RA) or CIH for 35-50 days (n = 18/group). At the end of the exposures, AMPA (4 pmol, 20 nl) and NMDA (80 pmol, 20 nl) were microinjected into the same location of the left NA (-200 microm to +200 microm relative to caudal end of area postrema; n = 6/group), and HR and arterial blood pressure responses were measured. In addition, brain stem sections at the level of -800, -400, 0, +400, and +800 microm relative to obex were processed for AMPA and NMDA receptor immunohistochemistry. The number of NA neurons expressing AMPA receptors and NMDA receptors (NMDARs) was quantified. Compared with RA, we found that after CIH 1) HR responses to microinjection of AMPA into the left NA were reduced (RA -290 +/- 30 vs. CIH -227 +/- 15 beats/min, P neurons expressing GluRs contributes to impaired baroreflex control of HR in rats exposed to CIH.

Regulation of spike timing-dependent plasticity of olfactory inputs in mitral cells in the rat olfactory bulb.

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Teng-Fei Ma

Full Text Available The recent history of activity input onto granule cells (GCs in the main olfactory bulb can affect the strength of lateral inhibition, which functions to generate contrast enhancement. However, at the plasticity level, it is unknown whether and how the prior modification of lateral inhibition modulates the subsequent induction of long-lasting changes of the excitatory olfactory nerve (ON inputs to mitral cells (MCs. Here we found that the repetitive stimulation of two distinct excitatory inputs to the GCs induced a persistent modification of lateral inhibition in MCs in opposing directions. This bidirectional modification of inhibitory inputs differentially regulated the subsequent synaptic plasticity of the excitatory ON inputs to the MCs, which was induced by the repetitive pairing of excitatory postsynaptic potentials (EPSPs with postsynaptic bursts. The regulation of spike timing-dependent plasticity (STDP was achieved by the regulation of the inter-spike-interval (ISI of the postsynaptic bursts. This novel form of inhibition-dependent regulation of plasticity may contribute to the encoding or processing of olfactory information in the olfactory bulb.

Genetic maps of polymorphic DNA loci on rat chromosome 1

Energy Technology Data Exchange (ETDEWEB)

Ding, Yan-Ping; Remmers, E.F.; Longman, R.E. [National Institutes of Health, Bethesda, MD (United States)] [and others

1996-09-01

Genetic linkage maps of loci defined by polymorphic DNA markers on rat chromosome 1 were constructed by genotyping F2 progeny of F344/N x LEW/N, BN/SsN x LEW/N, and DA/Bkl x F344/Hsd inbred rat strains. In total, 43 markers were mapped, of which 3 were restriction fragment length polymorphisms and the others were simple sequence length polymorphisms. Nineteen of these markers were associated with genes. Six markers for five genes, {gamma}-aminobutyric acid receptor {beta}3 (Gabrb3), syntaxin 2 (Stx2), adrenergic receptor {beta}3 (Gabrb3), syntaxin 2 (Stx2), adrenergic receptor {beta}1 (Adrb1), carcinoembryonic antigen gene family member 1 (Cgm1), and lipogenic protein S14 (Lpgp), and 20 anonymous loci were not previously reported. Thirteen gene loci (Myl2, Aldoa, Tnt, Igf2, Prkcg, Cgm4, Calm3, Cgm3, Psbp1, Sa, Hbb, Ins1, and Tcp1) were previously mapped. Comparative mapping analysis indicated that the large portion of rat chromosome 1 is homologous to mouse chromosome 7, although the homologous to mouse chromosome 7, although the homologs of two rat genes are located on mouse chromosomes 17 and 19. Homologs of the rat chromosome 1 genes that we mapped are located on human chromosomes 6, 10, 11, 12, 15, 16, and 19. 38 refs., 1 fig., 3 tabs.

NORMAL GENE EXPRESSION IN MALE F344 RAT NASAL TRANSITIONAL/RESPIRATORY EPITHELIUM

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Abstract The nasal epithelium is an important target site for chemically-induced toxicity and carcinogenicity in rodents. Gene expression profiles were determined in order to provide normal baseline data for nasal transitional/respiratory epithelium from healthy rats. Ce...

Vehicle-Dependent Disposition Kinetics of Fluoranthene in Fisher-344 Rats

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Aramandla Ramesh

2008-03-01

Full Text Available The objective of this study was to evaluate how the vehicles of choice affect the pharmacokinetics of orally administered Fluoranthene [FLA] in rats. Fluoranthene is a member of the family of polycyclic aromatic hydrocarbon chemicals. Fluoranthene exposure to humans may occur as a result of cigarette smoking, consumption of contaminated food and water, heating woods in stoves and boilers, industrial sources such as coal gasification, carbon and graphite electrode manufacturing. Adult male Fisher-344 rats were given single oral doses of 25 and 50 μg/kg FLA in tricaprylin, peanut oil, cod liver oil, tween 80/isotonic saline (1:5 and 2% Alkamuls-EL620 through gavage. After administration, the rats were housed individually in metabolic cages and sacrificed at 2, 4, 6, 8, 10 and 12 hours post FLA exposure. Blood, lung, liver, small intestine, adipose tissue samples, urine, and feces were collected at each time point. Samples were subjected to a liquid-liquid extraction using methanol, chloroform, and water. The extracts were analyzed by a reverse-phase HPLC, equipped with a fluorescence detector. The results revealed a dose-dependent increase in FLA concentrations in plasma and tissues for all the vehicles used. Plasma and tissue FLA concentrations were greater for peanut oil; cod liver oil, and tricaprylin vehicles compared to Alkamuls (p peanut oil > tricaprylin > alkamuls > tween 80/isotonic saline (1:5]. These findings suggest that uptake and elimination of FLA is accelerated when administered through oil-based vehicles. The low uptake of FLA from alkamuls and tween 80/isotonic saline may have been a result of the poor solubility of the chemical. In summary, our findings reiterate that absorption characteristics of FLA were governed by the dose as well as the dosing vehicle. The vehicle-dependent bioavailability of FLA suggests a need for the judicious selection of vehicles in evaluating oral toxicity studies for risk assessment purposes.

Exercise is More Effective at Altering Gut Microbial Composition and Producing Stable Changes in Lean Mass in Juvenile versus Adult Male F344 Rats.

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Agnieszka Mika

Full Text Available The mammalian intestine harbors a complex microbial ecosystem that influences many aspects of host physiology. Exposure to specific microbes early in development affects host metabolism, immune function, and behavior across the lifespan. Just as the physiology of the developing organism undergoes a period of plasticity, the developing microbial ecosystem is characterized by instability and may also be more sensitive to change. Early life thus presents a window of opportunity for manipulations that produce adaptive changes in microbial composition. Recent insights have revealed that increasing physical activity can increase the abundance of beneficial microbial species. We therefore investigated whether six weeks of wheel running initiated in the juvenile period (postnatal day 24 would produce more robust and stable changes in microbial communities versus exercise initiated in adulthood (postnatal day 70 in male F344 rats. 16S rRNA gene sequencing was used to characterize the microbial composition of juvenile versus adult runners and their sedentary counterparts across multiple time points during exercise and following exercise cessation. Alpha diversity measures revealed that the microbial communities of young runners were less even and diverse, a community structure that reflects volatility and malleability. Juvenile onset exercise altered several phyla and, notably, increased Bacteroidetes and decreased Firmicutes, a configuration associated with leanness. At the genus level of taxonomy, exercise altered more genera in juveniles than in the adults and produced patterns associated with adaptive metabolic consequences. Given the potential of these changes to contribute to a lean phenotype, we examined body composition in juvenile versus adult runners. Interestingly, exercise produced persistent increases in lean body mass in juvenile but not adult runners. Taken together, these results indicate that the impact of exercise on gut microbiota

Metabolism of 14C-tris(2-chloroethyl) phosphate (TRCP) in rats and mice

International Nuclear Information System (INIS)

Sanders, J.M.; Herr, D.W.; Burka, L.T.; Matthews, H.B.

1990-01-01

TRCP, a flame retardant, has been demonstrated to produce a dose-, sex-, and species-dependent lesion in the hippocampal region of the brain, following subchronic oral administration. This lesion is more common and more severe in female F344 rats than in male F344 rats, and is not observed in B6C3F1 mice. The present investigation of the metabolism of TRCP was designed to detect sex and species variations that might account for differences in toxicity. Elimination of TRCP-derived radioactivity was more rapid in mice, which excreted >70% of an oral dose of 175 mg/kg in urine in 8 hr vs ∼40% for male or female rats. However, the metabolic profile of TRCP-derived radioactivity in urine was similar for both species. The major metabolite in urine of rats and mice was identified as bis(2-chloroethyl) carboxymethyl phosphate. Two additional metabolites common to both species were bis(2-chloroethyl) hydrogen phosphate and the glucuronide of bis(2-chloroethyl) 2-hydroxyethyl phosphate. The major sex-related variation consisted of up to 2-fold higher levels of TRCP present in plasma of female rats (vs male rats) 5-30 min following an oral dose of 175 mg/kg. TRCP metabolism in rats was not induced or inhibited by 9 daily 175 mg/kg doses. Toxicity, as evidenced by seizures, was potentiated in male rats pretreated with inhibitors of aldehyde dehydrogenase

Assessment of Olfactory Memory in Olfactory Dysfunction.

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Kollndorfer, Kathrin; Reichert, Johanna; Braunsteiner, Josephine; Schöpf, Veronika

2017-01-01

To assess all clinically relevant components of olfactory perception, examinations for olfactory sensitivity, discrimination, and identification are performed. Besides the standard perceptual test battery, episodic olfactory memory might offer additional information about olfactory abilities relative to these standard clinical tests. As both olfactory deficits and memory deficits are early symptoms in neurodegenerative disorders, olfactory memory may be of particular interest. However, to date little is known about episodic olfactory memory performance in patients with decreased olfactory function. This study includes the investigation of olfactory memory performance in 14 hyposmic patients (8 female, mean age 52.6 years) completing two episodic odor memory tests (Sniffin' Test of Odor Memory and Odor Memory Test). To control for a general impairment in memory function, a verbal and a figural memory test were carried out. A regression model with multiple predictors was calculated for both odor memory tests separately. Odor identification was identified as the only significant predictor for both odor memory tasks. From our results, we conclude that currently available olfactory memory tests are highly influenced by odor identification abilities, implying the need for the development and validation of additional tests in this field which could serve as additional olfactory perception variables for clinical assessment.

A STUDY OF FISCHER 344 RATS EXPOSED TO SILICA DUST FOR SIX MONTHS AT CONCENTRATIONS OF 0, 2, 10 OR 20 MG / M3.

Energy Technology Data Exchange (ETDEWEB)

KUTZMAN,R.S.

1984-02-01

The major objective of this study was to relate the results of a series of functional tests to the compositional and structural alterations in the rat lung induced by subchronic exposure to silica dust. Fischer-344 rats were exposed for 6 hours/day, 5 days/week for 6 months to either 0, 2, 10, or 20 mg SiO{sub 2}/m{sup 3}. The general appearance of the exposed rats was not different from that of the controls. Interestingly, female rats exposed to silica dust, at all tested concentrations, gained more weight than the controls. The lung weight and the lung-to-body weight ratio was greater in the male rats exposed to the highest concentration of silica dust.

Diethylene glycol-induced toxicities show marked threshold dose response in rats

Energy Technology Data Exchange (ETDEWEB)

Landry, Greg M., E-mail: Landry.Greg@mayo.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Dunning, Cody L., E-mail: cdunni@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu [Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Latimer, Brian, E-mail: blatim@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Orchard, Elysse, E-mail: eorcha@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States); Division of Animal Resources, Louisiana State University Health Sciences Center, Shreveport, LA (United States); McMartin, Kenneth E., E-mail: kmcmar@lsuhsc.edu [Department of Pharmacology, Toxicology, & Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA (United States)

2015-02-01

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.

Respiratory tract toxicity in rats exposed to Mexico City air.

Science.gov (United States)

Moss, O R; Gross, E A; James, R A; Janszen, D B; Ross, P W; Roberts, K C; Howard, A M; Harkema, J R; Calderón-Garcidueñas, L; Morgan, K T

2001-03-01

The rat has been used extensively as a health sentinel, indicator, or monitor of environmental health hazards, but this model has not been directly validated against human exposures. Humans in Mexico City show upper respiratory tract lesions and evidence of pulmonary damage related to their environmental inhalation exposure. In this study, male and female F344 rats were exposed (23 hr/day) in Mexico City to local Mexico City air (MCA)* for up to seven weeks. Controls were maintained at the same location under filtered air. Prior to these exposures, several steps were taken. First, the nasal passages of normal male rats shipped from the United States and housed in Mexico City were examined for mycoplasma infection; no evidence of infection was found. In addition, a mobile exposure and monitoring system was assembled and, with an ozone (O3) exposure atmosphere, was tested along with supporting histopathology techniques and analysis of rat nasal and lung tissues. Last, the entire exposure model (equipment and animals) was transported to Mexico City and validated for a three-week period. During the seven-week study there were 18 one-hour intervals during which the average O3 concentration of MCA in the exposure chamber exceeded the US National Ambient Air Quality Standard (NAAQS) of 0.120 ppm 03 (hourly average, not to be exceeded more than once per year). This prolonged exposure of healthy F344 rats to MCA containing episodically low to moderate concentrations of 03 (as well as other urban air pollutants) did not induce inflammatory or epithelial lesions in the nasal airways or lung as measured by qualitative histologic techniques or quantitative morphometric techniques. These findings agree with those of previous controlled O3 inhalation studies, but they are in contrast to reports indicating that O3-polluted MCA causes significant nasal mucosal injury in adults and children living in southwestern Mexico City. Taken together, these findings may suggest that human

Changes in the interstitial cells of Cajal and neuronal nitric oxide synthase positive neuronal cells with aging in the esophagus of F344 rats.

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Hee Jin Kim

Full Text Available The aging-associated cellular and molecular changes in esophagus have not been established, yet. Thus we evaluated histological structure, interstitial cells of Cajal (ICCs, neuronal nitric oxide synthase (nNOS-positive cells, and contractility in the esophagus of Fischer 344 rat at different ages (6-, 31-, 74-weeks, and 2-years. The lamina propria thickness and endomysial area were calculated. The immunoreactivity of c-Kit, nNOS and protein gene product (PGP 9.5 was counted after immunohistochemistry. Expression of c-Kit, stem cell factor (SCF, nNOS and PGP 9.5 mRNA was measured by real-time PCR, and expression of c-Kit and nNOS protein was detected by Western blot. Isovolumetric contractile force measurement and electrical field stimulation (EFS were conducted. The lamina propria thickness increased (6 week vs 2 year, P = 0.005 and the endomysial area of longitudinal muscle decreased with aging (6 week vs 2 year, P<0.001, while endomysial area of circular muscle did not significantly decrease. The proportions of NOS-immunoreactive cells and c-Kit-immunoreactive areas declined with aging (6 week vs 2 year; P<0.001 and P = 0.004, respectively, but there was no significant change of PGP 9.5-immunopositiviy. The expressions of nNOS, c-Kit and SCF mRNA also reduced with aging (6 week vs 2 year; P = 0.006, P = 0.001 and P = 0.006, respectively, while the change of PGP 9.5 mRNA expression was not significant. Western blot showed the significant decreases of nNOS and c-Kit protein expression with aging (6 week vs 2 year; P = 0.008 and P = 0.012, respectively. The EFS-induced esophageal contractions significantly decreased in 2-yr-old rat compared with 6-wk-old rats, however, L-NG-Nitroarginine methylester did not significantly increase the spontaneous and EFS-induced contractions in the 6-wk- and 2-yr-old rat esophagus. In conclusion, an increase of lamina propria thickness, a decrease of endomysial area, c-Kit, SCF and NOS expression with preserved

Sperm mRNA transcripts are indicators of sub-chronic low dose testicular injury in the Fischer 344 rat.

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Sara E Pacheco

Full Text Available Current human reproductive risk assessment methods rely on semen and serum hormone analyses, which are not easily comparable to the histopathological endpoints and mating studies used in animal testing. Because of these limitations, there is a need to develop universal evaluations that reliably reflect male reproductive function. We hypothesized that toxicant-induced testicular injury can be detected in sperm using mRNA transcripts as indicators of insult. To test this, we exposed adult male Fischer 344 rats to low doses of model testicular toxicants and classically characterized the testicular injury while simultaneously evaluating sperm mRNA transcripts from the same animals. Overall, this study aimed to: 1 identify sperm transcripts altered after exposure to the model testicular toxicant, 2,5-hexanedione (HD using microarrays; 2 expand on the HD-induced transcript changes in a comprehensive time course experiment using qRT-PCR arrays; and 3 test these injury indicators after exposure to another model testicular toxicant, carbendazim (CBZ. Microarray analysis of HD-treated adult Fischer 344 rats identified 128 altered sperm mRNA transcripts when compared to control using linear models of microarray analysis (q<0.05. All transcript alterations disappeared after 3 months of post-exposure recovery. In the time course experiment, time-dependent alterations were observed for 12 candidate transcripts selected from the microarray data based upon fold change and biological relevance, and 8 of these transcripts remained significantly altered after the 3-month recovery period (p<0.05. In the last experiment, 8 candidate transcripts changed after exposure to CBZ (p<0.05. The two testicular toxicants produced distinct molecular signatures with only 4 overlapping transcripts between them, each occurring in opposite directions. Overall, these results suggest that sperm mRNA transcripts are indicators of low dose toxicant-induced testicular injury in the rat.

Calcium Signaling in Mitral Cell Dendrites of Olfactory Bulbs of Neonatal Rats and Mice during Olfactory Nerve Stimulation and Beta-Adrenoceptor Activation

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Yuan, Qi; Mutoh, Hiroki; Debarbieux, Franck; Knopfel, Thomas

2004-01-01

Synapses formed by the olfactory nerve (ON) provide the source of excitatory synaptic input onto mitral cells (MC) in the olfactory bulb. These synapses, which relay odor-specific inputs, are confined to the distally tufted single primary dendrites of MCs, the first stage of central olfactory processing. Beta-adrenergic modulation of electrical…

Structure of Masera's Septal Olfactory Organ in Cat (Felis silvestris f. catus - Light Microscopy in Selected Stages of Ontogeny

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I. Kociánová

2006-01-01

Full Text Available The septal organ /SO/ (Masera's organ /MO/ is a chemoreceptor presently considered one of three types of olfactory organs (along with the principal olfactory region and vomeronasal organ. Notwithstanding the septal organ having been first described by Rodolfo Masera in 1943, little is known of the properties of sensory neurons or of its functional significance in chemoreception. Until now the septal organ has been described only in laboratory rodents and some marsupials. This work refers to its existence in the domestic cat (Felis silvestris f. catus. The septal organ can be identified at the end of embryonic period - 27 or 28 days of ontogenesis in cats (the 6th developmental stage of Štěrba - coincident with formation of the principal olfactory region in nasal cavity. At 45 days of ontogenesis (the 9th developmental stage of Štěrba, this septal olfactory organ is of circular or oval shape, 120 μm in diameter, in ventral part of septum nasi, lying caudally to the opening of ductus incisivus. The structure of the epithelium of septal olfactory organ is clearly distinct from the respiratory epithelium of the nasal cavity. It varies in thickness, cellular composition, as well as free surface appearance, and even lack the typical structure of sensory epithelium, in this developmental period. Nerve bundles and glandular acini are lacking in the lamina propria mucosae of the septal organ and in the adjacent tissues. Glands appear as the single non-luminized cords of epithelia extending from the surface. The adjacent respiratory epithelium contains numerous goblet cells.

FORMATION OF HEMOGLOBIN AND ALBUMIN ADDUCTS OF BENZENE OXIDE IN MOUSE, RAT, AND HUMAN BLOOD

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Little is known about the formation and disposition of benzene oxide (BO), the initial metabolite arising from oxidation of benzene by cytochrome P450. In this study, reactions of BO with hemoglobin (Hb) and albumin (Alb) were investigated in blood from B6C3F1 mice, F344 rats, ...

Measurement and Analysis of Olfactory Responses with the Aim of Establishing an Objective Diagnostic Method for Central Olfactory Disorders

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Uno, Tominori; Wang, Li-Qun; Miwakeichi, Fumikazu; Tonoike, Mitsuo; Kaneda, Teruo

In order to establish a new diagnostic method for central olfactory disorders and to identify objective indicators, we measured and analyzed brain activities in the parahippocampal gyrus and uncus, region of responsibility for central olfactory disorders. The relationship between olfactory stimulation and brain response at region of responsibility can be examined in terms of fitted responses (FR). FR in these regions may be individual indicators of changes in brain olfactory responses. In the present study, in order to non-invasively and objectively measure olfactory responses, an odor oddball task was conducted on four healthy volunteers using functional magnetic resonance imaging (fMRI) and a odorant stimulator with blast-method. The results showed favorable FR and activation in the parahippocampal gyrus or uncus in all subjects. In some subjects, both the parahippocampal gyrus and uncus were activated. Furthermore, activation was also confirmed in the cingulate gyrus, middle frontal gyrus, precentral gyrus, postcentral gyrus, superior temporal gyrus and insula. The hippocampus and uncus are known to be involved in the olfactory disorders associated with early-stage Alzheimer's disease and other olfactory disorders. In the future, it will be necessary to further develop the present measurement and analysis method to clarify the relationship between central olfactory disorders and brain activities and establish objective indicators that are useful for diagnosis.

Effects of pectin-containing diets on the hepatic macromolecular covalent binding of 2,6-dinitro-[3H]toluene in Fischer-344 rats

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deBethizy, J.D.; Sherrill, J.M.; Rickert, D.E.; Hamm, T.E. Jr.

1983-01-01

The influence of diets varying in pectin content on intestinal microfloral metabolic capacity of rats has been investigated as a possible mechanism for the alteration of toxicity of 2,6-dinitrotoluene (2,6-DNT) produced by these diets. Male F-344 rats were fed a purified diet (AIN-76A), AIN-76A plus 5% or 10% citrus pectin, or either of two cereal-based diets that vary in pectin content, NIH-07 or Purina Chow 5002. After 28 days, rats were given tritium-labeled 2,6-DNT (10 or 75 mg/kg po) and killed 12 hr later. Total hepatic macromolecular covalent binding (CVB) was determined by exhaustive extraction. The CVB of 2,6-DNT was found to be independent of diet at 10 mg/kg. However, at 75 mg/kg CVB was increased 40% by feeding 5% pectin in the purified diet and 90% by feeding 10% pectin in the purified diet. Animals fed Purina 5002 and NIH-07 had 135 and 150% higher CVB, respectively, than animals fed the purified diet alone and significantly greater CVB than animals fed the pectin supplemented diets. Elevated (two- to threefold) beta-glucuronidase and nitroreductase activities, microfloral enzymes proposed to be involved in the activation of 2,6-DNT to a toxicant, were found in the cecal contents of animals fed the pectin-containing diets which correlated with a two- to threefold increase in total number of cecal anaerobes. These results suggest that pectin-induced changes in microflora may enhance hepatoxicity after high doses of 2,6-DNT

Type 2 diabetes impairs odour detection, olfactory memory and olfactory neuroplasticity; effects partly reversed by the DPP-4 inhibitor Linagliptin.

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Lietzau, Grazyna; Davidsson, William; Östenson, Claes-Göran; Chiazza, Fausto; Nathanson, David; Pintana, Hiranya; Skogsberg, Josefin; Klein, Thomas; Nyström, Thomas; Darsalia, Vladimer; Patrone, Cesare

2018-02-23

Recent data suggest that olfactory deficits could represent an early marker and a pathogenic mechanism at the basis of cognitive decline in type 2 diabetes (T2D). However, research is needed to further characterize olfactory deficits in diabetes, their relation to cognitive decline and underlying mechanisms.The aim of this study was to determine whether T2D impairs odour detection, olfactory memory as well as neuroplasticity in two major brain areas responsible for olfaction and odour coding: the main olfactory bulb (MOB) and the piriform cortex (PC), respectively. Dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used T2D drugs exerting also beneficial effects in the brain. Therefore, we aimed to determine whether DPP-4i could reverse the potentially detrimental effects of T2D on the olfactory system.Non-diabetic Wistar and T2D Goto-Kakizaki rats, untreated or treated for 16 weeks with the DPP-4i linagliptin, were employed. Odour detection and olfactory memory were assessed by using the block, the habituation-dishabituation and the buried pellet tests. We assessed neuroplasticity in the MOB by quantifying adult neurogenesis and GABAergic inhibitory interneurons positive for calbindin, parvalbumin and carletinin. In the PC, neuroplasticity was assessed by quantifying the same populations of interneurons and a newly identified form of olfactory neuroplasticity mediated by post-mitotic doublecortin (DCX) + immature neurons.We show that T2D dramatically reduced odour detection and olfactory memory. Moreover, T2D decreased neurogenesis in the MOB, impaired the differentiation of DCX+ immature neurons in the PC and altered GABAergic interneurons protein expression in both olfactory areas. DPP-4i did not improve odour detection and olfactory memory. However, it normalized T2D-induced effects on neuroplasticity.The results provide new knowledge on the detrimental effects of T2D on the olfactory system. This knowledge could constitute essentials for

Cladistic analysis of olfactory and vomeronasal systems.

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Ubeda-Bañon, Isabel; Pro-Sistiaga, Palma; Mohedano-Moriano, Alicia; Saiz-Sanchez, Daniel; de la Rosa-Prieto, Carlos; Gutierrez-Castellanos, Nicolás; Lanuza, Enrique; Martinez-Garcia, Fernando; Martinez-Marcos, Alino

2011-01-01

Most tetrapods possess two nasal organs for detecting chemicals in their environment, which are the sensory detectors of the olfactory and vomeronasal systems. The seventies' view that the olfactory system was only devoted to sense volatiles, whereas the vomeronasal system was exclusively specialized for pheromone detection was challenged by accumulating data showing deep anatomical and functional interrelationships between both systems. In addition, the assumption that the vomeronasal system appeared as an adaptation to terrestrial life is being questioned as well. The aim of the present work is to use a comparative strategy to gain insight in our understanding of the evolution of chemical "cortex." We have analyzed the organization of the olfactory and vomeronasal cortices of reptiles, marsupials, and placental mammals and we have compared our findings with data from other taxa in order to better understand the evolutionary history of the nasal sensory systems in vertebrates. The olfactory and vomeronsasal cortices have been re-investigated in garter snakes (Thamnophis sirtalis), short-tailed opossums (Monodelphis domestica), and rats (Rattus norvegicus) by tracing the efferents of the main and accessory olfactory bulbs using injections of neuroanatomical anterograde tracers (dextran-amines). In snakes, the medial olfactory tract is quite evident, whereas the main vomeronasal-recipient structure, the nucleus sphaericus is a folded cortical-like structure, located at the caudal edge of the amygdala. In marsupials, which are acallosal mammals, the rhinal fissure is relatively dorsal and the olfactory and vomeronasal cortices relatively expanded. Placental mammals, like marsupials, show partially overlapping olfactory and vomeronasal projections in the rostral basal telencephalon. These data raise the interesting question of how the telencephalon has been re-organized in different groups according to the biological relevance of chemical senses.

Olfactory Memory

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Eichenbaum, Howard; Robitsek, R. Jonathan

2009-01-01

Odor-recognition memory in rodents may provide a valuable model of cognitive aging. In a recent study we used signal detection analyses to distinguish odor recognition based on recollection versus that based on familiarity. Aged rats were selectively impaired in recollection, with relative sparing of familiarity, and the deficits in recollection were correlated with spatial memory impairments. These results complement electro-physiological findings indicating age-associated deficits in the ability of hippocampal neurons to differentiate contextual information, and this information-processing impairment may underlie the common age-associated decline in olfactory and spatial memory. PMID:19686208

Analysis of c-Fos induction in response to social interaction in male and female Fisher 344 rats.

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Perkins, Amy E; Woodruff, Elizabeth R; Chun, Lauren E; Spencer, Robert L; Varlinskaya, Elena; Deak, Terrence

2017-10-01

Sex differences in the expression of social behavior are typically apparent in adolescent and adult rats. While the neurobiology underlying juvenile social play behavior has been well characterized, less is known about discrete brain regions involved in adult responsiveness to a same sex peer. Furthermore, whether adult males and females differ in their responsiveness to a social interaction in terms of neuronal activation indexed via immediate early gene (IEG) expression remains to be determined. Thus, the present study was designed to identify key sites relevant to the processing of sensory stimuli (generally) or social stimuli (specifically) after brief exposure to a same-sex social partner by assessing IEG expression. Four-month-old male and female Fisher (F) 344 rats (N=38; n=5-8/group) were either left undisturbed in their home cage as controls (HCC), exposed to a testing context alone for 30min (CXT), or were placed in the context for 20min and then allowed to socially interact (SI) with a sex-matched conspecific for 10min. Females demonstrated greater levels of social behavior, relative to males. Analysis of c-Fos induction revealed that females exhibited greater c-Fos expression in the prefrontal cortex, regardless of condition. In many brain regions, induction was similar in the CXT and SI groups. However, in the bed nucleus of the stria terminalis (BNST), females exhibited greater c-Fos induction in response to the social interaction relative to their male counterparts, indicating a sex difference in responsivity to social stimuli. Taken together, these data suggest that the BNST is a sexually dimorphic region in terms of activation in response to social stimuli. Copyright © 2017 Elsevier B.V. All rights reserved.

Enhanced self-administration of the CB1 receptor agonist WIN55,212-2 in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms

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Petra eAmchova

2014-03-01

Full Text Available Depression has been associated with drug consumption, including heavy or problematic cannabis use. According to an animal model of depression and substance use disorder comorbidity, we combined the olfactory bulbectomy model of depression with intravenous drug self-administration procedure to verify whether depressive-like rats displayed higher voluntary intake of the CB1 receptor agonist WIN55,212-2 (WIN, 12.5 µg/kg/infusion. To this aim, olfactory-bulbectomized (OBX and sham-operated (SHAM Lister Hooded rats were allowed to self-administer WIN by lever-pressing under a continuous (FR-1 schedule of reinforcement in 2h daily sessions. Data showed that both OBX and SHAM rats developed stable WIN intake; yet, responses in OBX were constantly higher than in SHAM rats soon after the first week of training. In addition, OBX rats took significantly longer to extinguish the drug-seeking behaviour after vehicle substitution. Acute pre-treatment with serotonin 5HT1B receptor agonist, CGS-12066B (2.5-10 mg/kg, did not significantly modify WIN intake in OBX and SHAM Lister Hooded rats. Furthermore, acute pre-treatment with CGS-12066B (10 and 15 mg/kg did not alter responses in parallel groups of OBX and SHAM Sprague Dawley rats self-administering methamphetamine under higher (FR-2 reinforcement schedule with nose-poking as operandum. Finally, dopamine levels in the nucleus accumbens of OBX rats did not increase in response to a WIN challenge, as in SHAM rats, indicating a dopaminergic dysfunction in bulbectomized rats. Altogether, our findings suggest that a depressive state may alter cannabinoid CB1 receptor agonist-induced brain reward function and that a dopaminergic rather than a 5-HT1B mechanism is likely to underlie enhanced WIN self-administration in OBX rats.

SRXRF analysis of elemental distribution in the olfactory bulbs of rat after intranaris application of manganese chloride

International Nuclear Information System (INIS)

He Rui; Wang Xuxia; Lei Hao; Liu Nianqing; Huang Yuying; He Wei

2005-01-01

Manganese is a calcium analog, and it can enter activated neurons through voltage-gated calcium channel. Overexposure to manganese often result in its accumulation in the brain, causing symptoms similar to Parkinson's disease One of the routes by which manganese enters brain is the olfactory pathway. In this work, elementary distribution in the olfactory bulbs (OB) of rats after intranaris application of MnCl 2 solution was measured by SRXRF, and the effect of exogenous Mn on the distribution of other elements, particularly calcium, in the OB was also investigated. Four SD male rats were decapitated 9 hrs after intranaris application of MnCl 2 solution (5 μl, 400 mmol/L) in the right nasal cavity. The OB were removed, frozen by liquid nitrogen, cut into 100 m-thick sections with a microtome, and put onto polycarbonate films specially designed for SRXRF examination. It has been shown that unilateral intranaris application of MnCl 2 only results in manganese deposition in the ipsilateral hemisphere of the OB. The left hemisphere of the OB was therefore used as the control. All SRXRF spectra collected with a beam spot size of 60 m x 80 m were normalized to the acquisition time and the counting of the ion chambers, and the contribution from the supporting polycarbonate film was subtracted. The X-ray peak area for each element (A) and the Compton scattering intensity (B) for the whole OB section were obtained. The relative content for each element was taken as the ratio of A to B and analyzed by the SPSS software. The average Mn and Ca contents were found significantly higher in the ipsilateral hemisphere than in the contralateral hemisphere. The Mn content was found to be the highest in the glomerular layer (GL) of the ipsilateral OB hemisphere, consistent with previous findings obtained by magnetic resonance imaging detection. Bivariate correlation analysis showed that the distribution of Mn and Ca in the ipsilateral hemisphere had higher degree of correlation

Human olfactory bulb neural stem cells mitigate movement disorders in a rat model of Parkinson's disease.

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Marei, Hany E S; Lashen, Samah; Farag, Amany; Althani, Asmaa; Afifi, Nahla; A, Abd-Elmaksoud; Rezk, Shaymaa; Pallini, Roberto; Casalbore, Patrizia; Cenciarelli, Carlo

2015-07-01

Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 ± 2.88%), neuron-like (52.63 ± 4.16%), and astrocyte -like (22.36 ± 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease. © 2014 Wiley Periodicals, Inc.

Fenbendazole treatment may influence lipopolysaccharide effects in rat brain.

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Hunter, Randy L; Choi, Dong-Young; Kincer, Jeanie F; Cass, Wayne A; Bing, Guoying; Gash, Don M

2007-10-01

In evaluating discrepant results between experiments in our laboratory, we collected data that challenge the notion that anthelminthic drugs like FBZ do not alter inflammatory responses. We found that FBZ significantly modulates inflammation in F344 rats intrastriatally injected with LPS. FBZ treatment of LPS-injected rats significantly increased weight loss, microglial activation, and dopamine loss; in addition, FBZ attenuated the LPS-induced loss of astrocytes. Therefore, FBZ treatment altered the effects of LPS injection. Caution should be used in interpreting data collected from rats treated with LPS and FBZ.

Effects of MDMA on olfactory memory and reversal learning in rats.

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Hawkey, Andrew; April, L Brooke; Galizio, Mark

2014-10-01

The effects of acute and sub-chronic MDMA were assessed using a procedure designed to test rodent working memory capacity: the odor span task (OST). Rats were trained to select an odor that they had not previously encountered within the current session, and the number of odors to remember was incremented up to 24 during the course of each session. In order to separate drug effects on the OST from more general performance impairment, a simple olfactory discrimination was also assessed in each session. In Experiment 1, acute doses of MDMA were administered prior to select sessions. MDMA impaired memory span in a dose-dependent fashion, but impairment was seen only at doses (1.8 and 3.0 mg/kg) that also increased response omissions on both the simple discrimination and the OST. In Experiment 2, a sub-chronic regimen of MDMA (10.0 mg/kg, twice daily over four days) was administered after OST training. There was no evidence of reduced memory span following sub-chronic MDMA, but a temporary increase in omission errors on the OST was observed. In addition, rats exposed to sub-chronic MDMA showed delayed learning when the simple discrimination was reversed. Overall, the disruptive effects of both acute and sub-chronic MDMA appeared to be due to non-mnemonic processes, rather than effects on specific memory functions. Copyright © 2014 Elsevier Inc. All rights reserved.

Changes in olfactory bulb volume following lateralized olfactory training.

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Negoias, S; Pietsch, K; Hummel, T

2017-08-01

Repeated exposure to odors modifies olfactory function. Consequently, "olfactory training" plays a significant role in hyposmia treatment. In addition, numerous studies show that the olfactory bulb (OB) volume changes in disorders associated with olfactory dysfunction. Aim of this study was to investigate whether and how olfactory bulb volume changes in relation to lateralized olfactory training in healthy people. Over a period of 4 months, 97 healthy participants (63 females and 34 males, mean age: 23.74 ± 4.16 years, age range: 19-43 years) performed olfactory training by exposing the same nostril twice a day to 4 odors (lemon, rose, eucalyptus and cloves) while closing the other nostril. Before and after olfactory training, magnetic resonance imaging (MRI) scans were performed to measure OB volume. Furthermore, participants underwent lateralized odor threshold and odor identification testing using the "Sniffin' Sticks" test battery.OB volume increased significantly after olfactory training (11.3 % and 13.1 % respectively) for both trained and untrained nostril. No significant effects of sex, duration and frequency of training or age of the subjects were seen. Interestingly, PEA odor thresholds worsened after training, while olfactory identification remained unchanged.These data show for the first time in humans that olfactory training may involve top-down process, which ultimately lead to a bilateral increase in olfactory bulb volume.

Cellular and molecular cues of glucose sensing in the rat olfactory bulb

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Dolly eAl Koborssy

2014-10-01

Full Text Available In the brain, glucose homeostasis of extracellular fluid is crucial to the point that systems specifically dedicated to glucose sensing are found in areas involved in energy regulation and feeding behavior. Olfaction is a major sensory modality regulating food consumption. Nutritional status in turn modulates olfactory detection. Recently it has been proposed that some olfactory bulb (OB neurons respond to glucose similarly to hypothalamic neurons. However, the precise molecular cues governing glucose sensing in the OB are largely unknown. To decrypt these molecular mechanisms, we first used immunostaining to demonstrate a strong expression of two neuronal markers of glucose-sensitivity, insulin-dependent glucose transporter type 4 (GLUT4, and sodium glucose co-transporter type 1 (SGLT1 in specific OB layers. We showed that expression and mapping of GLUT4 but not SGLT1 were feeding state-dependent. In order to investigate the impact of metabolic status on the delivery of blood-borne glucose to the OB, we measured extracellular fluid glucose concentration using glucose biosensors simultaneously in the OB and cortex of anesthetized rats. We showed that glucose concentration in the OB is higher than in the cortex, that metabolic steady-state glucose concentration is independent of feeding state in the two brain areas, and that acute changes in glycemic conditions affect bulbar glucose concentration alone. These data provide new evidence of a direct relationship between the OB and peripheral metabolism, and emphasize the importance of glucose for the OB network, providing strong arguments toward establishing the OB as a glucose-sensing organ.

(-)-P7C3-S243 Protects a Rat Model of Alzheimer's Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia.

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Voorhees, Jaymie R; Remy, Matthew T; Cintrón-Pérez, Coral J; El Rassi, Eli; Khan, Michael Z; Dutca, Laura M; Yin, Terry C; McDaniel, Latisha N; Williams, Noelle S; Brat, Daniel J; Pieper, Andrew A

2017-11-06

In addition to cognitive deficits, Alzheimer's disease (AD) is associated with other neuropsychiatric symptoms, including severe depression. Indeed, depression often precedes cognitive deficits in patients with AD. Unfortunately, the field has seen only minimal therapeutic advances, underscoring the critical need for new treatments. P7C3 aminopropyl carbazoles promote neuronal survival by enhancing nicotinamide adenine dinucleotide flux in injured neurons. Neuroprotection with P7C3 compounds has been demonstrated in preclinical models of neurodegeneration by virtue of promoting neuronal survival independently of early disease-specific pathology, resulting in protection from cognitive deficits and depressive-like behavior. We hypothesize that P7C3 compounds might be uniquely applicable to patients with AD, given the comorbid presentation of depression and cognitive deficits. Aging male and female wild-type and TgF344-AD rats, a well-characterized preclinical AD model, were administered (-)-P7C3-S243 daily for 9 and 18 months, beginning at 6 months of age. Behavioral phenotypes related to cognition and depression were assessed at 15 and 24 months, and brain pathology and biochemistry were assessed at 24 months. (-)-P7C3-S243 safely protected aging male and female wild-type and TgF344-AD rats from cognitive deficits and depressive-like behavior. Depressive-like behavior occurred earlier than cognitive deficits in TgF344-AD rats, consistent with AD in many patients. Treatment with (-)-P7C3-S243 blocked neurodegeneration in TgF344-AD rats, without altering amyloid deposition or indicators of neuroinflammation. Neuronal cell death-specific treatment approaches, such as P7C3 compounds, may represent a new treatment approach for patients experiencing the combination of cognitive deficits and depression associated with AD. Published by Elsevier Inc.

Brain Region-Specific Expression of Genes Mapped within Quantitative Trait Loci for Behavioral Responsiveness to Acute Stress in Fisher 344 and Wistar Kyoto Male Rats (Postprint)

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2018-03-12

stress in Fisher 344 and Wistar Kyoto male rats. PLoS ONE 13(3): e0194293. https://doi. org /10.1371/journal.pone.0194293 Editor: Alexandra Kavushansky...complex traits in outbred rats. Nature genetics. 2013; 45(7): https://doi. org /10.1038/ng.2644 PMC3821058. PMID: 23708188 15. Ahmadiyeh N, Churchill GA...congenic mouse strains. Nature Genetics. 1997; 17:280. https://doi. org /10.1038/ng1197-280 PMID: 9354790 21. The SC. SNP and haplotype mapping for genetic

Short neuropeptide F acts as a functional neuromodulator for olfactory memory in Kenyon cells of Drosophila mushroom bodies.

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Knapek, Stephan; Kahsai, Lily; Winther, Asa M E; Tanimoto, Hiromu; Nässel, Dick R

2013-03-20

In insects, many complex behaviors, including olfactory memory, are controlled by a paired brain structure, the so-called mushroom bodies (MB). In Drosophila, the development, neuroanatomy, and function of intrinsic neurons of the MB, the Kenyon cells, have been well characterized. Until now, several potential neurotransmitters or neuromodulators of Kenyon cells have been anatomically identified. However, whether these neuroactive substances of the Kenyon cells are functional has not been clarified yet. Here we show that a neuropeptide precursor gene encoding four types of short neuropeptide F (sNPF) is required in the Kenyon cells for appetitive olfactory memory. We found that activation of Kenyon cells by expressing a thermosensitive cation channel (dTrpA1) leads to a decrease in sNPF immunoreactivity in the MB lobes. Targeted expression of RNA interference against the sNPF precursor in Kenyon cells results in a highly significant knockdown of sNPF levels. This knockdown of sNPF in the Kenyon cells impairs sugar-rewarded olfactory memory. This impairment is not due to a defect in the reflexive sugar preference or odor response. Consistently, knockdown of sNPF receptors outside the MB causes deficits in appetitive memory. Altogether, these results suggest that sNPF is a functional neuromodulator released by Kenyon cells.

Detection of acute renal allograft rejection by analysis of Renal TissueProteomics in rat models of renal transplantation

International Nuclear Information System (INIS)

Dai, Y.; Lv, T.; Wang, K.; Li, D.; Huang, Y.; Liu, J.

2008-01-01

At present, the diagnosis of renal allograft rejection requires a renalbiopsy. Clinical management of renal transplant patients would be improved ifrapid, noninvasive and reliable biomarkers of rejection were available. Thisstudy is designed to determine whether such protein biomarkers can be foundin renal graft tissue proteomic approach. Orthotopic kidney transplantationswere performed using Fisher (F344) or Lewis rats as donors and Lewis rats asrecipients. Hence, there were two groups of renal transplant models: one isallograft (from F344 to Lewis rats); another is syngrafts (from Lewis toLewis rats) serving as control. Renal tissues were collected 3, 7 and 14 daysafter transplantation. As many 18 samples were analyzed by 2-DElectrophoresis and mass spectrometry (MALDI-TOF-TOF-MS). Elevendifferentially expressed proteins were identified between groups. Inconclusion, proteomic technology can detect renal tissue proteins associatedwith acute renal allograft rejection. Identification of these proteins asdiagnostic markers for rejection in patient's urine or sera may be useful andnon-invasive, and these proteins might serve as novel therapeutic targetsthat also help to improve the understanding of mechanisms of renal rejection.(author)

Intestinal lymphangiectasis and lipidosis in rats following subchronic exposure to indole-3-carbinol via oral gavage.

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Boyle, Michael C; Crabbs, Torrie A; Wyde, Michael E; Painter, J Todd; Hill, Georgette D; Malarkey, David E; Lieuallen, Warren G; Nyska, Abraham

2012-06-01

To investigate the toxicity and carcinogenic potential of indole-3-carbinol (I3C), the National Toxicology Program has conducted 13-week subchronic studies in Fisher 344 rats and B6C3F1 mice, and chronic 2-year bioassays in Sprague-Dawley rats and B6C3F1 mice. While the chronic study results are not yet available, subchronic study results and short-term special evaluations of interim sacrifices in the 2-year rat bioassay are presented. F344 rats were orally gavaged ≤300 mg I3C/kg body weight 5 days a week for 13 weeks. Rats treated with ≥150 mg/kg demonstrated a dose-related dilation of lymphatics (lymphangiectasis) of the duodenum, jejunum, and mesenteric lymph nodes. Material within dilated lacteals stained positively for Oil Red O and Sudan Black, consistent with lipid. Electron microscopic evaluation confirmed extracellular lipid accumulation within the villar lamina propria, lacteals, and within villar macrophages. Analyses of hepatic and pulmonary CYP1A enzymes demonstrated dose-dependent I3C induction of CYP1A1 and 1A2. B6C3F1 mice orally gavaged ≤250 mg I3C/kg body weight did not demonstrate histopathological changes; however, hepatic CYP induction was similar to that in rats. The histopathologic changes of intestinal lymphangiectasis and lipidosis in this study share similarities with intestinal lymphangiectasia as observed in humans and dogs. However, the resultant clinical spectrum of protein-losing enteropathy was not present.

Microencapsulation improves inhibitory effects of transplanted olfactory ensheathing cells on pain after sciatic nerve injury

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Hao Zhao

2015-01-01

Full Text Available Olfactory bulb tissue transplantation inhibits P2X2/3 receptor-mediated neuropathic pain. However, the olfactory bulb has a complex cellular composition, and the mechanism underlying the action of purified transplanted olfactory ensheathing cells (OECs remains unclear. In the present study, we microencapsulated OECs in alginic acid, and transplanted free and microencapsulated OECs into the region surrounding the injured sciatic nerve in rat models of chronic constriction injury. We assessed mechanical nociception in the rat models 7 and 14 days after surgery by measuring paw withdrawal threshold, and examined P2X2/3 receptor expression in L 4-5 dorsal root ganglia using immunohistochemistry. Rats that received free and microencapsulated OEC transplants showed greater withdrawal thresholds than untreated model rats, and weaker P2X2/3 receptor immunoreactivity in dorsal root ganglia. At 14 days, paw withdrawal threshold was much higher in the microencapsulated OEC-treated animals. Our results confirm that microencapsulated OEC transplantation suppresses P2X2/3 receptor expression in L 4-5 dorsal root ganglia in rat models of neuropathic pain and reduces allodynia, and also suggest that transplantation of microencapsulated OECs is more effective than transplantation of free OECs for the treatment of neuropathic pain.

Susceptibility to radiation-induced mammary carcinoma in genetically resistant Copenhagen rats

International Nuclear Information System (INIS)

Kamiya, Kenji; Nitta, Yumiko; Gould, M.N.

2000-01-01

The objective of this experiment was to compare the cellular basis of mammary cancer induction by a chemical carcinogen with induction by ionizing radiation in three strains of rats (inbred that have different genetic susceptibilities: COP rats, F344 rats, and WF rats). Rats were given a single intraperitoneal injection of 50 mg MNU/kg body weight as a mammary-tumor-inducing chemical carcinogen and were irradiated with a 3.0 Gy dose of 60 Co gamma rays at a dose rate of 26.58±1.19 cGy/min. The rats were inspected weekly, and they were killed and necropsied whenever palpable tumors were detected or they became moribund. The histopathological and immunohistochemical characteristics of the mammary tumors were investigated. A transplantation experiment using selected primary mammary tumors that developed in COP rats exposed to gamma rays was also performed to investigate the transplantability of mammary tumors induced by ionizing radiation. The sensitivity of the WF and F344 rats and the resistance of the COP rats to mammary carcinoma induction by the chemical carcinogen MNU was confirmed. In contrast to the chemical carcinogens, no difference in susceptibility to radiation induction of mammary carcinomas was detected among the three strains of rats, and immunohistochemical examination indicated that the radiation-induced carcinomas consisted of more highly differentiated cells than the MNU-induced cancers. The results of the experiment appear to support the hypothesis that differentiated mammary gland tissue is more resistant to chemical carcinogens than to cancer induction by radiation. The authors conclude that radiation-induced cancers in rats may develop via different pathways or from different cell populations than chemically induced cancers. (K.H.)

Susceptibility to radiation-induced mammary carcinoma in genetically resistant Copenhagen rats

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Kamiya, Kenji; Nitta, Yumiko [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine; Gould, M.N.

2000-07-01

The objective of this experiment was to compare the cellular basis of mammary cancer induction by a chemical carcinogen with induction by ionizing radiation in three strains of rats (inbred that have different genetic susceptibilities: COP rats, F344 rats, and WF rats). Rats were given a single intraperitoneal injection of 50 mg MNU/kg body weight as a mammary-tumor-inducing chemical carcinogen and were irradiated with a 3.0 Gy dose of {sup 60} Co gamma rays at a dose rate of 26.58{+-}1.19 cGy/min. The rats were inspected weekly, and they were killed and necropsied whenever palpable tumors were detected or they became moribund. The histopathological and immunohistochemical characteristics of the mammary tumors were investigated. A transplantation experiment using selected primary mammary tumors that developed in COP rats exposed to gamma rays was also performed to investigate the transplantability of mammary tumors induced by ionizing radiation. The sensitivity of the WF and F344 rats and the resistance of the COP rats to mammary carcinoma induction by the chemical carcinogen MNU was confirmed. In contrast to the chemical carcinogens, no difference in susceptibility to radiation induction of mammary carcinomas was detected among the three strains of rats, and immunohistochemical examination indicated that the radiation-induced carcinomas consisted of more highly differentiated cells than the MNU-induced cancers. The results of the experiment appear to support the hypothesis that differentiated mammary gland tissue is more resistant to chemical carcinogens than to cancer induction by radiation. The authors conclude that radiation-induced cancers in rats may develop via different pathways or from different cell populations than chemically induced cancers. (K.H.)

Working Memory Systems in the Rat.

Science.gov (United States)

Bratch, Alexander; Kann, Spencer; Cain, Joshua A; Wu, Jie-En; Rivera-Reyes, Nilda; Dalecki, Stefan; Arman, Diana; Dunn, Austin; Cooper, Shiloh; Corbin, Hannah E; Doyle, Amanda R; Pizzo, Matthew J; Smith, Alexandra E; Crystal, Jonathon D

2016-02-08

A fundamental feature of memory in humans is the ability to simultaneously work with multiple types of information using independent memory systems. Working memory is conceptualized as two independent memory systems under executive control [1, 2]. Although there is a long history of using the term "working memory" to describe short-term memory in animals, it is not known whether multiple, independent memory systems exist in nonhumans. Here, we used two established short-term memory approaches to test the hypothesis that spatial and olfactory memory operate as independent working memory resources in the rat. In the olfactory memory task, rats chose a novel odor from a gradually incrementing set of old odors [3]. In the spatial memory task, rats searched for a depleting food source at multiple locations [4]. We presented rats with information to hold in memory in one domain (e.g., olfactory) while adding a memory load in the other domain (e.g., spatial). Control conditions equated the retention interval delay without adding a second memory load. In a further experiment, we used proactive interference [5-7] in the spatial domain to compromise spatial memory and evaluated the impact of adding an olfactory memory load. Olfactory and spatial memory are resistant to interference from the addition of a memory load in the other domain. Our data suggest that olfactory and spatial memory draw on independent working memory systems in the rat. Copyright © 2016 Elsevier Ltd. All rights reserved.

Neurobiology of mammalian olfactory learning that occurs during sensitive periods

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Hideto KABA

2010-12-01

Full Text Available This review examines the organizational principles underlying olfactory learning in three specialized contexts that occur during sensitive periods of enhanced neural plasticity and emphasizes some of their common features. All three forms of olfactory learning are associated with neural changes in the olfactory bulb (OB at the first stage of sensory processing. These changes require the association of the olfactory and somatosensory signals in the OB. They all depend on somatosensory stimulation-induced release of noradrenaline that induces structural and functional changes at mitral-granule cell reciprocal synapses in the OB, resulting in increases in inhibitory transmission. In the accessory olfactory bulb, this represents the enhanced self-inhibition of mitral cells, which selectively disrupts the transmission of the mating male’s pregnancy-blocking signal at this level. In contrast, an extensive network of secondary dendrites of mitral cells in the main olfactory bulb probably results in a sharpening of the odor-induced pattern of activity, due to increases in lateral inhibition, leading to offspring recognition in sheep and neonatal learning in rats and rabbits. These findings show that inhibitory interneurons play a critical role in olfactory learning. Further work on how these neurons shape olfactory circuit function could provide important clues to understand memory functions of interneurons in other systems. Moreover, recent research has suggested that three forms of olfactory learning are controlled by synergistic, redundant, and distributed neural mechanisms. This has general implications regarding the mechanisms that may contribute to the robustness of memories [Current Zoology 56 (6: 819–833, 2010].

Olfactory neural cells: an untapped diagnostic and therapeutic resource. The 2000 Ogura Lecture.

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Perry, Christopher; Mackay-Sim, Alan; Feron, Francois; McGrath, John

2002-04-01

This is an overview of the cellular biology of upper nasal mucosal cells that have special characteristics that enable them to be used to diagnose and study congenital neurological diseases and to aid neural repair. After mapping the distribution of neural cells in the upper nose, the authors' investigations moved to the use of olfactory neurones to diagnose neurological diseases of development, especially schizophrenia. Olfactory-ensheathing glial cells (OEGs) from the cranial cavity promote axonal penetration of the central nervous system and aid spinal cord repair in rodents. The authors sought to isolate these cells from the more accessible upper nasal cavity in rats and in humans and prove they could likewise promote neural regeneration, making these cells suitable for human spinal repair investigations. The schizophrenia-diagnosis aspect of the study entailed the biopsy of the olfactory areas of 10 schizophrenic patients and 10 control subjects. The tissue samples were sliced and grown in culture medium. The ease of cell attachment to fibronectin (artificial epithelial basement membrane), as well as the mitotic and apoptotic indices, was studied in the presence and absence of dopamine in those cell cultures. The neural repair part of the study entailed a harvesting and insertion of first rat olfactory lamina propria rich in OEGs between cut ends of the spinal cords and then later the microinjection of an OEG-rich suspension into rat spinal cords previously transected by open laminectomy. Further studies were done in which OEG insertion was performed up to 1 month after rat cord transection and also in monkeys. Schizophrenic patients' olfactory tissues do not easily attach to basement membrane compared with control subjects, adding evidence to the theory that cell wall anomalies are part of the schizophrenic "lesion" of neurones. Schizophrenic patient cell cultures had higher mitotic and apoptotic indices compared with control subjects. The addition of

Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30 on rat chromosome 12: identification of fry as a candidate Mcs gene.

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Xuefeng Ren

Full Text Available Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop and susceptible Fischer 344 (F344 strains, we mapped a novel mammary carcinoma susceptibility (Mcs30 locus to the centromeric region on chromosome 12 (LOD score of ∼8.6 at the D12Rat59 marker. The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs, one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression.

Statistical parametric mapping for effects of verapamil on olfactory connections of rat brain in vivo using manganese-enhanced MR imaging

International Nuclear Information System (INIS)

Soma, Tsutomu; Kurakawa, Masami; Koto, Daichi

2011-01-01

We investigated the effect of verapamil on the transport of manganese in the olfactory connections of rat brains in vivo using statistical parametric mapping and manganese-enhanced magnetic resonance (MR) imaging. We divided 12 7-week-old male Sprague-Dawley rats into 2 groups of six and injected 10 μL of saline into the right nasal cavities of the first group and 10 μL of verapamil (2.5 mg/mL) into the other group. Twenty minutes after the initial injection, we injected 10 μL of MnCl 2 (1 mol/L) into the right nasal cavities of both groups. We obtained serial T 1 -weighted MR images before administering the verapamil or saline and at 0.5, one, 24, 48, and 72 hours and 7 days after administering the MnCl 2 , spatially normalized the MR images on the rat brain atlas, and analyzed the data using voxel-based statistical comparison. Statistical parametric maps demonstrated the transport of manganese. Manganese ions created significant enhancement (t-score=36.6) 24 hours after MnCl 2 administration in the group administered saline but not at the same time point in the group receiving verapamil. The extent of significantly enhanced regions peaked at 72 hours in both groups and both sides of the brain. The peak of extent in the right side brain in the group injected with saline was 70.2 mm 3 and in the group with verapamil, 92.4 mm 3 . The extents in the left side were 64.0 mm 3 for the group with saline and 53.2 mm 3 for the group with verapamil. We applied statistical parametric mapping using manganese-enhanced MR imaging to demonstrate in vivo the transport of manganese in the olfactory connections of rat brains with and without verapamil and found that verapamil did affect this transport. (author)

Heterogeneous Stock Rat: A Unique Animal Model for Mapping Genes Influencing Bone Fragility

OpenAIRE

Alam, Imranul; Koller, Daniel L.; Sun, Qiwei; Roeder, Ryan K.; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Vicens-Costa, Elia; Mont, Carme; Díaz, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Whitley, Adam; Strid, Pernilla

2011-01-01

Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in 4 inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which ...

Projections from the posterolateral olfactory amygdala to the ventral striatum: neural basis for reinforcing properties of chemical stimuli

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Lanuza Enrique

2007-11-01

Full Text Available Abstract Background Vertebrates sense chemical stimuli through the olfactory receptor neurons whose axons project to the main olfactory bulb. The main projections of the olfactory bulb are directed to the olfactory cortex and olfactory amygdala (the anterior and posterolateral cortical amygdalae. The posterolateral cortical amygdaloid nucleus mainly projects to other amygdaloid nuclei; other seemingly minor outputs are directed to the ventral striatum, in particular to the olfactory tubercle and the islands of Calleja. Results Although the olfactory projections have been previously described in the literature, injection of dextran-amines into the rat main olfactory bulb was performed with the aim of delimiting the olfactory tubercle and posterolateral cortical amygdaloid nucleus in our own material. Injection of dextran-amines into the posterolateral cortical amygdaloid nucleus of rats resulted in anterograde labeling in the ventral striatum, in particular in the core of the nucleus accumbens, and in the medial olfactory tubercle including some islands of Calleja and the cell bridges across the ventral pallidum. Injections of Fluoro-Gold into the ventral striatum were performed to allow retrograde confirmation of these projections. Conclusion The present results extend previous descriptions of the posterolateral cortical amygdaloid nucleus efferent projections, which are mainly directed to the core of the nucleus accumbens and the medial olfactory tubercle. Our data indicate that the projection to the core of the nucleus accumbens arises from layer III; the projection to the olfactory tubercle arises from layer II and is much more robust than previously thought. This latter projection is directed to the medial olfactory tubercle including the corresponding islands of Calleja, an area recently described as critical node for the neural circuit of addiction to some stimulant drugs of abuse.

Metabolism and disposition of ethylene carbonate in male Fischer 344 rats

International Nuclear Information System (INIS)

Hanley, T.R. Jr.; Schumann, A.M.; Langvardt, P.W.; Rusek, T.F.; Watanabe, P.G.

1989-01-01

Ethylene carbonate (EC) has a toxicity profile which resembles that of ethylene glycol (EG). To determine whether the toxicity of EC could be explained on the basis of its metabolism to EG, male Fischer 344 rats were given 200 mg/kg of uniformly labeled [ 14 C]EC in water by gavage and the disposition of the radiolabel was then followed for 72 hr. EC was rapidly metabolized, with approximately 57 and 27% of the administered dose eliminated in the expired air as 14CO2 and in the urine, respectively; the remainder was found in the carcass. Separation of the urinary metabolites using liquid chromatography revealed a single radioactive peak. This metabolite was unequivocally identified as ethylene glycol via gas chromatography-mass spectrometry with the aid of 13C enrichment of the EC dose. Measurement of whole blood levels of EC and EG in rats given 200 mg/kg of EC by gavage revealed blood levels of EG approximately 100-fold higher than the levels of EC in these same animals, with a half-life of EG in blood of 2 hr, indicating rapid conversion of EC to EG. In a separate group of animals administered an equimolar dose of [ 14 C]EG (141 mg/kg), approximately 37% of the dose was expired as 14 CO 2 and 42% was excreted in the urine as parent compound. When expressed on the basis of the ethanediol moiety, the disposition of EC was identical to that of EG. In view of the rapid and extensive biotransformation of EC to EG and the similarity of the existing (though limited) toxicity data base of EC compared to EG, utilization of the extensive EG systemic toxicity data base for assessing the safety of EC appears justified

Olfactory Perceptual Learning Requires Action of Noradrenaline in the Olfactory Bulb: Comparison with Olfactory Associative Learning

Science.gov (United States)

Vinera, Jennifer; Kermen, Florence; Sacquet, Joëlle; Didier, Anne; Mandairon, Nathalie; Richard, Marion

2015-01-01

Noradrenaline contributes to olfactory-guided behaviors but its role in olfactory learning during adulthood is poorly documented. We investigated its implication in olfactory associative and perceptual learning using local infusion of mixed a1-ß adrenergic receptor antagonist (labetalol) in the adult mouse olfactory bulb. We reported that…

Donor dopamine treatment in brain dead rats is associated with an improvement in renal function early after transplantation and a reduction in renal inflammation

NARCIS (Netherlands)

Hoeger, Simone; Reisenbuechler, Anke; Gottmann, Uwe; Doyon, Fabian; Braun, Claude; Kaya, Ziya; Seelen, Marc A.; van Son, Willem J.; Waldherr, Ruediger; Schnuelle, Peter; Yard, Benito A.

Brain death (BD) is associated with tissue inflammation. As dopamine treatment of BD donor rats reduces renal monocyte infiltration, we tested if this treatment affects renal function and inflammation in recipients. BD was induced in F344 rats and was maintained for 6 h in all experiments. Dopamine

The effects of subchronic acrylamide exposure on gene expression, neurochemistry, hormones, and histopathology in the hypothalamus-pituitary-thyroid axis of male Fischer 344 rats

International Nuclear Information System (INIS)

Bowyer, J.F.; Latendresse, J.R.; Delongchamp, R.R.; Muskhelishvili, L.; Warbritton, A.R.; Thomas, M.; Tareke, E.; McDaniel, L.P.; Doerge, D.R.

2008-01-01

Acrylamide (AA) is an important industrial chemical that is neurotoxic in rodents and humans and carcinogenic in rodents. The observation of cancer in endocrine-responsive tissues in Fischer 344 rats has prompted hypotheses of hormonal dysregulation, as opposed to DNA damage, as the mechanism for tumor induction by AA. The current investigation examines possible evidence for disruption of the hypothalamic-pituitary-thyroid axis from 14 days of repeated exposure of male Fischer 344 rats to doses of AA that range from one that is carcinogenic after lifetime exposure (2.5 mg/kg/d), an intermediate dose (10 mg/kg/d), and a high dose (50 mg/kg/d) that is neurotoxic for this exposure time. The endpoints selected include: serum levels of thyroid and pituitary hormones; target tissue expression of genes involved in hormone synthesis, release, and receptors; neurotransmitters in the CNS that affect hormone homeostasis; and histopathological evaluation of target tissues. These studies showed virtually no evidence for systematic alteration of the hypothalamic-pituitary-thyroid axis and do not support hormone dysregulation as a plausible mechanism for AA-induced thyroid cancer in the Fischer 344 rat. Specifically, there were no significant changes in: 1) mRNA levels in hypothalamus or pituitary for TRH, TSH, thyroid hormone receptor α and β, as well 10 other hormones or releasing factors; 2) mRNA levels in thyroid for thyroglobulin, thyroid peroxidase, sodium iodide symporter, or type I deiodinases; 3) serum TSH or T3 levels (T4 was decreased at high dose only); 4) dopaminergic tone in the hypothalamus and pituitary or importantly 5) increased cell proliferation (Mki67 mRNA and Ki-67 protein levels were not increased) in thyroid or pituitary. These negative findings are consistent with a genotoxic mechanism of AA carcinogenicity based on metabolism to glycidamide and DNA adduct formation. Clarification of this mechanistic dichotomy may be useful in human cancer risk

Long-Term Oral Feeding of Lutein-Fortified Milk Increases Voluntary Running Distance in Rats

OpenAIRE

Matsumoto, Megumi; Hagio, Masahito; Inoue, Ryo; Mitani, Tomohiro; Yajima, Masako; Hara, Hiroshi; Yajima, Takaji

2014-01-01

To evaluate the effects of lutein-fortified milk administration on running exercise, a voluntary wheel-running model was performed in rats. Four-week-old F344 rats were administered test milk (10 mL/kg) daily following a 4-h fasting period, and their running distances were measured each day for a 9-week period. Total weekly running distance significantly increased from the sixth week until the end of the test period in lutein-supplemented rats (lutein-fortified milk administered) compared wit...

Radiochemical synthesis and biological evaluation of 3-[4-(4-[{sup 18}F]fluorobenzyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine as dopamine D{sub 4} receptor radioligand

Energy Technology Data Exchange (ETDEWEB)

Li, Gu-Cai; Zhang, Ru; Jiang, Kai-Jun; Chen, Bo [Hunan Institute of Engineering, Xiangtan (China). College of Chemistry and Chemical Engineering

2014-09-01

A potential dopamine D{sub 4} receptor radioligand, 3-[4-(4-[{sup 18}F]fluorobenzyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine was synthesized through a one-pot two-step procedure with total yield 18.5% (decay corrected). The molar radioactivity was 115 GBq/μmol and the radiochemical purity was greater than 95.5%. Its affinity and selectivity for dopamine D{sub 2}-like receptors were measured through in vitro receptor binding experiments and the K{sub i} for D{sub 4} receptor was determined to be 17 ± 0.5 nM. The partition coefficient (Log P) of it was determined to be 2.80 ± 0.10 through octanol experiment. The in vivo biodistribution of it in rat brain exposed that the radioligand penetrates through blood-brain- barrier (BBB) and may specifically bind to dopamine D{sub 4} receptor. The results indicated that the radioligand shows promise for the in vivo study of dopamine D{sub 4} receptor. (orig.)

Discordance between olfactory psychophysical measurements and olfactory event related potentials in five patients with olfactory dysfunction following upper respiratory infection.

Science.gov (United States)

Guan, Jing; Ni, Dao-feng; Wang, Jian; Gao, Zhi-qiang

2009-07-05

Subjective olfactory tests are easy to perform and popularly applied in the clinic, but using only these, it is difficult to diagnose all disorders of the olfactory system. The olfactory event related potentials technique offers further insight into the olfactory system and is an ideal objective test. This analysis was of subjective and objective data on the olfactory function of twelve patients with loss of smell associated with an upper respiratory infection (URI). We tested the twelve patients with URI induced olfactory loss by medical history, physical examination of the head and neck, olfactory tests and medical imaging. Olfactory function was assessed by Toyota and Takagi olfactometry including olfactory detection and recognition thresholds and olfactory event-related potentials (OERPs) recorded with OEP-98C Olfactometer. An unusual phenomenon was observed in five patients in whom the subjective detection and recognition thresholds were normal, while the expected OERPs were not detectable. We suggest that the discordance between olfactory psychophysical measurements and OERPs might be the results of abnormal electrophysiology related with olfactory neuropathy caused by viral URI. In addition, the measurement of OERPs might play a significant role in evaluating olfactory dysfunction.

Discordance between olfactory psychophysical measurements and olfactory event related potentials in five patients with olfactory dysfunction following upper respiratory infection

Institute of Scientific and Technical Information of China (English)

GUAN Jing; NI Dao-feng; WANG Jian; GAO Zhi-qiang

2009-01-01

Background Subjective olfactory tests are easy to perform and popularly applied in the clinic, but using only these, it is difficult to diagnose all disorders of the olfactory system. The olfactory event related potentials technique offers further insight into the olfactory system and is an ideal objective test. This analysis was of subjective and objective data on the olfactory function of twelve patients with loss of smell associated with an upper respiratory infection (URI). Methods We tested the twelve patients with URI induced olfactory loss by medical history, physical examination of the head and neck, olfactory tests and medical imaging. Olfactory function was assessed by Toyota and Takagi olfactometry including olfactory detection and recognition thresholds and olfactory event-related potentials (OERPs) recorded with OEP-98C Olfactometer. Results An unusual phenomenon was observed in five patients in whom the subjective detection and recognition thresholds were normal, while the expected OERPs were not detectable. Conclusions We suggest that the discordance between olfactory psychophysical measurements and OERPs might be the results of abnormal electrephysiology related with olfactory neuropathy caused by viral URI. In addition, the measurement of OERPs might play a significant role in evaluating olfactory dysfunction.

Electrophysiological evidence for a direct link between the main and accessory olfactory bulbs in the adult rat

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Victor eVargas-Barroso

2016-01-01

Full Text Available It is accepted that the main- and accessory- olfactory systems exhibit overlapping responses to pheromones and odorants. We performed whole-cell patch-clamp recordings in adult rat olfactory bulb slices to define a possible interaction between the first central relay of these systems: the accessory olfactory bulb (AOB and the main olfactory bulb (MOB. This was tested by applying electrical field stimulation in the dorsal part of the MOB while recording large principal cells (LPCs of the anterior AOB (aAOB. Additional recordings of LPCs were performed at either side of the plane of intersection between the aAOB and posterior-AOB (pAOB halves, or linea alba, while applying field stimulation to the opposite half. A total of 92 recorded neurons were filled during whole-cell recordings with biocytin and studied at the light microscope. Neurons located in the aAOB (n = 6, 8% send axon collaterals to the MOB since they were antidromically activated in the presence of glutamate receptor antagonists (APV and CNQX. Recorded LPCs evoked orthodromic excitatory post-synaptic responses (n = 6, aAOB; n = 1, pAOB or antidromic action potentials (n = 8, aAOB; n = 7, pAOB when applying field stimulation to the opposite half of the recording site (e.g. recording in aAOB; stimulating in pAOB and vice-versa. Observation of the filled neurons revealed that indeed, LPCs send axon branches that cross the linea alba to resolve in the internal cellular layer. Additionally, LPCs of the aAOB send axon collaterals to dorsal-MOB territory. Notably, while performing AOB recordings we found a sub-population of neurons (24 % of the total that exhibited voltage-dependent bursts of action potentials. Our findings support the existence of: 1. a direct projection from aAOB LPCs to dorsal-MOB, 2. physiologically active synapses linking aAOB and pAOB, and 3. pacemaker-like neurons in both AOB halves. This work was presented in the form of an Abstract on SfN 2014 (719.14/EE17.

Brain Region-Specific Expression of Genes Mapped within Quantitative Trait Loci for Behavioral Responsiveness to Acute Stress in Fisher 344 and Wistar Kyoto Male Rats (Open Access Postprint)

Science.gov (United States)

2018-03-12

responsiveness to acute stress in Fisher 344 and Wistar Kyoto male rats. PLoS ONE 13(3): e0194293. https://doi. org /10.1371/journal.pone.0194293 Editor...mapping analysis of complex traits in outbred rats. Nature genetics. 2013; 45(7): https://doi. org /10.1038/ng.2644 PMC3821058. PMID: 23708188 15...assisted breeding of congenic mouse strains. Nature Genetics. 1997; 17:280. https://doi. org /10.1038/ng1197-280 PMID: 9354790 21. The SC. SNP and haplotype

Gene alterations in radiation-induced F344 rat lung tumors

International Nuclear Information System (INIS)

Kelly, G.; Hahn, F.F.

1994-01-01

The p53 tumor suppressor gene is frequently altered in all major histopathologic types of human lung tumors. Reported p53 mutations include base substitutions, allelic loss, rearrangements, and deletions. Point mutations resulting in base substitutions are clustered within a highly conserved region of the gene encoding exons 508, and mutations in this region substantially extend the half-life of the p53 protein. In addition to its prominent importance in lung carcinogenesis, the p53 gene plays a critical role in the cellular response to genetic damage caused by radiation. Specifically, the protein product of p53 induces a pause or block at the G 1 to S boundary of the cell cycle following radiation-caused DNA damage. This G 1 block may allow the cell time to repair the damaged DNA prior to replication. Cells lacking a functional p53 protein fail to pause for repair and consequently accumulate mutations in the genome at an accelerated rate. p53 has also been implicated as a controlling factor in apoptosis or in programmed cell death induced by DNA-damaging agents, such as ionizing radiation. The p53 gene is mutated in approximately 50% of squamous cell carcinomas from uranium miners who inhaled high doses of radon daughters. The purpose of the present study was to determine if a similar percentage of squamous cell carcinomas with p53 mutations developed in the lungs of rats exposed to aerosols of 239 PuO 2

Histomorphology of the Olfactory Mucosa and Spinal Tissue Sparing Following Transplantation in the Partial Spinal Cord Injury in Rats

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H Delaviz

2011-01-01

Full Text Available Introduction & Objective: Nowadays, cellular and tissues transplant has become the focus of attention for spinal cord injury. It has been shown olfactory nerve cells or olfactory mucosa whi have more efficient on nervous tissue repair and they have been more studied in experimental study. Furthermore, they were used in a few clinical centers for spinal defect. But mucosa tissue and spinal tissue have different structure and there is doubt about the integration of mucosa tissue in nervous tissue. Thus, in this research the morphology and the effect of the fetal olfactory mucosa (FOM on spinal tissue sparing were studied after transplanted into the spinal cord hemisection in rats. Materials & Methods: This experimental study was conducted at Iran University of Medical Sciences in 2008. Of thirty eight female Sprague-Dawley (200-250g rats twenty- eight were spinally hemisected at the L1 spinal level and were randomized into two groups of 14 animals. Treatment group received FOM graft and the control group received fetal respiratory mucosa graft (FRM. The other animals received surgical procedure without spinal cord injury as a sham group. The morphology of the transplant region and spinal tissue sparing was examined histological eight weeks after transplantation. The collected data was analyzed by the SPSS software using ANOVA and the morphology of the transplant region were studied by light microscope. Results: Histological study showed that the both mucosa tissues could not integrate with the parenchyma of the spinal tissue. Although the FOM were fused more than the FRM with the host tissue but clear boundary was seen at the graft–host interface. The mean spinal tissue sparing of the treatment group increased a little compare to the control but a significant difference was not apparent whereas, the spinal tissue sparing in treatment and control groups compare to the sham group decreased significantly (P < 0.05. Conclusion: Transplantation of

Genomic expression analysis of rat chromosome 4 for skeletal traits at femoral neck.

Science.gov (United States)

Alam, Imranul; Sun, Qiwei; Liu, Lixiang; Koller, Daniel L; Liu, Yunlong; Edenberg, Howard J; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2008-10-08

Hip fracture is the most devastating osteoporotic fracture type with significant morbidity and mortality. Several studies in humans and animal models identified chromosomal regions linked to hip size and bone mass. Previously, we identified that the region of 4q21-q41 on rat chromosome (Chr) 4 harbors multiple femoral neck quantitative trait loci (QTLs) in inbred Fischer 344 (F344) and Lewis (LEW) rats. The purpose of this study is to identify the candidate genes for femoral neck structure and density by correlating gene expression in the proximal femur with the femoral neck phenotypes linked to the QTLs on Chr 4. RNA was extracted from proximal femora of 4-wk-old rats from F344 and LEW strains, and two other strains, Copenhagen 2331 and Dark Agouti, were used as a negative control. Microarray analysis was performed using Affymetrix Rat Genome 230 2.0 arrays. A total of 99 genes in the 4q21-q41 region were differentially expressed (P level of the gene in that strain. A total of 18 candidate genes were strongly correlated (r(2) > 0.50) with femoral neck width and prioritized for further analysis. Quantitative PCR analysis confirmed 14 of 18 of the candidate genes. Ingenuity pathway analysis revealed several direct or indirect relationships among the candidate genes related to angiogenesis (VEGF), bone growth (FGF2), bone formation (IGF2 and IGF2BP3), and resorption (TNF). This study provides a shortened list of genetic determinants of skeletal traits at the hip and may lead to novel approaches for prevention and treatment of hip fracture.

Prenatal prochloraz treatment significantly increases pregnancy length and reduces offspring weight but does not affect social-olfactory memory in rats.

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Dmytriyeva, Oksana; Klementiev, Boris; Berezin, Vladimir; Bock, Elisabeth

2013-07-01

Metabolites of the commonly used imidazole fungicide prochloraz are androgen receptor antagonists. They have been shown to block androgen-driven development and compromise reproductive function. We tested the effect of prochloraz on cognitive behavior following exposure to this fungicide during the perinatal period. Pregnant Wistar rats were administered a 200 mg/kg dose of prochloraz on gestational day (GD) 7, GD11, and GD15. The social recognition test (SRT) was performed on 7-week-old male rat offspring. We found an increase in pregnancy length and a significantly reduced pup weight on PND15 and PND40 but no effect of prenatal prochloraz exposure on social investigation or acquisition of social-olfactory memory. Copyright © 2012 Elsevier GmbH. All rights reserved.

Detection of acute renal allograft rejection by analysis of renal tissue proteomics in rat models of renal transplantation

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Dai Yong

2008-01-01

Full Text Available At present, the diagnosis of renal allograft rejection requires a renal biopsy. Clinical management of renal transplant patients would be improved if rapid, noninvasive and reliable biomarkers of rejection were available. This study is designed to determine whether such protein biomarkers can be found in renal-graft tissue proteomic approach. Orthotopic kidney transplantations were performed using Fisher (F344 or Lewis rats as donors and Lewis rats as recipients. Hence, there were two groups of renal transplant models: one is allograft (from F344 to Lewis rats; another is syngrafts (from Lewis to Lewis rats serving as control. Renal tissues were collected 3, 7 and 14 days after transplantation. As many as 18 samples were analyzed by 2-D Electrophoresis and mass spectrometry (MALDI-TOF-TOF-MS. Eleven differentially expressed proteins were identified between groups. In conclusion, proteomic technology can detect renal tissue proteins associated with acute renal allograft rejection. Identification of these proteins as diagnostic markers for rejection in patients′ urine or sera may be useful and non-invasive, and these proteins might serve as novel therapeutic targets that also help to improve the understanding of mechanism of renal rejection.

Effect of basal forebrain stimulation on extracellular acetylcholine release and blood flow in the olfactory bulb.

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Uchida, Sae; Kagitani, Fusako

2017-05-12

The olfactory bulb receives cholinergic basal forebrain input, as does the neocortex; however, the in vivo physiological functions regarding the release of extracellular acetylcholine and regulation of regional blood flow in the olfactory bulb are unclear. We used in vivo microdialysis to measure the extracellular acetylcholine levels in the olfactory bulb of urethane-anesthetized rats. Focal chemical stimulation by microinjection of L-glutamate into the horizontal limb of the diagonal band of Broca (HDB) in the basal forebrain, which is the main source of cholinergic input to the olfactory bulb, increased extracellular acetylcholine release in the ipsilateral olfactory bulb. When the regional cerebral blood flow was measured using laser speckle contrast imaging, the focal chemical stimulation of the HDB did not significantly alter the blood flow in the olfactory bulb, while increases were observed in the neocortex. Our results suggest a functional difference between the olfactory bulb and neocortex regarding cerebral blood flow regulation through the release of acetylcholine by cholinergic basal forebrain input.

Inhibition of beta-catenin and KRAS expressions by Piper betle in azoxymethane-induced colon cancer of male Fischer 344 rats.

Science.gov (United States)

Esa, Faezah; Ngah, Wan Zurinah Wan; Jamal, A Rahman A; Mohd Yusof, Yasmin Anum

2013-12-01

To investigate the chemopreventive effect of Piper betle (PB) on preneoplastic lesions (aberrant crypt foci [ACF]) induced by azoxymethane (AOM) in rats and its effect on colorectal cancer biomarkers (beta-catenin, KRAS, p53 and p21). A total of 32 male Fischer 344 rats were divided into phase 1 and phase 2 groups (8 and 24 weeks of AOM administration, respectively). Each phase was divided into 4 groups: control or normal saline (NS) (1 mL/kg), AOM (15 mg/kg body weight, once weekly for 2 weeks), PB (75 mg/kg body weight) and AOM + PB. PB was force-fed to rats a week after the second dose of AOM and NS. The colon was cut open longitudinally for methylene blue and immunohistochemistry staining. AOM administration showed formation of ACF at 8 and 24 weeks. PB, however, did not reduce ACF formation at either week, but it managed to reduce beta-catenin expression and KRAS found highly expressed in the AOM group of phase 1 rats. No immunoreactivities of p53 and p21 were detected in phase 2 rats, but instead inflammatory cells were visible in between the lesions. PB may act as a potential chemopreventive agent in the early stage of colon carcinogenesis by suppressing the expressions of beta-catenin and KRAS.

Interhemispheric EEG differences in olfactory bulbectomized rats with different cognitive abilities and brain beta-amyloid levels.

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Bobkova, Natalia; Vorobyov, Vasily; Medvinskaya, Natalia; Aleksandrova, Irina; Nesterova, Inna

2008-09-26

Alterations in electroencephalogram (EEG) asymmetry and deficits in interhemispheric integration of information have been shown in patients with Alzheimer's disease (AD). However, no direct evidence of an association between EEG asymmetry, morphological markers in the brain, and cognition was found either in AD patients or in AD models. In this study we used rats with bilateral olfactory bulbectomy (OBX) as one of the AD models and measured their learning/memory abilities, brain beta-amyloid levels and EEG spectra in symmetrical frontal and occipital cortices. One year after OBX or sham-surgery, the rats were tested with the Morris water paradigm and assigned to three groups: sham-operated rats, SO, and OBX rats with virtually normal, OBX(+), or abnormal, OBX(-), learning (memory) abilities. In OBX vs. SO, the theta EEG activity was enhanced to a higher extent in the right frontal cortex and in the left occipital cortex. This produced significant interhemispheric differences in the frontal cortex of the OBX(-) rats and in the occipital cortex of both OBX groups. The beta1 EEG asymmetry in SO was attenuated in OBX(+) and completely eliminated in OBX(-). OBX produced highly significant beta2 EEG decline in the right frontal cortex, with OBX(-)>OBX(+) rank order of strength. The beta-amyloid level, examined by post-mortem immunological DOT-analysis in the cortex-hippocampus samples, was about six-fold higher in OBX(-) than in SO, but significantly less (enhanced by 82% vs. SO) in OBX(+) than in OBX(-). The involvement of the brain mediatory systems in the observed EEG asymmetry differences is discussed.

Effects of a thirteen-week inhalation exposure to ethyl tertiary butyl ether on fischer-344 rats and CD-1 mice.

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Medinsky, M A; Wolf, D C; Cattley, R C; Wong, B; Janszen, D B; Farris, G M; Wright, G A; Bond, J A

1999-09-01

The 1990 Clean Air Act Amendments require that oxygenates be added to automotive fuels to reduce emissions of carbon monoxide and hydrocarbons. One potential oxygenate is the aliphatic ether ethyl tertiary butyl ether (ETBE). Our objective was to provide data on the potential toxic effects of ETBE. Male and female Fisher 344 rats and CD-1 mice were exposed to 0 (control), 500, 1750, or 5000 ppm of ETBE for 6 h/day and 5 days/wk over a 13-week period. ETBE exposure had no effect on mortality and body weight with the exception of an increase in body weights of the female rats in the 5000-ppm group. No major changes in clinical pathology parameters were noted for either rats or mice exposed to ETBE for 6 (rats only) or 13 weeks. Liver weights increased with increasing ETBE-exposure concentration for both sexes of rats and mice. Increases in kidney, adrenal, and heart (females only) weights were noted in rats. Degenerative changes in testicular seminiferous tubules were observed in male rats exposed to 1750 and 5000 ppm but were not seen in mice. This testicular lesion has not been reported previously for aliphatic ethers. Increases in the incidence of regenerative foci, rates of renal cell proliferation, and alpha2u-globulin containing protein droplets were noted in the kidneys of all treated male rats. These lesions are associated with the male rat-specific syndrome of alpha2u-globulin nephropathy. Increases in the incidence of centrilobular hepatocyte hypertrophy and rates of hepatocyte cell proliferation were seen in the livers of male and female mice in the 5000-ppm group, consistent with a mitogenic response to ETBE. These two target organs for ETBE toxicity, mouse liver and male rat kidney, have also been reported for methyl tertiary butyl ether and unleaded gasoline.

Dose patterns for 106RuO4 inhaled by Fischer-344 rats and Beagle dogs

International Nuclear Information System (INIS)

Runkle, G.E.; Snipes, M.B.

1978-01-01

Ruthenium-106 is an abundant fission product radionuclide in the nuclear fuel cycle which has potential for release as ruthenium tetroxide. Ruthenium tetroxide is a vapor, diffuses rapidly through air and porous materials, is chemically reactive and is rapidly reduced by any organic material to the dioxide form. Current ICRP recommendations consider the lung and gastrointestinal tract as critical organs for inhaled particles of radioactive ruthenium. This study was designed to provide additional data needed to adequately assess the risk for humans potentially exposed to 106 Ru encountered in this vapor form. Fischer-344 rats and Beagle dogs were given a nose-only exposure to 106 RuO 4 vapor to determine its distribution and retention patterns. The largest percentage of the initial body burden was found in the nasopharyngeal region of the respiratory tract. Less than 1% of the initial body burden was deposited in the pulmonary region. Most of the 106 Ru was cleared via the feces. A biomathematical simulation model was developed to fit the tissue and excreta data from the rat. This model was used to assess the short-term and long-term risks after inhalation of 106 RuO 4 . The observed deposition, retention and dose patterns for ruthenium tetroxide indicate the nasopharyngeal region should be considered as a critical region when considering the consequences of human exposure to this vapor

Comparative Study of Histopathologic Characterization of Azoxymethane-induced Colon Tumors in Three Inbred Rat Strains

DEFF Research Database (Denmark)

Kobæk Larsen, Morten; Fenger, Claus; Hansen, Ket

2002-01-01

To obtain controlled genetic variation, colon cancer was chemically induced by use of four subcutaneous injections of azoxymethane (15 mg/kg of body weight/wk) to rats of 3 inbred strains (BDIX/OrlIco, F344/NHsd, WAG/Rij). The selection was based on the availability of established colon cancer cell...

Disposition of inhaled 1-chloro-2-propanol in F344/N rats

International Nuclear Information System (INIS)

Bond, J.A.; Birnbaum, L.S.; Dahl, A.R.; Medinsky, M.A.; Sabourin, P.J.; Henderson, R.F.

1988-01-01

Propylene chlorohydrins, of which 1-chloro-2-propanol (1-CP) is a constituent, used as intermediates in the manufacture of propylene oxide and have been identified as potential air pollutants. The objective of these studies was to determine whether changes in the inhaled exposure concentration would affect the disposition of 1-CP in rats. In addition, experiments were conducted to identify the carbon atom of 1-CP that is metabolized to CO2. Rats were exposed nose-only to [14C]1-CP for 6 hr to 8.3 +/- 1.0 ppm (26.1 +/- 3.2 micrograms/liter air) or 77 +/- 4 ppm (245 +/- 13 micrograms/liter air) (mean +/- SE). There were two major routes of elimination of 14C, urinary and exhalation of CO2, which together accounted for about 80% of the total 14C in excreta and carcass. Half-times for elimination of 14C in urine as 14CO2 were between 3 and 7 hr with no effect of exposure concentration on the elimination half-times for either route. After the end of exposure, kidneys, livers, trachea, and nasal turbinates contained high concentrations of [14C]1-CP equivalents at both exposure concentrations (30-50 nmol 14C/g tissue for the 8 ppm exposure level and 200-350 nmol 14C/g tissue for the 80 ppm exposure level). Elimination of 14C from tissues was biphasic with about 50% of the material in a tissue being rapidly eliminated with a half-time of 1 to 3 hr and the remaining material slowly eliminated with a half-time of 40 to 80 hr. There was no effect of exposure concentration on elimination half-times in tissues. Major metabolites detected in urine and tissues (liver, kidney, and lung) were N-acetyl-S-(hydroxypropyl)cysteine and/or S-(2-hydroxypropyl)-cysteine. Little unmetabolized 1-CP (less than 1%) was detected in analyzed tissues or urine

Heterogeneous stock rat: a unique animal model for mapping genes influencing bone fragility.

Science.gov (United States)

Alam, Imranul; Koller, Daniel L; Sun, Qiwei; Roeder, Ryan K; Cañete, Toni; Blázquez, Gloria; López-Aumatell, Regina; Martínez-Membrives, Esther; Vicens-Costa, Elia; Mont, Carme; Díaz, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Whitley, Adam; Strid, Pernilla; Diez, Margarita; Johannesson, Martina; Flint, Jonathan; Econs, Michael J; Turner, Charles H; Foroud, Tatiana

2011-05-01

Previously, we demonstrated that skeletal mass, structure and biomechanical properties vary considerably among 11 different inbred rat strains. Subsequently, we performed quantitative trait loci (QTL) analysis in four inbred rat strains (F344, LEW, COP and DA) for different bone phenotypes and identified several candidate genes influencing various bone traits. The standard approach to narrowing QTL intervals down to a few candidate genes typically employs the generation of congenic lines, which is time consuming and often not successful. A potential alternative approach is to use a highly genetically informative animal model resource capable of delivering very high resolution gene mapping such as Heterogeneous stock (HS) rat. HS rat was derived from eight inbred progenitors: ACI/N, BN/SsN, BUF/N, F344/N, M520/N, MR/N, WKY/N and WN/N. The genetic recombination pattern generated across 50 generations in these rats has been shown to deliver ultra-high even gene-level resolution for complex genetic studies. The purpose of this study is to investigate the usefulness of the HS rat model for fine mapping and identification of genes underlying bone fragility phenotypes. We compared bone geometry, density and strength phenotypes at multiple skeletal sites in HS rats with those obtained from five of the eight progenitor inbred strains. In addition, we estimated the heritability for different bone phenotypes in these rats and employed principal component analysis to explore relationships among bone phenotypes in the HS rats. Our study demonstrates that significant variability exists for different skeletal phenotypes in HS rats compared with their inbred progenitors. In addition, we estimated high heritability for several bone phenotypes and biologically interpretable factors explaining significant overall variability, suggesting that the HS rat model could be a unique genetic resource for rapid and efficient discovery of the genetic determinants of bone fragility. Copyright �

Diabetes Enhances Dental Caries and Apical Periodontitis in Caries-Susceptible WBN/KobSlc Rats

OpenAIRE

Kodama, Yasushi; Matsuura, Masahiro; Sano, Tomoya; Nakahara, Yutaka; Ozaki, Kiyokazu; Narama, Isao; Matsuura, Tetsuro

2011-01-01

Many epidemiologic studies have suggested that diabetes may be an important risk factor for periodontal disease. To determine whether diabetes induces or enhances periodontal disease or dental caries, dental tissue from diabetic male and nondiabetic female WBN/KobSlc rats and male and female age-matched nondiabetic F344 rats was analyzed morphologically and morphometrically for these 2 types of lesions. Soft X-ray examination revealed that the incidence and severity of both molar caries and a...

Dose-response study in F344 rats exposed to (U,Pu)O2 or PuO2

International Nuclear Information System (INIS)

Mewhinney, J.A.; Eidson, A.F.; Hahn, F.F.; Scott, B.R.; Seiler, F.A.; Boecker, B.B.

1987-01-01

The relationship of radiation dose to lung and the biological effect observed was investigated following inhalation of two types of plutonium-containing particulate materials in rats. Bulk powder samples of the two materials were obtained from within gloveboxes used in the routine manufacture of mixed plutonium and uranium oxide nuclear fuel. The materials were a solid solution of uranium and plutonium treated at 1750 0 C and a PuO 2 feedstock. Groups of rats received a single inhalation exposure to a material to achieve one of three levels of initial pulmonary burden. Rats were maintained for their lifespan to observe the biological effects produced. These effects were observed in the lungs of rats exposed to either type of particle. The same types of lung cancer were produced by both particulate materials. The incidences of cancers were also similar at comparable levels of initial pulmonary burden for the two materials. The crude incidence of lung cancers for rats exposed to these materials was not different than those reported for similar studies that used laboratory-produced aerosols of PuO 2 . Using a linear dose-effect model, the relative risk of lung cancer for rats exposed to these industrial materials was 2.3 +- 1.0 (SE) at a lung dose of 100 rad. The doubling dose for lung cancers was 78 +- 63 rad to lung to median life span. 21 refs., 9 figs., 10 tabs

Cytological organization of the alpha component of the anterior olfactory nucleus and olfactory limbus

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Jorge A Larriva-Sahd

2012-06-01

Full Text Available This study describes the microscopic organization of a wedge-shaped area at the intersection of the main and accessory olfactory bulbs, or olfactory limbus , and an additional component of the anterior olfactory nucleus or alpha accessory olfactory bulb that lies underneath of the accessory olfactory bulb. The olfactory limbus consists of a modified bulbar cortex bounded anteriorly by the main olfactory bulb and posteriorly by the accessory olfactory bulb. In Nissl-stained specimens the olfactory limbus differs from the main olfactory bulb by a progressive, antero-posterior decrease in thickness or absence of the external plexiform, mitral/tufted cell, and granule cell layers. On cytoarchitectual grounds the olfactory limbus is divided from rostral to caudal into three distinct components: a stripe of glomerular-free cortex or preolfactory area, a second or necklace glomerular area, and a wedge-shaped or interstitial area crowned by the so-called modified glomeruli that appear to belong to the anterior accessory olfactory bulb. The strategic location and interactions with the main and accessory olfactory bulbs, together with the previously noted functional and connectional evidence, suggest that the olfactory limbus may be related to both sensory modalities. The alpha component of the anterior olfactory nucleus, a slender cellular cluster (i.e., 650 x 150 µm paralleling the base of the accessory olfactory bulb, contains two neuron types: a pyramidal-like neuron and an interneuron. Dendrites of pyramidal-like cells organize into a single bundle that ascends avoiding the accessory olfactory bulb to resolve in a trigone bounded by the edge of the olfactory limbus, the accessory olfactory bulb and the dorsal part of the anterior olfactory nucleus. Utrastructurally, the neuropil of the alpha component contains three types of synaptic terminals; one of them immunoreactive to the enzyme glutamate decarboxylase, isoform 67.

Transcriptional responses in the rat nasal epithelium following subchronic inhalation of naphthalene vapor

International Nuclear Information System (INIS)

Clewell, H.J.; Efremenko, A.; Campbell, J.L.; Dodd, D.E.; Thomas, R.S.

2014-01-01

Male and female Fischer 344 rats were exposed to naphthalene vapors at 0 (controls), 0.1, 1, 10, and 30 ppm for 6 h/d, 5 d/wk, over a 90-day period. Following exposure, the respiratory epithelium and olfactory epithelium from the nasal cavity were dissected separately, RNA was isolated, and gene expression microarray analysis was conducted. Only a few significant gene expression changes were observed in the olfactory or respiratory epithelium of either gender at the lowest concentration (0.1 ppm). At the 1.0 ppm concentration there was limited evidence of an oxidative stress response in the respiratory epithelium, but not in the olfactory epithelium. In contrast, a large number of significantly enriched cellular pathway responses were observed in both tissues at the two highest concentrations (10 and 30 ppm, which correspond to tumorigenic concentrations in the NTP bioassay). The nature of these responses supports a mode of action involving oxidative stress, inflammation and proliferation. These results are consistent with a dose-dependent transition in the mode of action for naphthalene toxicity/carcinogenicity between 1.0 and 10 ppm in the rat. In the female olfactory epithelium (the gender/site with the highest incidences of neuroblastomas in the NTP bioassay), the lowest concentration at which any signaling pathway was significantly affected, as characterized by the median pathway benchmark dose (BMD) or its 95% lower bound (BMDL) was 6.0 or 3.7 ppm, respectively, while the lowest female olfactory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 16.1, 11.1, and 8.4 ppm, respectively. In the male respiratory epithelium (the gender/site with the highest incidences of adenomas in the NTP bioassay), the lowest pathway BMD and BMDL were 0.4 and 0.3 ppm, respectively, and the lowest male respiratory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 0.5, 0.7, and 0.9 ppm

Transcriptional responses in the rat nasal epithelium following subchronic inhalation of naphthalene vapor

Energy Technology Data Exchange (ETDEWEB)

Clewell, H.J., E-mail: hclewell@thehamner.org; Efremenko, A.; Campbell, J.L.; Dodd, D.E.; Thomas, R.S.

2014-10-01

Male and female Fischer 344 rats were exposed to naphthalene vapors at 0 (controls), 0.1, 1, 10, and 30 ppm for 6 h/d, 5 d/wk, over a 90-day period. Following exposure, the respiratory epithelium and olfactory epithelium from the nasal cavity were dissected separately, RNA was isolated, and gene expression microarray analysis was conducted. Only a few significant gene expression changes were observed in the olfactory or respiratory epithelium of either gender at the lowest concentration (0.1 ppm). At the 1.0 ppm concentration there was limited evidence of an oxidative stress response in the respiratory epithelium, but not in the olfactory epithelium. In contrast, a large number of significantly enriched cellular pathway responses were observed in both tissues at the two highest concentrations (10 and 30 ppm, which correspond to tumorigenic concentrations in the NTP bioassay). The nature of these responses supports a mode of action involving oxidative stress, inflammation and proliferation. These results are consistent with a dose-dependent transition in the mode of action for naphthalene toxicity/carcinogenicity between 1.0 and 10 ppm in the rat. In the female olfactory epithelium (the gender/site with the highest incidences of neuroblastomas in the NTP bioassay), the lowest concentration at which any signaling pathway was significantly affected, as characterized by the median pathway benchmark dose (BMD) or its 95% lower bound (BMDL) was 6.0 or 3.7 ppm, respectively, while the lowest female olfactory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 16.1, 11.1, and 8.4 ppm, respectively. In the male respiratory epithelium (the gender/site with the highest incidences of adenomas in the NTP bioassay), the lowest pathway BMD and BMDL were 0.4 and 0.3 ppm, respectively, and the lowest male respiratory BMD values for pathways related to glutathione homeostasis, inflammation, and proliferation were 0.5, 0.7, and 0.9 ppm

NTP technical report on the toxicity studies of Cupric Sulfate (CAS No. 7758-99-8) Administered in Drinking Water and Feed to F344/N Rats and B6C3F1 Mice.

Science.gov (United States)

Hebert, Charles

1993-07-01

Cupric sulfate is an inorganic salt which is widely used in industry, agriculture, and veterinary medicine. Its applications include use as an algicide in potable waters and as a feed additive and therapeutic agent in swine, sheep, and cattle. Because copper salts are found in human water supplies, toxicity studies of cupric sulfate pentahydrate were conducted in male and female F344/N rats and B6C3F1 mice by the drinking water (2-week studies only) and dosed feed routes (2-week and 13-week studies). Animals were evaluated for hematology, clinical chemistry, urinalysis, reproductive toxicity, tissue metal accumulation, and histopathology. In the 2-week drinking water studies, groups of five rats and five mice per sex received cupric sulfate at concentrations of 300 to 30,000 ppm for 15 days. One female rat, one male mouse, and three female mice in the 3000 ppm groups and all rats and mice in the 10,000 and 30,000 ppm groups died before the end of the studies. The remaining mice and rats in the 3000 ppm groups gained little or lost weight. Water consumption in the three highest dose groups of both species was reduced by more than 65%. Clinical signs observed in these groups were typical of those seen in moribund animals and were attributed to dehydration. The only gross or microscopic change specifically related to cupric sulfate toxicity was an increase in the size and number of cytoplasmic protein droplets in the epithelium of the renal proximal convoluted tubule in male rats from the 300 and 1000-ppm groups. In the 2-week feed studies, groups of five rats and five mice per sex were fed diets containing 1000 to 16,000 ppm cupric sulfate. No chemical-related deaths occurred in any dose group. Compared to the controls, rats and mice in the two highest dose groups had reduced body weight gains which were attributed to decreased feed consumption. Hyperplasia with hyperkeratosis of the squamous epithelium on the limiting ridge of the forestomach was seen in rats and

Continuous spatial representations in the olfactory bulb may reflect perceptual categories

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Benjamin eAuffarth

2011-10-01

Full Text Available In sensory processing of odors, the olfactory bulb is an important relay station, where odor representations are noise-filtered, sharpened, and possibly re-organized. An organization by perceptual qualities has been found previously in the piriform cortex, however several recent studies indicate that the olfactory bulb code reflects behaviorally relevant dimensions spatially as well as at the population level. We apply a statistical analysis on 2-deoxyglucose images, taken over the entire bulb of glomerular layer of the rat, in order to see how the recognition of odors in the nose is translated into a map of odor quality in the brain. We first confirm previous studies that the first principal component could be related to pleasantness, however the next higher principal components are not directly clear. We then find mostly continuous spatial representations for perceptual categories. We compare the space spanned by spatial and population codes to human reports of perceptual similarity between odors and our results suggest that perceptual categories could be already embedded in glomerular activations and that spatial representations give a better match than population codes. This suggests that human and rat perceptual dimensions of odorant coding are related and indicates that perceptual qualities could be represented as continuous spatial codes of the olfactory bulb glomerulus population.

Gender-typical olfactory regulation of sexual behavior in goldfish

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Makito eKobayashi

2014-04-01

Full Text Available It is known that olfaction is essential for the occurrence of sexual behavior in male goldfish. Sex pheromones from ovulatory females elicit male sexual behavior, chasing and sperm releasing act. In female goldfish, ovarian prostaglandin F2α (PGF elicits female sexual behavior, egg releasing act. It has been considered that olfaction does not affect sexual behavior in female goldfish. In the present study, we reexamined the involvement of olfaction in sexual behavior of female goldfish. Olfaction was blocked in male and female goldfish by two methods: nasal occlusion (NO which blocks the reception of olfactants, and olfactory tract section (OTX which blocks transmission of olfactory information from the olfactory bulb to the telencephalon. Sexual behavior of goldfish was induced by administration of PGF to females, an established method for inducing goldfish sexual behavior in both sexes. Sexual behavior in males was suppressed by NO and OTX as previously reported because of lack of pheromone stimulation. In females, NO suppressed sexual behavior but OTX did not affect the occurrence of sexual behavior. Females treated with both NO and OTX performed sexual behavior normally. These results indicate that olfaction is essential in female goldfish to perform sexual behavior as in males but in a different manner. The lack of olfaction in males causes lack of pheromonal stimulation, resulting in no behavior elicited. Whereas the results of female experiments suggest that lack of olfaction in females causes strong inhibition of sexual behavior mediated by the olfactory pathway. Olfactory tract section is considered to block the pathway and remove this inhibition, resulting in the resumption of the behavior. By subtract sectioning of the olfactory tract, it was found that this inhibition was mediated by the medial olfactory tracts, not the lateral olfactory tracts. Thus, it is concluded that goldfish has gender-typical olfactory regulation for sexual

Methyl isobutyl ketone (MIBK) induction of α2u-globulin nephropathy in male, but not female rats

International Nuclear Information System (INIS)

Borghoff, S.J.; Hard, G.C.; Berdasco, N.M.; Gingell, R.; Green, S.M.; Gulledge, W.

2009-01-01

Male F-344 rats were administered corn oil (vehicle control), d-limonene (positive control, 300 mg/kg), or MIBK (1000 mg/kg) and female F-344 rats corn oil (vehicle control) or MIBK for 10 consecutive days by oral gavage. Approximately 24 h after the final dose the kidneys were excised and the left kidney prepared and evaluated for histological changes including protein (hyaline) droplet accumulation, immunohistochemical staining for α2u-globulin (α2u), and proliferating cell nuclear antigen (PCNA) to quantitate renal cell proliferation. The right kidney was prepared for quantitation of total protein and α2u using an ELISA. MIBK elicited an increase in protein droplets, accumulation of α2u, and renal cell proliferation in male, but not female rats, responses characteristic of α2u-mediated nephropathy. MIBK produced identical histopathological changes in the male rat kidney when compared to d-limonene, an acknowledged inducer of α2u-nephropathy except that the grade of severity tended to be slightly lower with MIBK. MIBK did not induce any effects in female rats. Therefore, renal histopathology, along with the other measures of α2u accumulation, provides additional weight of evidence to support the inclusion of MIBK in the category of chemicals exerting renal effects through a α2u-nephropathy-mediated mode-of-action

Green tea, phytic acid, and inositol in combination reduced the incidence of azoxymethane-induced colon tumors in Fisher 344 male rats.

Science.gov (United States)

Khatiwada, Janak; Verghese, Martha; Davis, Shurrita; Williams, Leonard L

2011-11-01

Experimental as well as epidemiologic studies in human populations provide evidence that consumption of phytochemicals reduces the incidence of degenerative diseases. Green tea (GT) catechins are known for their antioxidative potential. Phytic acid (PA) also acts as a natural antioxidant and may have numerous health benefits. This experiment was designed to investigate the inhibitory effects of combinations of 1% and 2% GT, PA, and inositol (I) in reducing the incidence of azoxymethane-induced colon tumors in Fisher 344 male rats. After an acclimatization period of 1 week, nine groups of rats (15 rats per group) were initially assigned to consume AIN 93 G diet and later AIN 93 M diet after 20 weeks of age. Treatments were given in drinking water. All rats received azoxymethane injections (16 mg/kg of body weight) subcutaneously at 7 and 8 weeks of age. Rats were killed at 45 weeks of age by CO(2) euthanasia. Tumor incidence (93.76%) and the number of tumors per tumor-bearing rat ratio (2.25) were significantly (P<.05) higher in the control group compared with treatment groups. Glutathione S-transferase activity was significantly (P<.05) higher in rats fed combinations of 2% GT+PA+I and GT+PA (33.25 ± 1.23 and 29.83 ± 1.10 μmol/mL, respectively) compared with other groups. These findings suggest that the synergistic effect of the 2% level of GT, PA, and I may reduce the incidence of colon tumors and therefore have potential as a chemopreventive agent.

Odor-evoked inhibition of olfactory sensory neurons drives olfactory perception in Drosophila.

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Cao, Li-Hui; Yang, Dong; Wu, Wei; Zeng, Xiankun; Jing, Bi-Yang; Li, Meng-Tong; Qin, Shanshan; Tang, Chao; Tu, Yuhai; Luo, Dong-Gen

2017-11-07

Inhibitory response occurs throughout the nervous system, including the peripheral olfactory system. While odor-evoked excitation in peripheral olfactory cells is known to encode odor information, the molecular mechanism and functional roles of odor-evoked inhibition remain largely unknown. Here, we examined Drosophila olfactory sensory neurons and found that inhibitory odors triggered outward receptor currents by reducing the constitutive activities of odorant receptors, inhibiting the basal spike firing in olfactory sensory neurons. Remarkably, this odor-evoked inhibition of olfactory sensory neurons elicited by itself a full range of olfactory behaviors from attraction to avoidance, as did odor-evoked olfactory sensory neuron excitation. These results indicated that peripheral inhibition is comparable to excitation in encoding sensory signals rather than merely regulating excitation. Furthermore, we demonstrated that a bidirectional code with both odor-evoked inhibition and excitation in single olfactory sensory neurons increases the odor-coding capacity, providing a means of efficient sensory encoding.

Ex vivo adenoviral vector-mediated neurotrophin gene transfer to olfactory ensheathing glia : effects on rubrospinal tract regeneration, lesion size, and functional recovery after implantation in the injured rat spinal cord

NARCIS (Netherlands)

Ruitenberg, Marc J; Plant, Giles W; Hamers, Frank P T; Wortel, Joke; Blits, Bas; Dijkhuizen, Paul A; Gispen, Willem Hendrik; Boer, Gerard J; Verhaagen, J.

2003-01-01

The present study uniquely combines olfactory ensheathing glia (OEG) implantation with ex vivo adenoviral (AdV) vector-based neurotrophin gene therapy in an attempt to enhance regeneration after cervical spinal cord injury. Primary OEG were transduced with AdV vectors encoding rat brain-derived

Inhalation exposure to ethylene induces eosinophilic rhinitis and nasal epithelial remodeling in Fischer 344 rats.

Science.gov (United States)

Brandenberger, Christina; Hotchkiss, Jon A; Krieger, Shannon M; Pottenger, Lynn H; Harkema, Jack R

2015-11-05

This study investigated the time- and concentration-dependent effects of inhaled ethylene on eosinophilic rhinitis and nasal epithelial remodeling in Fisher 344 rats exposed to 0, 10, 50, 300, or 10,000 ppm ethylene, 6 h/day, 5 days/week for up to 4 weeks. Morphometric quantitation of eosinophilic inflammation and mucous cell metaplasia/hyperplasia (MCM) and nasal mucosal gene expression were evaluated at anatomic sites previously shown to undergo ethylene-induced epithelial remodeling. Serum levels of total IgE, IgG1 and IgG2a were measured to determine if ethylene exposure increased the expression of Th2-associated (IgE and IgG1) relative to Th1-associated (IgG2a) antibody isotypes. Rats exposed to 0 or 10,000 ppm for 1, 3, 5, 10, or 20 days were analyzed to assess the temporal pattern of ethylene-induced alterations in nasal epithelial cell proliferation, morphology and gene expression. Rats exposed to 0, 10, 50, 300, and 10,000 ppm ethylene for 20 days were analyzed to assess concentration-dependent effects on lesion development. Additional rats exposed 4 weeks to 0, 300, or 10,000 ppm ethylene were held for 13 weeks post-exposure to examine the persistence of ethylene-induced mucosal alterations. The data indicate that cell death and reparative cell proliferation were not a part of the pathogenesis of ethylene-induced nasal lesions. Enhanced gene expression of Th2 cytokines (e.g., IL-5, IL-13) and chitinase (YM1/2) in the nasal mucosa was much greater than that of Th1 cytokines (e.g., IFNγ) after ethylene exposure. A significant increase in MCM was measured after 5 days of exposure to 10,000 ppm ethylene and after 20 days of exposure 10 ppm ethylene. Ethylene-induced MCM was reversible after cessation of exposure. No increase in total serum IgE, IgG1 or IgG2a was measured in any ethylene-exposed group. These data do not support involvement of an immune-mediated allergic mechanism in the pathogenesis of ethylene-induced nasal lesions in rats. Repeated

Subchronic toxicity studies of t-butyl alcohol in rats and mice.

Science.gov (United States)

Lindamood, C; Farnell, D R; Giles, H D; Prejean, J D; Collins, J J; Takahashi, K; Maronpot, R R

1992-07-01

The purpose of this study was to evaluate the toxicity of t-butyl alcohol, an important commodity chemical, an additive to unleaded gasoline, and a contaminant of drinking water. Ninety-day toxicity studies were conducted in B6C3F1 mice and Fischer 344 (F344) rats of both sexes using dosed water. Dose levels of t-butyl alcohol were 0, 0.25, 0.5, 1, 2, and 4% (w/v). Lethality was observed at the 4% level of both sexes and species. Weight-gain depression was present in all dose levels of male rats; 4% female rats; 1, 2, and 4% male mice; and 2 and 4% female mice. Water consumption was increased at lower dose levels in male rats and decreased in the higher dose levels of both sexes of rats and female mice. Clinical signs in rats were ataxia in both sexes and hypoactivity in males. Clinical signs in mice were ataxia, abnormal posture, and hypoactivity. In rats, urine volumes were reduced, in association with crystalluria. Gross lesions at necropsy were urinary tract calculi, renal pelvic and ureteral dilatation, and thickening of the urinary bladder mucosa. Microscopic lesions were hyperplasia of transitional epithelia and inflammation of the urinary bladder. In male rats treated with t-butyl alcohol, microscopic renal changes were suggestive of alpha-2 mu-globulin nephropathy. No-effect levels for the urinary tract lesions were 1% in male rats and mice (803.7 mg/kg/day for the male rats and 1565.8 mg/kg/day for the male mice) and 2% in female rats and mice (1451.5 mg/kg/day for the female rats and 4362.9 mg/kg/day for the female mice). The results indicate that in rodents the urinary tract is the target organ for t-butyl alcohol toxicity, and males are more sensitive to t-butyl alcohol toxicity than females.

Transient reversal of olfactory preference following castration in male rats: Implication for estrogen receptor involvement.

Science.gov (United States)

Xiao, Kai; Chiba, Atsuhiko; Sakuma, Yasuo; Kondo, Yasuhiko

2015-12-01

We examined the effects of the sex steroid milieu on sexual odor preference of sexually-experienced male rats using an alternate choice paradigm after endocrine manipulations. Gonadally intact (GI) males showed a male typical preference, i.e. spent longer time sniffing estrous females than males or ovariectomized females. At 1-2 weeks after orchidectomy (ORx), the males exhibited a transient preference for sexually vigorous males, a female typical preference pattern, followed by a total loss of preference after 4 weeks. Subcutaneous implantation of a Silastic capsule containing formestane (4-OHA), an aromatase inhibitor, had no effect on the preference of gonadally intact rats, but successfully prevented the emergence of the female typical preference after ORx. Capsules containing testosterone (T), dihydrotestosterone (DHT), or estradiol benzoate (EB), but not those with cholesterol (CH), restored masculine typical preference in ORx males at 2 weeks after the placement. The feminine preference for males was observed at 2-3 weeks after removal of T or EB capsules, but not by the removal of DHT and CH capsules. The results suggest that either exogenous androgen or estrogen maintains the masculine typical odor preference. Estrogen itself or produced through aromatization of circulating T, induces a transient feminine typical preference at a certain decreased titer during its disappearance from the circulation. Estrogen at different titers might determine appearance of masculine or feminine typical olfactory preference in adult ORx rats. Copyright © 2015 Elsevier Inc. All rights reserved.

Neuronal and glial release of (3H)GABA from the rat olfactory bulb

Energy Technology Data Exchange (ETDEWEB)

Jaffe, E.H.; Cuello, A.C.

1981-12-01

Neuronal versus glial components of the (3H)gamma-aminobutyric acid ((3H)GABA) release studies were performed with two different microdissected layers of the olfactory bulb of the rat. In some experiments substantia nigra was used as a GABAergic axonal system and the trigeminal ganglia as a peripheral glial model. Spontaneous release of (3H)GABA was always lower in neuronal elements as compared with glial cells. A veratridine-evoked release was observed from the ONL but not from the trigeminal ganglia. Tetrodotoxin (TTX) abolished the veratridine-evoked release from the ONL, which also showed a partial inhibition when high magnesium concentrations were used in a Ca2+-free solution. beta-Alanine was strongly exchanged with (3H)GABA from the ONL of animals with the olfactory nerve lesioned and from animals with no lesion; but only a small heteroexchange was found from the external plexiform layer. The beta-alanine heteroexchange was able to deplete the releasable GABA store from the ONL of lesioned animals. In nonlesioned animals and the external plexiform layer, the veratridine-stimulated release of (3H)GABA was not significantly reduced after the beta-alanine heteroexchange. Stimulation of the (3H)GABA release by high concentrations of potassium elicited a higher release rate from axonal terminals than from dendrites or glia. Neurones and glia showed a similar inhibition of (3H)GABA release when a high magnesium concentration was added to a calcium-free solution. When D-600 was used as a calcium-flux blocker no inhibition of the release was observed in glial cells, whereas an almost complete blockage was found in both neuronal preparations (substantia nigra and EPL). These results provide further evidence for differential release mechanisms of GABA from CNS neurones and glial cells.

Neural representations of novel objects associated with olfactory experience.

Science.gov (United States)

Ghio, Marta; Schulze, Patrick; Suchan, Boris; Bellebaum, Christian

2016-07-15

Object conceptual knowledge comprises information related to several motor and sensory modalities (e.g. for tools, how they look like, how to manipulate them). Whether and to which extent conceptual object knowledge is represented in the same sensory and motor systems recruited during object-specific learning experience is still a controversial question. A direct approach to assess the experience-dependence of conceptual object representations is based on training with novel objects. The present study extended previous research, which focused mainly on the role of manipulation experience for tool-like stimuli, by considering sensory experience only. Specifically, we examined the impact of experience in the non-dominant olfactory modality on the neural representation of novel objects. Sixteen healthy participants visually explored a set of novel objects during the training phase while for each object an odor (e.g., peppermint) was presented (olfactory-visual training). As control conditions, a second set of objects was only visually explored (visual-only training), and a third set was not part of the training. In a post-training fMRI session, participants performed an old/new task with pictures of objects associated with olfactory-visual and visual-only training (old) and no training objects (new). Although we did not find any evidence of activations in primary olfactory areas, the processing of olfactory-visual versus visual-only training objects elicited greater activation in the right anterior hippocampus, a region included in the extended olfactory network. This finding is discussed in terms of different functional roles of the hippocampus in olfactory processes. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of combined exposure of F344 rats to radiation and chronically inhaled cigarette smoke

International Nuclear Information System (INIS)

Finch, G.L.; Nikula, K.J.; Barr, E.B.

1995-01-01

Nuclear workers may be exposed to radiation in various forms, such as low-LET γ-irradiation or α-irradiation from inhaled 239 PuO 2 particles. These workers may then have increased risk for lung cancer compared to the general population. Of additional concern is the possibility that interactions between radiation and other carcinogens may increase the risk of cancer induction, compared to the risks from either type of agent alone. An important and common lung carcinogen is cigarette smoke. The purpose of this project is to better determine the combined effects of chronically inhaled cigarette smoke and either inhaled 239 PuO 2 or external, thoracic X-irradiation on the induction of lung cancer in rats. Histologic and dosimetric evaluations of rats in the CS + 239 PuO 2 study continue, and the study of CS + X rays is beginning

Dominance of layer-specific microvessel dilation in contrast-enhanced high-resolution fMRI: Comparison between hemodynamic spread and vascular architecture with CLARITY.

Science.gov (United States)

Poplawsky, Alexander John; Fukuda, Mitsuhiro; Kang, Bok-Man; Kim, Jae Hwan; Suh, Minah; Kim, Seong-Gi

2017-08-16

Contrast-enhanced cerebral blood volume-weighted (CBVw) fMRI response peaks are specific to the layer of evoked synaptic activity (Poplawsky et al., 2015), but the spatial resolution limit of CBVw fMRI is unknown. In this study, we measured the laminar spread of the CBVw fMRI evoked response in the external plexiform layer (EPL, 265 ± 65 μm anatomical thickness, mean ± SD, n = 30 locations from 5 rats) of the rat olfactory bulb during electrical stimulation of the lateral olfactory tract and examined its potential vascular source. First, we obtained the evoked CBVw fMRI responses with a 55 × 55 μm 2 in-plane resolution and a 500-μm thickness at 9.4 T, and found that the fMRI signal peaked predominantly in the inner half of EPL (136 ± 54 μm anatomical thickness). The mean full-width at half-maximum of these fMRI peaks was 347 ± 102 μm and the functional spread was approximately 100 or 200 μm when the effects of the laminar thicknesses of EPL or inner EPL were removed, respectively. Second, we visualized the vascular architecture of EPL from a different rat using a Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue hYdrogel (CLARITY)-based tissue preparation method and confocal microscopy. Microvascular segments with an outer diameter of limit of the fMRI spatial resolution is approximately the average length of 1-2 microvessel segments, which may be sufficient for examining sublaminar circuits. Copyright © 2017 Elsevier Inc. All rights reserved.

Sexual activity increases the number of newborn cells in the accessory olfactory bulb of male rats.

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Wendy ePortillo

2012-07-01

Full Text Available In rodents, sexual behavior depends on the adequate detection of sexually relevant stimuli. The olfactory bulb (OB is a region of the adult mammalian brain undergoing constant cell renewal by continuous integration of new granular and periglomerular neurons in the accessory (AOB and main (MOB olfactory bulbs. The proliferation, migration, survival, maturation, and integration of these new cells to the OB depend on the stimulus that the subjects received. We have previously shown that 15 days after females control (paced the sexual interaction an increase in the number of cells is observed in the AOB. No changes are observed in the number of cells when females are not allowed to control the sexual interaction. In the present study we investigated if in male rats sexual behavior increases the number of new cells in the OB. Male rats were divided in five groups: 1 males that did not receive any sexual stimulation, 2 males that were exposed to female odors, 3 males that mated for 1 h and could not pace their sexual interaction, 4 males that paced their sexual interaction and ejaculated 1 time and 5 males that paced their sexual interaction and ejaculated 3 times. All males received three injections of the DNA synthesis marker bromodeoxyuridine at 1h intervals, starting 1h before the beginning of the behavioral test. Fifteen days later, males were sacrificed and the brains were processed to identify new cells and to evaluate if they differentiated into neurons. The number of newborn cells increased in the granular cell layer (also known as the internal cell layer of the AOB in males that ejaculated one or three times controlling (paced the rate of the sexual interaction. Some of these new cells were identified as neurons. In contrast, no significant differences were found in the mitral cell layer (also known as the external cell layer and glomerular cell layer of the AOB. In addition, no significant differences were found between groups in the MOB in

Oxytocin Removes Estrous Female vs. Male Preference of Virgin Male Rats: Mediation of the Supraoptic Nucleus Via Olfactory Bulbs

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Xiao-Yu Liu

2017-10-01

Full Text Available Social functions of oxytocin (OT have been explored extensively; however, relationship between the effect of intranasally applied OT (nasal OT on the social preference (SP and intracerebral actions of endogenous OT remains unclear. To resolve this question, we first observed effects of nasal OT on the SP of virgin young adult male rats toward unfamiliar virgin estrous female (EF vs. virgin male rats. The results showed that the test male rats exhibited significantly more times and longer duration accessing the female than the male, which were acutely eliminated by nasal OT. Then, we examined the approaches mediating nasal OT effects on the activity of potential brain targets in Western blots and found that nasal OT activated the olfactory bulbs (OBs and the supraoptic nucleus (SON, but not the piriform cortex, amygdala and hippocampus as shown by significant changes in the expression of c-Fos and/or phosphorylated extracellular signal-regulated protein kinase (pERK 1/2. Moreover, microinjection of TTX into the OBs blocked nasal OT-evoked increases in pERK1/2 levels as well as the molecular association between ERK1/2 and OT-neurophysin in the SON. Electrolytic lesions of the lateral olfactory tract did not significantly change the basal levels of pERK 1/2 in the SON; however, upon nasal OT, pERK 1/2 levels in the SON reduced significantly. Lastly, microinjection of L-aminoadipic acid (gliotoxin into the SON to reduce OT levels reduced the duration of the test male’s accessing the EF and blocked the nasal OT-evoked increase in the duration of test male’s accessing the male while significantly increasing pERK1/2 levels in the amygdala. These findings reveal for the first time that nasal OT acutely eliminates virgin males’ SP to EFs via the OB-SON route and that OT neurons could mediate the social effects of nasal OT by suppressing social phobia generated in the amygdala.

32 CFR 344.5 - Relationships.

Science.gov (United States)

2010-07-01

... 32 National Defense 2 2010-07-01 2010-07-01 false Relationships. 344.5 Section 344.5 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL CHARTERS ASSISTANT SECRETARY OF DEFENSE FOR RESERVE AFFAIRS (ASD(RA)) § 344.5 Relationships. (a) In the...

The role of mitochondrial DNA large deletion for the development of presbycusis in Fischer 344 rats.

Science.gov (United States)

Yin, Shankai; Yu, Zhiping; Sockalingam, Ravi; Bance, Manohar; Sun, Genlou; Wang, Jian

2007-09-01

Age-related hearing loss, or presbycusis, has been associated with large-scale mitochondrial DNA (mtDNA) deletion in previous studies. However, the role of this mtDNA damage in presbycusis is still not clear because the deletion in inner ears has not been measured quantitatively and analyzed in parallel with the time course of presbycusis. In the present study, the deletion was quantified using quantitative real-time PCR (qRT-PCR) in male Fischer 344 rats of different ages. It was found that the deletion increased quickly during young adulthood and reached over 60% at 6 months of age. However, a significant hearing loss was not seen until after 12 months of age. The results suggest that the existence of the deletion per se does not necessarily imply cochlear damage, but rather a critical level of the accumulated deletion seems to precede the hearing loss. The long delay may indicate the involvement of mechanisms other than mtDNA deletion in the development of presbycusis.

Effects of combined exposure of F344 rats to radiation and chronically inhaled cigarette smoke

Energy Technology Data Exchange (ETDEWEB)

Finch, G.L.; Nikula, K.J.; Barr, E.B. [and others

1995-12-01

Nuclear workers may be exposed to radiation in various forms, such as low-LET {gamma}-irradiation or {alpha}-irradiation from inhaled {sup 239}PuO{sub 2} particles. These workers may then have increased risk for lung cancer compared to the general population. Of additional concern is the possibility that interactions between radiation and other carcinogens may increase the risk of cancer induction, compared to the risks from either type of agent alone. An important and common lung carcinogen is cigarette smoke. The purpose of this project is to better determine the combined effects of chronically inhaled cigarette smoke and either inhaled {sup 239}PuO{sub 2} or external, thoracic X-irradiation on the induction of lung cancer in rats. Histologic and dosimetric evaluations of rats in the CS + {sup 239}PuO{sub 2} study continue, and the study of CS + X rays is beginning.

Radiation-induced mesotheliomas in rats

International Nuclear Information System (INIS)

Hahn, F.F.; Haley, P.J.; Hubbs, A.F.; Hoover, M.D.; Lundgren, D.L.

1990-01-01

Mesotheliomas have been reported in rats that inhaled plutonium, but these tumors have not been extensively studied. To investigate a possible role for inhaled radionuclides in the induction of mesotheliomas, four life-span studies conducted at the Inhalation Toxicology Research Institute are reviewed. A total of 3076 F344 rats were exposed by inhalation to aerosols of 239 PuO 2 , mixed uranium-plutonium oxide, or 144 CeO 2 . Results showed that a low incidence of pleural mesotheliomas was induced by either alpha- or beta-emitting radionuclides deposited and retained in the lung. Chronic alpha irradiation was more effective per unit dose in producing mesotheliomas than chronic beta irradiation of the lung by a factor of 15. 7 refs., 1 tab., 7 figs

Role of Centrifugal Projections to the Olfactory Bulb in Olfactory Processing

Science.gov (United States)

Kiselycznyk, Carly L.; Zhang, Steven; Linster, Christine

2006-01-01

While there is evidence that feedback projections from cortical and neuromodulatory structures to the olfactory bulb are crucial for maintaining the oscillatory dynamics of olfactory bulb processing, it is not clear how changes in dynamics are related to odor perception. Using electrical lesions of the olfactory peduncle, sparing output from the…

Early survival factor deprivation in the olfactory epithelium enhances activity-dependent survival

Directory of Open Access Journals (Sweden)

Adrien eFrançois

2013-12-01

Full Text Available The neuronal olfactory epithelium undergoes permanent renewal because of environmental aggression. This renewal is partly regulated by factors modulating the level of neuronal apoptosis. Among them, we had previously characterized endothelin as neuroprotective. In this study, we explored the effect of cell survival factor deprivation in the olfactory epithelium by intranasal delivery of endothelin receptors antagonists to rat pups. This treatment induced an overall increase of apoptosis in the olfactory epithelium. The responses to odorants recorded by electroolfactogram were decreased in treated animal, a result consistent with a loss of olfactory sensory neurons (OSNs. However, the treated animal performed better in an olfactory orientation test based on maternal odor compared to non-treated littermates. This improved performance could be due to activity-dependent neuronal survival of OSNs in the context of increased apoptosis level. In order to demonstrate it, we odorized pups with octanal, a known ligand for the rI7 olfactory receptor (Olr226. We quantified the number of OSN expressing rI7 by RT-qPCR and whole mount in situ hybridization. While this number was reduced by the survival factor removal treatment, this reduction was abolished by the presence of its ligand. This improved survival was optimal for low concentration of odorant and was specific for rI7-expressing OSNs. Meanwhile, the number of rI7-expressing OSNs was not affected by the odorization in non-treated littermates; showing that the activity-dependant survival of OSNs did not affect the OSN population during the 10 days of odorization in control conditions. Overall, our study shows that when apoptosis is promoted in the olfactory mucosa, the activity-dependent neuronal plasticity allows faster tuning of the olfactory sensory neuron population towards detection of environmental odorants.

Olfactory disfunction and its relation olfactory bulb volume in Parkinson's disease.

Science.gov (United States)

Altinayar, S; Oner, S; Can, S; Kizilay, A; Kamisli, S; Sarac, K

2014-01-01

Olfactory dysfunction is the most frequently seen non-motor symptom of Idiopathic Parkinson's disease (IPD). The aim of this study is to analyze selective olfactory dysfunction, and olfactory bulb volume (OBV) in subtypes of IPD, and compare them with those of the healthy controls. Our study included 41 patients with IPD and age and gender matched 19 healthy controls. IPD patients were either tremor dominant (65.9%; TDPD) or non-tremor dominant (34.1%; NTDPD) type. All patients underwent neurological, ear, nose, and throat examinations, and orthonasal olfaction testing. Magnetic resonance imaging (MRI) technique was used to measure the volume of the olfactory bulb. A significant decrease in olfactory identification scores was found in the patient group. The patients had difficulty in discriminating between odors of mothballs, chocolate, Turkish coffee and soap. OBV did not differ between the patient, and the control groups. In the TDPD group, odor identification ability was decreased when compared to the control group. However, odor test results of NTDPD, control and TDPD groups were similar. OBV estimates of the TDPD group were not different from those of the control group, while in the NTDPD group OBVs were found to be decreased. In all patients with Parkinson's disease OBV values did not vary with age of the patients, duration of the disease, age at onset of the disease, and Unified Parkinson's Disease Rating Scale motor scores (UPDRS-m). Olfactory function is a complex process involving olfactory, and cortical structures as well. In Idiopathic Parkinson's disease, changes in OBV do not seem to be directly related to olfactory dysfunction.

[3H]GABA uptake as a marker for cell type in primary cultures of cerebellum and olfactory bulb

International Nuclear Information System (INIS)

Currie, D.N.; Dutton, G.R.

1980-01-01

Uptake of [ 3 H]GABA into cell cultures of rat cerebellum and olfactory bulb was studied by autoradiography, using β-alanine and aminocyclohexane carboxylic acid to distinguish neuronal-specific and glial-specific uptake. Neurons and astrocytes were also labelled by tetanus toxin and anti-GFAP respectively. This combination of markers allowed identification and quantification of several cell types. Cerebellar cultures were found to contain 77% granule neurons, 7.5% inhibitory neurons (probably stellate and basket cells) and 15% astrocytes. Olfactory bulb cultures were over 50% in small neurons which accumulated GABA, the olfactory bulb granule neuron being GABAergic in vivo. (Auth.)

Sevoflurane impairs post-operative olfactory memory but preserves olfactory function.

Science.gov (United States)

Kostopanagiotou, Georgia; Kalimeris, Konstantinos; Kesidis, Kyriakos; Matsota, Paraskevi; Dima, Cleanthi; Economou, Maria; Papageorgiou, Charalambos

2011-01-01

The effect of anaesthesia on olfaction has not been systematically studied. Our aim is to compare the effects of general and regional anaesthesia on olfactory acuity and memory in the immediate post-operative period. Sixty adult patients with the American Society of Anesthesiologists I and II status scheduled for elective minor surgery were included. Exclusion criteria were smoking, alcoholism, psychiatric disease and recent or past airway infection with resulting hyposmia. Patients were randomly allocated to one of three groups (in the analysis, n = 16 in each group): epidural anaesthesia (group E), general anaesthesia with propofol (group P) and general anaesthesia with sevoflurane (group S) of 40-120 min duration. The evening before surgery, at 0.5 and at 3 h post-operatively olfactory acuity and memory were tested, along with blood sampling to measure plasma melatonin and oxytocin levels. Olfactory acuity was tested with successive dilutions of n-butyl-alcohol, and olfactory memory (interpretation of odours) with the University of Pennsylvania Smell Identification Test. Patient characteristics did not differ between groups. Olfactory acuity was intact in all patients, before and after anaesthesia. Olfactory memory deteriorated in group S compared to groups P and E at both post-operative time-points. This was accompanied by a significant post-operative reduction of plasma melatonin levels in group S. Oxytocin levels remained constant in all groups. Our results manifest a specific effect of sevoflurane on olfactory memory, not observed with neuraxial or total intravenous anaesthesia. The misinterpretation of odours in the immediate post-operative period by sevoflurane could be mediated by the decreased levels of melatonin.

Differential response of olfactory sensory neuron populations to copper ion exposure in zebrafish

International Nuclear Information System (INIS)

Lazzari, Maurizio; Bettini, Simone; Milani, Liliana; Maurizii, Maria Gabriella; Franceschini, Valeria

2017-01-01

Highlights: • Copper exposure affects ciliated olfactory receptors more than microvillar cells. • Crypt olfactory sensory neurons are not affected by copper exposure. • Copper exposure induces an increase in the amount of sensory epithelium. - Abstract: The peripheral olfactory system of fish is in direct contact with the external aqueous environment, so dissolved contaminants can easily impair sensory functions and cause neurobehavioral injuries. The olfactory epithelium of fish is arranged in lamellae forming a rosette in the olfactory cavity and contains three main types of olfactory sensory neurons (OSNs): ciliated (cOSNs) and microvillous olfactory sensory neurons (mOSNs), common to all vertebrates, and a third minor group of olfactory neurons, crypt cells, absent in tetrapods. Since copper is a ubiquitously diffusing olfactory toxicant and a spreading contaminant in urban runoff, we investigated the effect of low copper concentration on the three different OSNs in the olfactory epithelium of zebrafish, a model system widely used in biological research. Image analysis was applied for morphometry and quantification of immunohistochemically detected OSNs. Copper exposure resulted in an evident decrease in olfactory epithelium thickness. Moreover, after exposure, the lamellae of the dorsal and ventral halves of the olfactory rosettes showed a different increase in their sensory areas, suggesting a lateral migration of new cells into non-sensory regions. The results of the present study provide clear evidence of a differential response of the three neural cell populations of zebrafish olfactory mucosa after 96 h of exposure to copper ions at the sublethal concentration of 30 μg L"−"1. Densitometric values of cONS, immunostained with anti-G _α_o_l_f, decreased of about 60% compared to the control. When the fish were transferred to water without copper addition and examined after 3, 10 and 30 days, we observed a partial restoration of anti-G _α_o_l_f

The Metabolism of Tetralin in Fischer 344 Rats

Science.gov (United States)

1986-04-01

would die from the disease . The relevance of nephropathy observed in male rats exposed to various hydrocarbons to the occurrence of renal neoplasia in man...34 often obscure pathologic evaluations. "Old-rat nephropathy" is a common degenerative kidney disease predominantly seen in the male rat. By careful...studies have been performed with n-hexane and n-heptane to characterize their metabolism and role in neurotoxicity (Perbellini et al., 1982; Bahima et

Effects of x irradiation on the postnatally-forming granule cell populations in the olfactory bulb, hippocampus, and cerebellum of the rat

International Nuclear Information System (INIS)

Bayer, S.A.; Altman, J.

1975-01-01

Beginning on the second postnatal day, either two (2X group), four (4X group) or six (6X group) daily or alternate daily exposures to low-level x irradiation (150 to 200 R) were used to interfere with the acquisition of granule cells in the olfactory bulb, hippocampus, and cerebellum of the rat. At 60 days of age, the relationship between post-irradiation recovery and permanent granule cell loss was assessed with two quantitative techniques. First, the total number of granule cells was determined to estimate the magnitude of permanent loss. Secondly, the number of labeled granule cells were counted on day 60 after a 3 H-thymidine injection given on either day 15 or on day 20 to estimate differential rates of cell proliferation during the recovery period. Permanent loss of granule cells was sustained in all regions by all schedules of irradiation. The time for the most effective exposures was earlier in the hippocampus and olfactory bulb than in the cerebellum. In all regions, both the irradiated groups and the controls showed a decrease in the level of cell proliferation between 15 and 20 days. The number of cells that could be labeled after either the 15 or 20 day injection was below control levels for all groups in the hippocampus, at control levels for all groups in the cerebellum, and either at (2X and 4X) or below (6X) control levels in the olfactory bulb. These results are discussed in the light of the formation time of the granule cells in each region

Effects of x-irradiation on the postnatally-forming granule cell populations in the olfactory bulb, hippocampus, and cerebellum of the rat

International Nuclear Information System (INIS)

Bayer, S.A.; Altman, J.

1975-01-01

Beginning on the second postnatal day, either two (2X group), four (4X group) or six (6X group) daily or alternate daily exposures to low-level x irradiation (150-200 r) were used to interfere with the acquisition of granule cells in the olfactory bulb, hippocampus, and cerebellum of the rat. At 60 days of age, the relationship between post-irradiation recovery and permanent granule cell loss was assessed with two quantitative techniques. First, the total number of granule cells was determined to estimate the magnitude of permanent loss. Secondly, the number of labeled granule cells were counted on day 60 after a 3 H-thymidine injection given on either day 15 or on day 20 to estimate differential rates of cell proliferation during the recovery period. Permanent loss of granule cells was sustained in all regions by all schedules of irradiation. The time for the most effective exposures was earlier in the hippocampus and olfactory bulb than in the cerebellum. In all regions, both the irradiated groups and the controls showed a decrease in the level of cell proliferation between 15 and 20 days. The number of cells that could be labeled after either the 15 or 20 day injection was below control levels for all groups in the hippocampus, at control levels for all groups in the cerebellum, and either at (2X and 4X) or below (6X) control levels in the olfactory bulb. These results are discussed in the light of the formation time of the granule cells in each region

Radiation-induced mesotheliomas in rats

Energy Technology Data Exchange (ETDEWEB)

Hahn, F.F.; Haley, P.J.; Hubbs, A.F.; Hoover, M.D.; Lundgren, D.L.

1990-01-01

Mesotheliomas have been reported in rats that inhaled plutonium, but these tumors have not been extensively studied. To investigate a possible role for inhaled radionuclides in the induction of mesotheliomas, four life-span studies conducted at the Inhalation Toxicology Research Institute are reviewed. A total of 3076 F344 rats were exposed by inhalation to aerosols of {sup 239}PuO{sub 2}, mixed uranium-plutonium oxide, or {sup 144}CeO{sub 2}. Results showed that a low incidence of pleural mesotheliomas was induced by either alpha- or beta-emitting radionuclides deposited and retained in the lung. Chronic alpha irradiation was more effective per unit dose in producing mesotheliomas than chronic beta irradiation of the lung by a factor of 15. 7 refs., 1 tab., 7 figs. (MHB)

Olfactory Neuroblastoma: Diagnostic Difficulty

Directory of Open Access Journals (Sweden)

Vidya MN,

2011-01-01

Full Text Available Olfactory neuroblastoma is an uncommon malignant tumor of sinonasal tract arising from the olfactory neuro epithelium. The olfactory neuroblastomas presenting with divergent histomorphologies like, epithelial appearance of cells, lacking a neuro fibrillary background and absence of rosettes are difficult to diagnose. Such cases require immunohistochemistry to establish the diagnosis. We describe the clinical features, pathological and immunohistochemical findings of grade IV Olfactory neuroblastoma in a 57 year old man

Internal cholinergic regulation of learning and recall in a model of olfactory processing

Directory of Open Access Journals (Sweden)

Licurgo Benemann Almeida

2016-11-01

Full Text Available In the olfactory system, cholinergic modulation has been associated with contrast modulation and changes in receptive fields in the olfactory bulb, as well the learning of odor associations in olfactory cortex. Computational modeling and behavioral studies suggest that cholinergic modulation could improve sensory processing and learning while preventing pro-active interference when task demands are high. However, how sensory inputs and/or learning regulate incoming modulation has not yet been elucidated. We here use a computational model of the olfactory bulb, piriform cortex (PC and horizontal limb of the diagonal band of Broca (HDB to explore how olfactory learning could regulate cholinergic inputs to the system in a closed feedback loop. In our model, the novelty of an odor is reflected in firing rates and sparseness of cortical neurons in response to that odor and these firing rates can directly regulate learning in the system by modifying cholinergic inputs to the system. In the model, cholinergic neurons reduce their firing in response to familiar odors – reducing plasticity in the PC, but increase their firing in response to novel odor – increasing PC plasticity. Recordings from HDB neurons in awake behaving rats reflect predictions from the model by showing that a subset of neurons decrease their firing as an odor becomes familiar.

Stimulatory effect of the D2 antagonist sulpiride on glucose utilization in dopaminergic regions of rat brain

Energy Technology Data Exchange (ETDEWEB)

Pizzolato, G; Soncrant, T T; Larson, D M; Rapoport, S I

1987-08-01

Local cerebral glucose utilization (LCGU) was measured, using the quantitative autoradiographic (/sup 14/C)2-deoxy-D-glucose method, in 56 brain regions of 3-month-old, awake Fischer-344 rats, after intraperitoneal administration of sulpiride (SULP) 100 mg/kg. SULP, an atypical neuroleptic, is a selective antagonist of D2 dopamine receptors. LCGU was reduced in a few nondopaminergic regions at 1 h after drug administration. Thereafter, SULP progressively elevated LCGU in many other regions. At 3 h, LCGU was elevated in 23% of the regions examined, most of which are related to the CNS dopaminergic system (caudate-putamen, nucleus accumbens, olfactory tubercle, lateral habenula, median eminence, paraventricular hypothalamic nucleus). Increases of LCGU were observed also in the suprachiasmatic nucleus, lateral geniculate, and inferior olive. These effects of SULP on LCGU differ from the effects of the typical neuroleptic haloperidol, which produces widespread decreases in LCGU in the rat brain. Selective actions on different subpopulations of dopamine receptors may explain the different effects of the two neuroleptics on brain metabolism, which correspond to their different clinical and behavioral actions.

Effects of mtDNA in SHR-mtF344 versus SHR conplastic strains on reduced OXPHOS enzyme levels, insulin resistance, cardiac hypertrophy, and systolic dysfunction

Czech Academy of Sciences Publication Activity Database

Houštěk, Josef; Vrbacký, Marek; Hejzlarová, Kateřina; Zídek, Václav; Landa, Vladimír; Šilhavý, Jan; Šimáková, Miroslava; Mlejnek, Petr; Kazdová, L.; Mikšík, Ivan; Neckář, Jan; Papoušek, František; Kolář, František; Kurtz, T. W.; Pravenec, Michal

2014-01-01

Roč. 46, č. 18 (2014), s. 671-678 ISSN 1094-8341 R&D Projects: GA MŠk(CZ) LL1204; GA ČR(CZ) GB14-36804G; GA ČR(CZ) GA13-10267S; GA MŠk(CZ) 7E10067 Institutional support: RVO:67985823 Keywords : SHR conplastic strain with F344 mtDNA * impaired glucose tolerance * systolic dysfunction Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 2.374, year: 2014

Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15ppm formaldehyde vapor

NARCIS (Netherlands)

Kuper, C. F.; Oostrum, L. van; Ma-Hock, L.; Durrer, S.; Woutersen, R.A.

2011-01-01

To investigate if local lymphoid tissues are a target of FA, nasopharynx-associated lymphoid tissues (NALT) and upper-respiratory tract-draining lymph nodes were examined in a 28-day inhalation study with FA vapor in Fischer-344 rats and B6C3F1 mice.Paraffin-embedded tissues were sectioned and

Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15 ppm formaldehyde vapor

NARCIS (Netherlands)

Kuper, C.F.; Oostrum, van L.; Ma-Hock, I.; Durrer, S.; Woutersen, R.A.

2011-01-01

To investigate if local lymphoid tissues are a target of FA, nasopharynx-associated lymphoid tissues (NALT) and upper-respiratory tract-draining lymph nodes were examined in a 28-day inhalation study with FA vapor in Fischer-344 rats and B6C3F1 mice. Paraffin-embedded tissues were sectioned and

Combined exposure of F344 rats to beryllium metal and plutonium-239 dioxide

Energy Technology Data Exchange (ETDEWEB)

Finch, G.L.; Carlton, W.W.; Rebar, A.H. [Purdue Univ., Lafayette, IN (United States)] [and others

1995-12-01

Nuclear weapons industry workers have the potential for inhalation exposures to plutonium (Pu) and other agents, such as beryllium (Be) metal. The purpose of this ongoing study is to investigate potential interactions between Pu and Be in the production of lung tumors in rats exposed by inhalation to particles of {sup 239}PuO{sub 2}, Be metal, or these agents in combination. Inhaled Pu deposited in the lung delivers high-linear-energy transfer, alpha-particle radiation and is known to induce pulmonary cancer in laboratory animals. Although the epidemiological evidence implicating Be in the induction of human lung cancer is weak and controversial, various studies in laboratory animals have demonstrated the pulmonary carcinogenicity of Be. As a result, Be is classified as a suspect human carcinogen in the United STates and as a demonstrated human carcinogen by the International Agency for Research on Cancer. This study is in progress.

Nanolipoprotein Particles (NLPs) as Versatile Vaccine Platforms for Co-delivery of Multiple Adjuvants with Subunit Antigens from Burkholderia spp. and F. tularensis - Annual Technical Report

Energy Technology Data Exchange (ETDEWEB)

Fischer, N. O. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

2015-04-16

The goal of this proposal is to demonstrate that co-localization of protein subunit antigens and adjuvants on nanolipoprotein particles (NLPs) can increase the protective efficacy of recombinant subunit antigens from Burkholderia spp. and Francisella tularensis against an aerosol challenge. NLPs are are biocompatible, high-density lipoprotein mimetics that are amenable to the incorporation of multiple, chemically-disparate adjuvant and antigen molecules. We hypothesize that the ability to co-localize optimized adjuvant formulations with subunit antigens within a single particle will enhance the stimulation and activation of key immune effector cells, increasing the protective efficacy of subunit antigen-based vaccines. While Burkholderia spp. and F. tularensis subunit antigens are the focus of this proposal, we anticipate that this approach is applicable to a wide range of DOD-relevant biothreat agents. The F344 rat aerosol challenge model for F. tularensis has been successfully established at Battelle under this contract, and Year 3 efficacy studies performed at Battelle demonstrated that an NLP vaccine formulation was able to enhance survival of female F344 rats relative to naïve animals. In addition, Year 3 focused on the incorporation of multiple Burkholderia antigens (both polysaccharides and proteins) onto adjuvanted NLPs, with immunological analysis poised to begin in the next quarter.

Passive immunization of fetal rats with antiserum to luteinizing hormone-releasing hormone (LHRH) or transection of the central roots of the nervus terminalis does not affect rat pups' preference for home nest.

Science.gov (United States)

Schwanzel-Fukuda, M; Pfaff, D W

1987-01-01

Luteinizing hormone-releasing hormone (LHRH) is found immunocytochemically in cell bodies and fibers of the nervus terminalis, a cranial nerve which courses from the nasal septum through the cribriform plate of the ethmoid bone (medial to the olfactory and vomeronasal nerves) and enters the forebrain, caudal to the olfactory bulbs. Immunoreactive LHRH is first detected in the nervus terminalis of the fetal rat at 15 days of gestation, preceding its detection by immunocytochemistry in any other area of the brain, including the median eminence, and preceding detection of immunoreactive luteinizing hormone (LH) in the anterior pituitary. During development of the rat fetus, the nervus terminalis is the principal source of LHRH in the nervous system from days 15 through 19 of a 21 day gestation period. We tested the notion that the LHRH system of the nervus terminalis is important for olfactory performance by examining the effects of administration of antisera to LHRH during fetal development (versus saline controls), or medial olfactory peduncle transections, in the neonatal rat, which would sever the central projections of the nervus terminalis (versus lateral peduncle transection, complete transection of the olfactory peduncles and the central nervus terminalis or controls) on preferences of rat pups for home nest. The hypothesis that LHRH is important for this chemosensory response was not confirmed. Neither antisera to LHRH nor medical olfactory peduncle transection disrupted preference for home shavings. Only complete olfactory peduncle transection had a significant effect compared to unoperated and sham-operated controls.

Effect of irradiation on olfactory function

International Nuclear Information System (INIS)

Aiba, Tsunemasa; Sugimoto, Midori; Matsuda, Yasuaki; Sugiura, Yoshikazu; Nakai, Yoshiaki; Nakajima, Toshifumi

1990-01-01

The effects of therapeutic irradiation on olfactory function were investigated in 20 patients who received radiation therapy because of a malignant tumor of the nose or paranasal sinuses. The standard olfaction test with a T and T olfactometer and an intravenous olfaction test were given before the radiation therapy, during the period of radiation therapy and 1, 3, 6 and 12 months or more later. Five patients whose olfactory epithelium was outside the radiation field showed no damage to olfactory function. The olfactory function of the other 15 patients whose olfactory epithelium had been exposed to radiation was not obviously changed or damaged at the time of radiation therapy. However, 6 months after irradiation, some patients showed a decline in olfactory function, and after 12 months, 4 of 7 patients showed severe damage to olfactory function. These results suggest that a therapeutic dose of irradiation will not cause severe damage to the olfactory function during the period of radiation therapy, but could cause delayed olfactory disorders in some patients after a few years. These olfactory disorders might be caused by damage to or degeneration of the olfactory epithelium or olfactory nerve. (author)

Involvement of right piriform cortex in olfactory familiarity judgments. : Familiarity judgment in olfaction

OpenAIRE

Plailly , Jane; Bensafi , Moustafa; Pachot-Clouard , Mathilde; Delon-Martin , Chantal; Kareken , David ,; Rouby , Catherine; Segebarth , Christoph; Royet , Jean ,

2005-01-01

International audience; Previous studies have shown activation of right orbitofrontal cortex during judgments of odor familiarity. In the present study, we sought to extend our knowledge about the neural circuits involved in such a task by exploring the involvement of the right prefrontal areas and limbic/primary olfactory structures. Fourteen right-handed male subjects were tested using fMRI with a single functional run of two olfactory conditions (odor detection and familiarity judgments). ...

Refined carbohydrate enhancement of aberrant crypt foci (ACF) in rat colon induced by the food-borne carcinogen 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ)

DEFF Research Database (Denmark)

Kristiansen, E.; Meyer, Otto A.; Thorup, I.

1996-01-01

,2-dimethylhydrazine dihydrochloride (DMH) and azoxymethane (AOM), the use of a diet-related colon cancer initiator, such as the heterocyclic amine 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ) formed during meat cooking, would probably give a more relevant insight into diet-related colon carcinogenesis......The aberrant crypt foci (ACF) bioassay has been used extensively to study the early effects of different dietary components on the colonic mucosa of laboratory rodents. ACF are proposed to represent preneoplastic lesions of colon cancer. Compared to the normally used initiators 1....... In the present study it is shown that a feeding regimen with continuous low IQ doses (0.03% in the diet) throughout a study period of 10 weeks has a significant effect on the induction of ACF in the colon of male F344 rats. In addition, the study illustrates that the incidence of the IQ-induced ACF can...

Immunocytochemistry of the olfactory marker protein.

Science.gov (United States)

Monti-Graziadei, G A; Margolis, F L; Harding, J W; Graziadei, P P

1977-12-01

The olfactory marker protein has been localized, by means of immunohistochemical techniques in the primary olfactory neurons of mice. The olfactory marker protein is not present in the staminal cells of the olfactory neuroepithelium, and the protein may be regarded as indicative of the functional stage of the neurons. Our data indicate that the olfactory marker protein is present in the synaptic terminals of the olfactory neurons at the level of the olfactory bulb glomeruli. The postsynaptic profiles of both mitral and periglomerular cells are negative.

Ionotropic crustacean olfactory receptors.

Directory of Open Access Journals (Sweden)

Elizabeth A Corey

Full Text Available The nature of the olfactory receptor in crustaceans, a major group of arthropods, has remained elusive. We report that spiny lobsters, Panulirus argus, express ionotropic receptors (IRs, the insect chemosensory variants of ionotropic glutamate receptors. Unlike insects IRs, which are expressed in a specific subset of olfactory cells, two lobster IR subunits are expressed in most, if not all, lobster olfactory receptor neurons (ORNs, as confirmed by antibody labeling and in situ hybridization. Ligand-specific ORN responses visualized by calcium imaging are consistent with a restricted expression pattern found for other potential subunits, suggesting that cell-specific expression of uncommon IR subunits determines the ligand sensitivity of individual cells. IRs are the only type of olfactory receptor that we have detected in spiny lobster olfactory tissue, suggesting that they likely mediate olfactory signaling. Given long-standing evidence for G protein-mediated signaling in activation of lobster ORNs, this finding raises the interesting specter that IRs act in concert with second messenger-mediated signaling.

Learning-dependent neurogenesis in the olfactory bulb determines long-term olfactory memory.

Science.gov (United States)

Sultan, S; Mandairon, N; Kermen, F; Garcia, S; Sacquet, J; Didier, A

2010-07-01

Inhibitory interneurons of the olfactory bulb are subjected to permanent adult neurogenesis. Their number is modulated by learning, suggesting that they could play a role in plastic changes of the bulbar network associated with olfactory memory. Adult male C57BL/6 mice were trained in an associative olfactory task, and we analyzed long-term retention of the task 5, 30, and 90 d post-training. In parallel, we assessed the fate of these newborn cells, mapped their distribution in the olfactory bulb and measured their functional implication using the immediate early gene Zif268. In a second set of experiments, we pharmacologically modulated glutamatergic transmission and using the same behavioral task assessed the consequences on memory retention and neurogenesis. Finally, by local infusion of an antimitotic drug, we selectively blocked neurogenesis during acquisition of the task and looked at the effects on memory retention. First we demonstrated that retrieval of an associative olfactory task recruits the newborn neurons in odor-specific areas of the olfactory bulb selected to survive during acquisition of the task and that it does this in a manner that depends on the strength of learning. We then demonstrated that acquisition is not dependent on neurogenesis if long-term retention of the task is abolished by blocking neurogenesis. Adult-born neurons are thus involved in changes in the neural representation of an odor; this underlies long-term olfactory memory as the strength of learning is linked to the duration of this memory. Neurogenesis thus plays a crucial role in long-term olfactory memory.

Disposition of 1,2,3-trichloropropane in the Fischer 344 rat: conventional and physiological pharmacokinetics

International Nuclear Information System (INIS)

Volp, R.F.; Sipes, I.G.; Falcoz, C.; Carter, D.E.; Gross, J.F.

1984-01-01

To investigate the disposition of 1,2,3-trichloropropane (TCP), [14C]-TCP was administered iv to male Fischer 344 rats. Unchanged TCP and total radiolabel were determined in tissues and excreta at varying intervals after administration. The compound was distributed and eliminated rapidly. Initial and terminal half-lives of unchanged TCP in the blood were 0.29 and 23 hr. Adipose tissue accumulated 37% of the dose within 15 min and retained more of the dose than any other tissue until 4 hr; most (69%) of the radiolabel in adipose tissue through 4 hr was unchanged TCP. After 4 hr, the liver contained the largest fraction of the dose, primarily as metabolites. Thus TCP disappeared from adipose tissue while metabolites appeared in liver and other tissues. Excretion was nearly complete (90% of the dose) in 24 hr and was predominantly via the urine (47% of the dose). Expiration was the only route by which unchanged TCP (5% of the dose) was excreted. In addition, 25% of the dose was expired as carbon dioxide. There were numerous other metabolites, none accounting for more than 10% of the dose. Nonvolatile metabolites were longer lived than the parent compound. On the basis of high water solubility, reaction with 2,4-dinitrofluorobenzene, and diminished radiolabel in bile of glycidol-treated rats, glutathione conjugation is suggested as an important metabolic route for TCP. A physiological pharmacokinetic model was developed to describe the time course of trichloropropane concentration in tissues. The model demonstrates the possibility of using physiological and pharmacokinetic data to predict concentration-time relations for toxic compounds

Comparison of Biomarkers in Transgenic Alzheimer Rats Using Multi-shell Diffusion MRI

OpenAIRE

Fick , Rutger ,; Daianu , Madelaine; Pizzolato , Marco; Wassermann , Demian; Jacobs , Russel E.; Thompson , Paul M.; Town , Terrence; Deriche , Rachid

2016-01-01

International audience; In this study, we assessed the evolution of diffusion MRI (dMRI) derived markers from different white matter models as progressive neurodegeneration occurs in transgenic Alzheimer rats (TgF344-AD) at 10, 15 and 24 months. We compared biomarkers reconstructed from Diffusion Tensor Imaging (DTI), Neurite Orientation Dispersion and Density Imaging (NODDI) and Mean Apparent Propagator (MAP)-MRI in the hippocampus, cingulate cortex and corpus callosum using multi-shell dMRI...

Acute administration of fluoxetine normalizes rapid eye movement sleep abnormality, but not depressive behaviors in olfactory bulbectomized rats.

Science.gov (United States)

Wang, Yi-Qun; Tu, Zhi-Cai; Xu, Xing-Yuan; Li, Rui; Qu, Wei-Min; Urade, Yoshihiro; Huang, Zhi-Li

2012-01-01

In humans, depression is associated with altered rapid eye movement (REM) sleep. However, the exact nature of the relationship between depressive behaviors and sleep abnormalities is debated. In this study, bilateral olfactory bulbectomy (OBX) was carried out to create a model of depression in rats. The sleep-wake profiles were assayed using a cutting-edge sleep bioassay system, and depressive behaviors were evaluated by open field and forced swimming tests. The monoamine content and monoamine metabolite levels in the brain were determined by a HPLC-electrochemical detection system. OBX rats exhibited a significant increase in REM sleep, especially between 15:00 and 18:00 hours during the light period. Acute treatment with fluoxetine (10 mg/kg, i.p.) immediately abolished the OBX-induced increase in REM sleep, but hyperactivity in the open field test and the time spent immobile in the forced swimming test remained unchanged. Neurochemistry studies revealed that acute administration of fluoxetine increased serotonin (5-HT) levels in the hippocampus, thalamus, and midbrain and decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). The ratio of 5-HIAA to 5-HT decreased in almost all regions of the brain. These results indicate that acute administration of fluoxetine can reduce the increase in REM sleep but does not change the depressive behaviors in OBX rats, suggesting that there was no causality between REM sleep abnormalities and depressive behaviors in OBX rats. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Olfactory receptors for a smell sensor: a comparative study of the electrical responses of rat I7 and human 17-40

International Nuclear Information System (INIS)

Alfinito, E; Millithaler, J-F; Reggiani, L

2011-01-01

In this paper, we explore the relevant electrical properties of two olfactory receptors (ORs), one from rat, OR I7, and the other from human, OR 17-40, which are of interest for the realization of smell nanobiosensors. The investigation compares existing experiments, coming from electrochemical impedance spectroscopy, with the theoretical expectations obtained from an impedance network protein analogue, recently developed. The changes in the response due to the sensing action of the proteins are correlated with the conformational change undergone by the single protein. The satisfactory agreement between theory and experiments points to a promising development of a new class of nanobiosensors based on the electrical properties of sensing proteins

Induction of associative olfactory memory by targeted activation of single olfactory neurons in Drosophila larvae.

Science.gov (United States)

Honda, Takato; Lee, Chi-Yu; Yoshida-Kasikawa, Maki; Honjo, Ken; Furukubo-Tokunaga, Katsuo

2014-04-25

It has been postulated that associative memory is formed by at least two sets of external stimuli, CS and US, that are transmitted to the memory centers by distinctive conversing pathways. However, whether associative memory can be induced by the activation of only the olfactory CS and a biogenic amine-mediated US pathways remains to be elucidated. In this study, we substituted the reward signals with dTrpA1-mediated thermogenetic activation of octopaminergic neurons and the odor signals by ChR2-mediated optical activation of a specific class of olfactory neurons. We show that targeted activation of the olfactory receptor and the octopaminergic neurons is indeed sufficient for the formation of associative olfactory memory in the larval brain. We also show that targeted stimulation of only a single type of olfactory receptor neurons is sufficient to induce olfactory memory that is indistinguishable from natural memory induced by the activation of multiple olfactory receptor neurons.

Improved Neural Regeneration with Olfactory Ensheathing Cell Inoculated PLGA Scaffolds in Spinal Cord Injury Adult Rats

Directory of Open Access Journals (Sweden)

Changxing Wang

2017-03-01

Full Text Available Background/Aims: Every year, around the world, between 250000 and 500000 people suffer from spinal cord injury (SCI. This study investigated the potential for poly (lactic-co-glycolic acid (PLGA complex inoculated with olfactory ensheathing cells (OECs to treat spinal cord injury in a rat model. Methods: OECs were identified by immunofluorescence based on the nerve growth factor receptor (NGFR p75. The Basso, Beattie, and Bresnahan (BBB score, together with an inclined plane (IP test were used to detect functional recovery. Nissl staining along with the luxol fast blue (LFB staining were independently employed to illustrate morphological alterations. More so, immunofluorescence labeling of the glial fibrillary acidic protein (GFAP and the microtubule-associated protein-2 (MAP-2, representing astrocytes and neurons respectively, were investigated at time points of weeks 2 and 8 post-operation. Results: The findings showed enhanced locomotor recovery, axon myelination and better protected neurons post SCI when compared with either PLGA or untreated groups (P < 0.05. Conclusion: PLGA complexes inoculated with OECs improve locomotor functional recovery in transected spinal cord injured rat models, which is most likely due to the fact it is conducive to a relatively benevolent microenvironment, has nerve protective effects, as well as the ability to enhance remyelination, via a promotion of cell differentiation and inhibition of astrocyte formation.

Therapeutic effects of NogoA vaccine and olfactory ensheathing glial cell implantation on acute spinal cord injury

Directory of Open Access Journals (Sweden)

Zhang Z

2013-10-01

Full Text Available Zhicheng Zhang, Fang Li, Tiansheng Sun, Dajiang Ren, Xiumei Liu PLA Institute of Orthopedics, Beijing Army General Hospital, Beijing, People's Republic of China Background: Many previous studies have focused on the effects of IN-1, a monoclonal antibody that neutralizes Nogo (a neurite growth inhibitory protein, on neurologic regeneration in spinal cord injury (SCI. However, safety problems and the short half-life of the exogenous antibody are still problematic. In the present study, the NogoA polypeptide was used as an antigen to make a therapeutic NogoA vaccine. Rats were immunized with this vaccine and were able to secrete the polyclonal antibody before SCI. The antibody can block NogoA within the injured spinal cord when the antibody gains access to the spinal cord due to a compromised blood–spinal cord barrier. Olfactory ensheathing glial cell transplantation has been used in a spinal cord contusion model to promote the recovery of SCI. The present study was designed to verify the efficacy and safety of NogoA polypeptide vaccine, the effects of immunotherapy with this vaccine, and the synergistic effects of the vaccine and olfactory ensheathing glial cells in repair of SCI. Methods: A 13-polypeptide fragment of NogoA was synthesized. This fragment was then coupled with keyhole limpet hemocyanin to improve the immunogenicity of the polypeptide vaccine. Immunization via injection into the abdominal cavity was performed in rats before SCI. The serum antibody level and ability of the vaccine to bind with Nogo were detected by enzyme-linked immunosorbent assay. The safety of the vaccine was evaluated according to the incidence and severity of experimental autoimmune encephalomyelitis. Olfactory ensheathing glia cells were obtained, purified, and subsequently implanted into a Wistar rat model of thoracic spinal cord contusion injury. The rats were divided into four groups, ie, an SCI model group, an olfactory ensheathing glia group, a vaccine

Inhibition of Inflammation-Associated Olfactory Loss by Etanercept in an Inducible Olfactory Inflammation Mouse Model.

Science.gov (United States)

Jung, Yong Gi; Lane, Andrew P

2016-06-01

To determine the effect of a soluble human tumor necrosis factor alpha (TNF-α) receptor blocker (etanercept) on an inducible olfactory inflammation (IOI) mouse model. An in vivo study using a transgenic mouse model. Research laboratory. To study the impact of chronic inflammation on the olfactory system, a transgenic mouse model of chronic rhinosinusitis-associated olfactory loss was utilized (IOI mouse), expressing TNF-α in a temporally controlled fashion within the olfactory epithelium. In one group of mice (n = 4), etanercept was injected intraperitoneally (100 μg/dose, 3 times/week) concurrent with a 2-week period of TNF-α expression. A second group of mice (n = 2) underwent induction of TNF-α expression for 8 weeks, with etanercept treatment administered during the final 2 weeks of inflammation. Olfactory function was assayed by elecro-olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. Each group was compared with an equal-number control group. Compared with nontreated IOI mice, etanercept-treated IOI mice showed significantly improved EOG responses after 2 weeks (P loss of olfactory epithelium and no EOG response in nontreated IOI mice. However, in etanercept-treated mice, regeneration of olfactory epithelium was observed. Concomitant administration of etanercept in IOI mice results in interruption of TNF-α-induced olfactory loss and induction of neuroepithelial regeneration. This demonstrates that etanercept has potential utility as a tool for elucidating the role of TNF-α in other olfactory inflammation models. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.

Morphological study on dental caries induced in WBN/KobSlc rats (Rattus norvegicus) fed a standard laboratory diet.

Science.gov (United States)

Fukuzato, Yoko; Matsuura, Tetsuro; Ozaki, Kiyokazu; Matsuura, Masahiro; Sano, Tomoya; Nakahara, Yutaka; Kodama, Yasushi; Nakagawa, Akihito; Okamura, Sumie; Suido, Hirohisa; Torii, Kayo; Makino, Taketoshi; Narama, Isao

2009-10-01

In our previous studies, WBN/KobSlc was characterized as a rat strain in which only males began to develop pancreatitis, and then presented with diabetic symptoms. In the course of studying their pancreatic inflammation, we detected molar caries in prediabetic males feeding on a standard diet (CRF-1) widely used for experimental animals. The purpose of this study is to confirm whether the WBN/KobSlc strain is caries-susceptible to the diet reported to be non-cariogenic, and to examine the effect of a prediabetic condition on their dental caries. For a morphological study, 25 male WBN/KobSlc rats aged 3.2-7.8 months and 24 females of the same strain aged 3.3-6.6 months were used, along with 10 males and 10 females of 8.2-month-old F344 rats. Marked dental caries were detected in the mandibular molars of male and female WBN/KobSlc rats regardless of pancreatitis, although no similar changes were observed in any teeth of the F344 strain fed the same diet. Soft X-ray examination revealed that the caries began in the crown and progressed horizontally and vertically, and that a severe radiolucent lesion extensively expanded to the entire crown, corresponding to a macroscopically deleted molar. The caries had gradually developed mainly in the second mandibular molar from more than 3.5 months of age, while none were seen in any rats before that time. The WBN/KobSlc rats were caries-susceptible even to the standard laboratory diet, and pancreatitis was not directly associated with the onset of dental caries in this strain.

Dietary milk fat globule membrane reduces the incidence of aberrant crypt foci in Fischer-344 rats.

Science.gov (United States)

Snow, Dallin R; Jimenez-Flores, Rafael; Ward, Robert E; Cambell, Jesse; Young, Michael J; Nemere, Ilka; Hintze, Korry J

2010-02-24

Milk fat globule membrane (MFGM) is a biopolymer composed primarily of membrane proteins and lipids that surround the fat globules in milk. Although it is considered to have potential as a bioactive ingredient, few feeding studies have been conducted to measure its potential benefits. The aim of this investigation was to determine if dietary MFGM confers protection against colon carcinogenesis compared to diets containing corn oil (CO) or anhydrous milk fat (AMF). Male, weanling Fischer-344 rats were randomly assigned to one of three dietary treatments that differed only in the fat source: (1) AIN-76A diet, corn oil; (2) AIN-76A diet, AMF; and (3) AIN-76A diet, 50% MFGM, 50% AMF. Each diet contained 50 g/kg diet of fat. With the exception of the fat source, diets were formulated to be identical in macro and micro nutrient content. Animals were injected with 1,2-dimethylhydrazine once per week at weeks 3 and 4, and fed experimental diets for a total of 13 weeks. Over the course of the study dietary treatment did not affect food consumption, weight gain or body composition. After 13 weeks animals were sacrificed, colons were removed and aberrant crypt foci (ACF) were counted by microscopy. Rats fed the MFGM diet (n = 16) had significantly fewer ACF (20.9 +/- 5.7) compared to rats fed corn oil (n = 17) or AMF (n = 16) diets (31.3 +/- 9.5 and 29.8 +/- 11.4 respectively; P < 0.05). Gene expression analysis of colonic mucosa did not reveal differential expression of candidate colon cancer genes, and the sphingolipid profile of the colonic mucosa was not affected by diet. While there were notable and significant differences in plasma and red blood cell lipids, there was no relationship to the cancer protection. These results support previous findings that dietary sphingolipids are protective against colon carcinogenesis yet extend this finding to MFGM, a milk fat fraction available as a food ingredient.

Early-stage attenuation of phase-amplitude coupling in the hippocampus and medial prefrontal cortex in a transgenic rat model of Alzheimer's disease.

Science.gov (United States)

Bazzigaluppi, Paolo; Beckett, Tina L; Koletar, Margaret M; Lai, Aaron Y; Joo, Illsung L; Brown, Mary E; Carlen, Peter L; McLaurin, JoAnne; Stefanovic, Bojana

2018-03-01

Alzheimer's disease (AD) is pathologically characterized by amyloid-β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aβ-dependent neuronal dysfunction including modulation of gamma-aminobutyric acid-ergic signaling. The present work focuses on the early stage of disease progression and uses TgF344-AD rats that recapitulate a broad repertoire of AD-like pathologies to investigate the neuronal network functioning using simultaneous intracranial recordings from the hippocampus (HPC) and the medial prefrontal cortex (mPFC), followed by pathological analyses of gamma-aminobutyric acid (GABA A ) receptor subunits α1 , α5, and δ, and glutamic acid decarboxylases (GAD65 and GAD67). Concomitant to amyloid deposition and tau hyperphosphorylation, low-gamma band power was strongly attenuated in the HPC and mPFC of TgF344-AD rats in comparison to those in non-transgenic littermates. In addition, the phase-amplitude coupling of the neuronal networks in both areas was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude in TgF344-AD animals. Finally, the gamma coherence between HPC and mPFC was attenuated as well. These results demonstrate significant neuronal network dysfunction at an early stage of AD-like pathology. This network dysfunction precedes the onset of cognitive deficits and is likely driven by Aβ and tau pathologies. This article is part of the Special Issue "Vascular Dementia". © 2017 Her Majesty the Queen in Right of Canada Journal of Neurochemistry © 2017 International Society for Neurochemistry.

32 CFR 344.6 - Authorities.

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2010-07-01

... 32 National Defense 2 2010-07-01 2010-07-01 false Authorities. 344.6 Section 344.6 National Defense Department of Defense (Continued) OFFICE OF THE SECRETARY OF DEFENSE (CONTINUED) ORGANIZATIONAL... Information Service (NTIS), US Department of Commerce, 5285 Port Royal Road, Springfield, VA 22161. (c) Obtain...

Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors

International Nuclear Information System (INIS)

Wilson, Alan A.; Garcia, Armando; Parkes, Jun; McCormick, Patrick; Stephenson, Karin A.; Houle, Sylvain; Vasdev, Neil

2008-01-01

Introduction: A novel [ 18 F]-radiolabelled phenoxyanilide, [ 18 F]-FEPPA, has been synthesized and evaluated, in vitro and ex vivo, as a potential positron emission tomography imaging agent for the peripheral benzodiazepine receptor (PBR). Methods: [ 18 F]-FEPPA and two other radiotracers for imaging PBR, namely [ 11 C]-PBR28 and [ 11 C]-PBR28-d3, were synthesised and evaluated in vitro and ex vivo as potential PBR imaging agents. Results: [ 18 F]-FEPPA is efficiently prepared in one step from its tosylate precursor and [ 18 F]-fluoride in high radiochemical yields and at high specific activity. FEPPA displayed a K i of 0.07 nM for PBR in rat mitochondrial membrane preparations and a suitable lipophilicity for brain penetration (log P of 2.99 at pH 7.4). Upon intravenous injection into rats, [ 18 F]-FEPPA showed moderate brain uptake [standard uptake value (SUV) of 0.6 at 5 min] and a slow washout (SUV of 0.35 after 60 min). Highest uptake of radioactivity was seen in the hypothalamus and olfactory bulb, regions previously reported to be enriched in PBR in rat brain. Analysis of plasma and brain extracts demonstrated that [ 18 F]-FEPPA was rapidly metabolized, but no lipophilic metabolites were observed in either preparation and only 5% radioactive metabolites were present in brain tissue extracts. Blocking studies to determine the extent of specific binding of [ 18 F]-FEPPA in rat brain were problematic due to large perturbations in circulating radiotracer and the lack of a reference region. Conclusions: Further evaluation of the potential of [ 18 F]-FEPPA will require the employment of rigorous kinetic models and/or appropriate animal models

Rapidly acquired multisensory association in the olfactory cortex.

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Karunanayaka, Prasanna R; Wilson, Donald A; Vasavada, Megha; Wang, Jianli; Martinez, Brittany; Tobia, Michael J; Kong, Lan; Eslinger, Paul; Yang, Qing X

2015-11-01

The formation of an odor percept in humans is strongly associated with visual information. However, much less is known about the roles of learning and memory in shaping the multisensory nature of odor representations in the brain. The dynamics of odor and visual association in olfaction was investigated using three functional magnetic resonance imaging (fMRI) paradigms. In two paradigms, a visual cue was paired with an odor. In the third, the same visual cue was never paired with an odor. In this experimental design, if the visual cue was not influenced by odor-visual pairing, then the blood-oxygen-level-dependent (BOLD) signal elicited by subsequent visual cues should be similar across all three paradigms. Additionally, intensity, a major dimension of odor perception, was used as a modulator of associative learning which was characterized in terms of the spatiotemporal behavior of the BOLD signal in olfactory structures. A single odor-visual pairing cue could subsequently induce primary olfactory cortex activity when only the visual cue was presented. This activity was intensity dependent and was also detected in secondary olfactory structures and hippocampus. This study provides evidence for a rapid learning response in the olfactory system by a visual cue following odor and visual cue pairing. The novel data and paradigms suggest new avenues to explore the dynamics of odor learning and multisensory representations that contribute to the construction of a unified odor percept in the human brain.

Early brain connectivity alterations and cognitive impairment in a rat model of Alzheimer's disease

OpenAIRE

Munoz-Moreno, Emma; Tudela, Raúl; López-Gil, Xavier; Soria, Guadalupe

2018-01-01

Background Animal models of Alzheimer’s disease (AD) are essential to understanding the disease progression and to development of early biomarkers. Because AD has been described as a disconnection syndrome, magnetic resonance imaging (MRI)-based connectomics provides a highly translational approach to characterizing the disruption in connectivity associated with the disease. In this study, a transgenic rat model of AD (TgF344-AD) was analyzed to describe both cognitive performance and brain c...

Olfactory nerve transport of macromolecular drugs to the brain. A problem in olfactory impaired patients

International Nuclear Information System (INIS)

Shiga, Hideaki; Yamamoto, Junpei; Miwa, Takaki

2012-01-01

Nasal administration of macromolecular drugs (including peptides and nanoparticles) has the potential to enable drug delivery system beyond the blood brain barrier (BBB) via olfactory nerve transport. Basic research on drug deliver systems to the brain via nasal administration has been well reported. Insulin-like growth factor-I (IGF-I) is associated with the development and growth of the central nervous system. Clinical application of IGF-I with nasal administration is intended to enable drug delivery to brain through the BBB. Uptake of IGF-I in the olfactory bulb and central nervous system increased according to the dosage of nasally administered IGF-I in normal ICR mice, however IGF-I uptake in the trigeminal nerve remained unchanged. Olfactory nerve transport is important for the delivery of nasally administered IGF-I to the brain in vivo. Because a safe olfactory nerve tracer has not been clinically available, olfactory nerve transport has not been well studied in humans. Nasal thallium-201 ( 201 Tl) administration has been safely used to assess the direct pathway to the brain via the nose in healthy volunteers with a normal olfactory threshold. 201 Tl olfactory nerve transport has recently been shown to decrease in patients with hyposmia. The olfactory nerve transport function in patients with olfactory disorders will be determined using 201 Tl olfacto-scintigraphy for the exclusion of candidates in a clinical trial to assess the usefulness of nasal administration of IGF-I. (author)

Neural correlates of olfactory and visual memory performance in 3D-simulated mazes after intranasal insulin application.

Science.gov (United States)

Brünner, Yvonne F; Rodriguez-Raecke, Rea; Mutic, Smiljana; Benedict, Christian; Freiherr, Jessica

2016-10-01

This fMRI study intended to establish 3D-simulated mazes with olfactory and visual cues and examine the effect of intranasally applied insulin on memory performance in healthy subjects. The effect of insulin on hippocampus-dependent brain activation was explored using a double-blind and placebo-controlled design. Following intranasal administration of either insulin (40IU) or placebo, 16 male subjects participated in two experimental MRI sessions with olfactory and visual mazes. Each maze included two separate runs. The first was an encoding maze during which subjects learned eight olfactory or eight visual cues at different target locations. The second was a recall maze during which subjects were asked to remember the target cues at spatial locations. For eleven included subjects in the fMRI analysis we were able to validate brain activation for odor perception and visuospatial tasks. However, we did not observe an enhancement of declarative memory performance in our behavioral data or hippocampal activity in response to insulin application in the fMRI analysis. It is therefore possible that intranasal insulin application is sensitive to the methodological variations e.g. timing of task execution and dose of application. Findings from this study suggest that our method of 3D-simulated mazes is feasible for studying neural correlates of olfactory and visual memory performance. Copyright © 2016 Elsevier Inc. All rights reserved.

PET imaging with [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) following selective lesion of cholinergic pedunculopontine tegmental neurons in rat

International Nuclear Information System (INIS)

Cyr, Marilyn; Parent, Maxime J.; Mechawar, Naguib; Rosa-Neto, Pedro; Soucy, Jean-Paul; Aliaga, Antonio; Kostikov, Alexey; Maclaren, Duncan A.A.; Clark, Stewart D.; Bedard, Marc-Andre

2014-01-01

Introduction: [ 18 F]fluoroethoxybenzovesamicol ([ 18 F]FEOBV) is a PET radiotracer with high selectivity and specificity to the vesicular acetylcholine transporter (VAChT). It has been shown to be a sensitive in vivo measurement of changes of cholinergic innervation densities following lesion of the nucleus basalis of Meynert (NBM) in rat. The current study used [ 18 F]FEOBV with PET imaging to detect the effect of a highly selective lesion of the pedunculopontine (PPTg) nucleus in rat. Methods: After bilateral and selective lesions of the PPTg cholinergic neurons, rats were scanned using [ 18 F]FEOBV, then sacrificed, and their brain tissues collected for immunostaining and quantification of the VAChT. Results: Comparisons with control rats revealed that cholinergic losses can be detected in the brainstem, lateral thalamus, and pallidum by using both in vivo imaging methods with [ 18 F]FEOBV, and ex vivo measurements. In the brainstem PPTg area, significant correlations were observed between in vivo and ex vivo measurements, while this was not the case in the thalamic and pallidal projection sites. Conclusions: These findings support PET imaging with [ 18 F]FEOBV as a reliable in vivo method for the detection of neuronal terminal losses resulting from lesion of the PPTg. Useful applications can be found in the study of neurodegenerative diseases in human, such as Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, or dementia with Lewy bodies

Selective involvement of the lateral entorhinal cortex in the control of the olfactory memory trace during conditioned odor aversion in the rat.

Science.gov (United States)

Ferry, Barbara; Ferreira, Guillaume; Traissard, Natalia; Majchrzak, Monique

2006-10-01

Evidence from the effect of aspiration lesions of the entorhinal cortex (EC) has shown that this region is involved in conditioned odor-aversion (COA) learning--that is, the avoidance of an odorized tasteless solution the ingestion of which precedes toxicosis--by rendering COA tolerant to long odor-toxicosis delay. The present study examined whether neurotoxic lesions restricted to the lateral or medial parts of the EC, in comparison with large aspiration lesions, were sufficient to produce this effect. Male Long-Evans rats received odor-intoxication pairing with either a short (5-min) or long (120-min) delay between the presentation of the odor and toxicosis. All groups, including sham-lesioned controls, showed COA at the 5-min odor-toxicosis delay interval, but only rats with lateral EC damage displayed COA at the longer delay. These data show that the lateral EC is part of the substrate involved in the control of the olfactory memory trace during COA.

Immunotoxic effects of iodine-131 in prenatally exposed rats

International Nuclear Information System (INIS)

Cole, D.A.; Stevens, R.H.; Lindholm, P.A.; Cheng, H.F.

1985-01-01

Present results suggest that offspring exposed in utero to radioactive iodine-131 develop a measureable cell-mediated immune (CMI) response. Regnant Fischer F344 inbred rats were exposed to 370 kBg to 3.7 MBg (10 to 100 μCi) Na 131I on 16 to 18 days of gestation and evaluated for CMI responsiveness 2 to 3 months post exposure using an 125I radiolabeled membrane release assay. Current data suggest that not only the F1, but also the F2 pups develop a measureable CMI response. In order to determine whether other immune functions are altered studies have been initiated to evaluate the immunotoxic effect of prenatal exposure to 131I. These studies include the evaluation of the delayed hypersensitivity response and the blastogenic responses to phytoheemagglutinin, concanavalin A, and lipopolysaccharide

Olfactory training in patients with Parkinson's disease.

Directory of Open Access Journals (Sweden)

Antje Haehner

Full Text Available OBJECTIVE: Decrease of olfactory function in Parkinson's disease (PD is a well-investigated fact. Studies indicate that pharmacological treatment of PD fails to restore olfactory function in PD patients. The aim of this investigation was whether patients with PD would benefit from "training" with odors in terms of an improvement of their general olfactory function. It has been hypothesized that olfactory training should produce both an improved sensitivity towards the odors used in the training process and an overall increase of olfactory function. METHODS: We recruited 70 subjects with PD and olfactory loss into this single-center, prospective, controlled non-blinded study. Thirty-five patients were assigned to the olfactory training group and 35 subjects to the control group (no training. Olfactory training was performed over a period of 12 weeks while patients exposed themselves twice daily to four odors (phenyl ethyl alcohol: rose, eucalyptol: eucalyptus, citronellal: lemon, and eugenol: cloves. Olfactory testing was performed before and after training using the "Sniffin' Sticks" (thresholds for phenyl ethyl alcohol, tests for odor discrimination, and odor identification in addition to threshold tests for the odors used in the training process. RESULTS: Compared to baseline, trained PD patients experienced a significant increase in their olfactory function, which was observed for the Sniffin' Sticks test score and for thresholds for the odors used in the training process. Olfactory function was unchanged in PD patients who did not perform olfactory training. CONCLUSION: The present results indicate that olfactory training may increase olfactory sensitivity in PD patients.

Effects of radiotherapy on olfactory function

International Nuclear Information System (INIS)

Hoelscher, Tobias; Seibt, Annedore; Appold, Steffen; Doerr, Wolfgang; Herrmann, Thomas; Huettenbrink, Karl-Bernd; Hummel, Thomas

2005-01-01

Background and Purpose: Changes in olfactory function have been reported in patients receiving significant doses of radiation to the olfactory epithelium. Aim of this study was to investigate severity and time course of changes in olfactory function in patients irradiated for tumours of the head and neck region. Material and Methods: Forty-four patients receiving radiotherapy (RT) for tumours in the area of the head and neck participated (16 women, 28 men; age 11-81 y; mean 55 y). Olfactory function was measured before and bi-weekly during RT for 6 weeks. A subgroup (25 patients) was followed for 12 months. Patients were divided into two groups according to the dose to the olfactory epithelium. Twenty-two patients ('OLF group') had radiation doses to the olfactory epithelium between 23.7 and 79.5 Gy (median 62.2 Gy). In the 22 patients of the 'non-OLF group' the dose applied to the olfactory epithelium was significantly lower (2.9-11.1 Gy, median 5.9 Gy). Total tumour dose (30-76.8 Gy), age, sex distribution, and baseline chemosensory function were not significantly different between groups. Testing was performed for odour identification, odour discrimination, and olfactory thresholds. Results: Odour discrimination, but not odour identification or odour threshold, was significantly decreased 2-6 weeks after begin of therapy in the OLF group. In addition, a significant effect of the radiation dose was observed for odour discrimination. More than 6 months after therapy, OLF group patients had significantly lower odour identification scores compared to the non-OLF group. Conclusion: As indicated through the non-significant change of olfactory thresholds, the olfactory epithelium is relatively resistant against effects of radiation. It is hypothesized that RT has additional effects on the olfactory bulb/orbitofrontal cortex responsible for the observed changes of suprathreshold olfactory function

Evaluation of F-18-labeled amino acid derivatives and [18F]FDG as PET probes in a brain tumor-bearing animal model

International Nuclear Information System (INIS)

Wang, H.-E.; Wu, S.-Y.; Chang, C.-W.; Liu, R.-S.; Hwang, L.-C.; Lee, T.-W.; Chen, J.-C.; Hwang, J.-J.

2005-01-01

2-Deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) has been extensively used as positron emission tomography (PET) tracer in clinical tumor imaging. This study compared the pharmacokinetics of two 18 F-labeled amino acid derivatives, O-2-[ 18 F]fluoroethyl-L-tyrosine (L-[ 18 F]FET) and 4-borono-2-[ 18 F]fluoro-L-phenylalanine-fructose (L-[ 18 F]FBPA-Fr), to that of [ 18 F]FDG in an animal brain tumor model. Methods: A self-modified automated PET tracer synthesizer was used to produce no-carrier-added (nca) L-[ 18 F]FET. The cellular uptake, biodistribution, autoradiography and microPET imaging of L-[ 18 F]FET, L-[ 18 F]FBPA-Fr and [ 18 F]FDG were performed with F98 glioma cell culture and F98 glioma-bearing Fischer344 rats. Results: The radiochemical purity of L-[ 18 F]FET was >98% and the radiochemical yield was 50% in average of 16 runs. The uptake of L-[ 18 F]FET and L-[ 18 F]FBPA-Fr in the F98 glioma cells increased rapidly for the first 5 min and reached a steady-state level after 10 min of incubation, whereas the cellular uptake of [ 18 F]FDG kept increasing during the study period. The biodistribution of L-[ 18 F]FET, L-[ 18 F]FBPA-Fr and [ 18 F]FDG in the brain tumors was 1.26±0.22, 0.86±0.08 and 2.77±0.44 %ID/g at 60 min postinjection, respectively, while the tumor-to-normal brain ratios of L-[ 18 F]FET (3.15) and L-[ 18 F]FBPA-Fr (3.44) were higher than that of [ 18 F]FDG (1.44). Both microPET images and autoradiograms of L-[ 18 F]FET and L-[ 18 F]FBPA-Fr exhibited remarkable uptake with high contrast in the brain tumor, whereas [ 18 F]FDG showed high uptake in the normal brain and gave blurred brain tumor images. Conclusion: Both L-[ 18 F]FET and L-[ 18 F]FBPA-Fr are superior to [ 18 F]FDG for the brain tumor imaging as shown in this study with microPET

Visualization of haemophilic arthropathy in F8(-/-) rats by ultrasonography and micro-computed tomography

DEFF Research Database (Denmark)

Christensen, K R; Roepstorff, K; Petersen, M

2017-01-01

opportunities. Recently, a F8(-/-) rat model of HA was developed. The size of the rat allows for convenient and high resolution imaging of the joints, which could enable in vivo studies of HA development. AIM: To determine whether HA in the F8(-/-) rat can be visualized using ultrasonography (US) and micro......-computed tomography (μCT). METHODS: Sixty F8(-/-) and 20 wild-type rats were subjected to a single or two induced knee bleeds. F8(-/-) rats were treated with either recombinant human FVIII (rhFVIII) or vehicle before the induction of knee bleeds. Haemophilic arthropathy was visualized using in vivo US and ex vivo μCT......, and the observations correlated with histological evaluation. RESULTS: US and μCT detected pathologies in the knee related to HA. There was a strong correlation between disease severity determined by μCT and histopathology. rhFVIII treatment reduced the pathology identified with both imaging techniques. CONCLUSION: US...

Trichloroethylene and trichloroethanol-induced formic aciduria and renal injury in male F-344 rats following 12 weeks exposure.

Science.gov (United States)

Yaqoob, Noreen; Evans, Andrew; Foster, John R; Lock, Edward A

2014-09-02

Trichloroethylene (TCE) is widely used as a cleaning and decreasing agent and has been shown to cause liver tumours in rodents and a small incidence of renal tubule tumours in male rats. The basis for the renal tubule injury is believed to be related to metabolism of TCE via glutathione conjugation to yield the cysteine conjugate that can be activated by the enzyme cysteine conjugate β-lyase in the kidney. More recently TCE and its major metabolite trichloroethanol (TCE-OH) have been shown to cause formic aciduria which can cause renal injury after chronic exposure in rats. In this study we have compared the renal toxicity of TCE and TCE-OH in rats to try and ascertain whether the glutathione pathway or formic aciduria can account for the toxicity. Male rats were given TCE (500mg/kg/day) or TCE-OH at (100mg/kg/day) for 12 weeks and the extent of renal injury measured at several time points using biomarkers of nephrotoxicity and prior to termination assessing renal tubule cell proliferation. The extent of formic aciduria was also determined at several time points, while renal pathology and plasma urea and creatinine were determined at the end of the study. TCE produced a very mild increase in biomarkers of renal injury, total protein, and glucose over the first two weeks of exposure and increased Kim-1 and NAG in urine after 1 and 5 weeks exposure, while TCE-OH did not produce a consistent increase in these biomarkers in urine. However, both chemicals produced a marked and sustained increase in the excretion of formic acid in urine to a very similar extent. The activity of methionine synthase in the liver of TCE and TCE-OH treated rats was inhibited by about 50% indicative of a block in folate synthesis. Both renal pathology and renal tubule cell proliferation were reduced after TCE and TCE-OH treatment compared to controls. Our findings do not clearly identify the pathway which is responsible for the renal toxicity of TCE but do provide some support for metabolism

Trichloroethylene and trichloroethanol-induced formic aciduria and renal injury in male F-344 rats following 12 weeks exposure

International Nuclear Information System (INIS)

Yaqoob, Noreen; Evans, Andrew; Foster, John R.; Lock, Edward A.

2014-01-01

Trichloroethylene (TCE) is widely used as a cleaning and decreasing agent and has been shown to cause liver tumours in rodents and a small incidence of renal tubule tumours in male rats. The basis for the renal tubule injury is believed to be related to metabolism of TCE via glutathione conjugation to yield the cysteine conjugate that can be activated by the enzyme cysteine conjugate β-lyase in the kidney. More recently TCE and its major metabolite trichloroethanol (TCE-OH) have been shown to cause formic aciduria which can cause renal injury after chronic exposure in rats. In this study we have compared the renal toxicity of TCE and TCE-OH in rats to try and ascertain whether the glutathione pathway or formic aciduria can account for the toxicity. Male rats were given TCE (500 mg/kg/day) or TCE-OH at (100 mg/kg/day) for 12 weeks and the extent of renal injury measured at several time points using biomarkers of nephrotoxicity and prior to termination assessing renal tubule cell proliferation. The extent of formic aciduria was also determined at several time points, while renal pathology and plasma urea and creatinine were determined at the end of the study. TCE produced a very mild increase in biomarkers of renal injury, total protein, and glucose over the first two weeks of exposure and increased Kim-1 and NAG in urine after 1 and 5 weeks exposure, while TCE-OH did not produce a consistent increase in these biomarkers in urine. However, both chemicals produced a marked and sustained increase in the excretion of formic acid in urine to a very similar extent. The activity of methionine synthase in the liver of TCE and TCE-OH treated rats was inhibited by about 50% indicative of a block in folate synthesis. Both renal pathology and renal tubule cell proliferation were reduced after TCE and TCE-OH treatment compared to controls. Our findings do not clearly identify the pathway which is responsible for the renal toxicity of TCE but do provide some support for

In vivo imaging of brain androgen receptors in rats: a [18F]FDHT PET study

International Nuclear Information System (INIS)

Khayum, M.A.; Doorduin, J.; Antunes, I.F.; Kwizera, C.; Zijlma, R.; Boer, J.A. den; Dierckx, R.A.J.O.; Vries, E.F.J. de

2015-01-01

Introduction: Steroid hormones like androgens play an important role in the development and maintenance of several brain functions. Androgens can act through androgen receptors (AR) in the brain. This study aims to demonstrate the feasibility of positron emission tomography (PET) with 16β-[ 18 F]fluoro-5α-dihydrotestosterone ([ 18 F]FDHT) to image AR expression in the brain. Methods: Male Wistar rats were either orchiectomized to inhibit endogenous androgen production or underwent sham-surgery. Fifteen days after surgery, rats were subjected to a 90-min dynamic [ 18 F]FDHT PET scan with arterial blood sampling. In a subset of orchiectomized rats, 1 mg/kg dihydrotestosterone was co-injected with the tracer in order to saturate the AR. Plasma samples were analyzed for the presence of radioactive metabolites by radio-TLC. Pharmacokinetic modeling was performed to quantify brain kinetics of the tracer. After the PET scan, the animals were terminated for ex-vivo biodistribution. Results: PET imaging and ex vivo biodistribution studies showed low [ 18 F]FDHT uptake in all brain regions, except pituitary. [ 18 F]FDHT uptake in the surrounding cranial bones was high and increased over time. [ 18 F]FDHT was rapidly metabolized in rats. Metabolism was significantly faster in orchiectomized rats than in sham-orchiectomized rats. Quantitative analysis of PET data indicated substantial spill-over of activity from cranial bones into peripheral brain regions, which prevented further analysis of peripheral brain regions. Logan graphical analysis and kinetic modeling using 1- and 2-tissue compartment models showed reversible and homogenously distributed tracer uptake in central brain regions. [ 18 F]FDHT uptake in the brain could not be blocked by endogenous androgens or administration of dihydrotestosterone. Conclusion: The results of this study indicate that imaging of AR availability in rat brain with [ 18 F]FDHT PET is not feasible. The low AR expression in the brain, the

Acetylcholine and Olfactory Perceptual Learning

Science.gov (United States)

Wilson, Donald A.; Fletcher, Max L.; Sullivan, Regina M.

2004-01-01

Olfactory perceptual learning is a relatively long-term, learned increase in perceptual acuity, and has been described in both humans and animals. Data from recent electrophysiological studies have indicated that olfactory perceptual learning may be correlated with changes in odorant receptive fields of neurons in the olfactory bulb and piriform…

Gene Expression Profiling in Lung Tissues from Rat Exposed to Lunar Dust Particles

Science.gov (United States)

Zhang, Ye; Lam, Chiu-Wing; Zalesak, Selina M.; Kidane, Yared H.; Feiveson, Alan H.; Ploutz-Snyder, Robert; Scully, Robert R.; Williams, Kyle; Wu, Honglu; James, John T.

2014-01-01

The Moon's surface is covered by a layer of fine, reactive dust. Lunar dust contain about 1-2% of very fine dust (gene expression changes in lung tissues from rats exposed to lunar dust particles. F344 rats were exposed for 4 weeks (6h/d; 5d/wk) in nose-only inhalation chambers to concentrations of 0 (control air), 2.1, 6.8, 21, and 61 mg/m(exp 3) of lunar dust. Five rats per group were euthanized 1 day, and 3 months after the last inhalation exposure. The total RNAs were isolated from lung tissues after being lavaged. The Agilent Rat GE v3 microarray was used to profile global gene expression (44K). The genes with significant expression changes are identified and the gene expression data were further analyzed using various statistical tools.

Olfactory memory impairment in neurodegenerative diseases.

Science.gov (United States)

Bahuleyan, Biju; Singh, Satendra

2012-10-01

Olfactory disorders are noted in a majority of neurodegenerative diseases, but they are often misjudged and are rarely rated in the clinical setting. Severe changes in the olfactory tests are observed in Parkinson's disease. Olfactory deficits are an early feature in Alzheimer's disease and they worsen with the disease progression. Alterations in the olfactory function are also noted after severe head injuries, temporal lobe epilepsy, multiple sclerosis, and migraine. The purpose of the present review was to discuss the available scientific knowledge on the olfactory memory and to relate its impairment with neurodegenerative diseases.

Antidepressant-like effects of salidroside on olfactory bulbectomy-induced pro-inflammatory cytokine production and hyperactivity of HPA axis in rats.

Science.gov (United States)

Yang, Shui-Jin; Yu, Hai-Yang; Kang, Dan-Yu; Ma, Zhan-Qiang; Qu, Rong; Fu, Qiang; Ma, Shi-Ping

2014-09-01

Salidroside (SA) is the primary bioactive marker compound in the standardized extracts from Rhodiola rosea. Although it has potential antidepressant activity in a rat behavioral despair model, the mechanisms of antidepressant effect for SA remain unclear. The objective of this study was to evaluate the antidepressant effects of SA and to discuss the potential mechanisms in olfactory bulbectomized (OBX) rats. SA of 20, 40 mg/kg (p.o.) for 2 weeks notably alleviated OBX-induced hyperactivity in open field test, decreased immobility time in TST and FST. Chronic treatment with SA could remarkably reduce TNF-α and IL-1β levels in hippocampus. Western blot showed that SA could markedly increase glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Besides, SA could also attenuate corticotropin-releasing hormone (CRH) expression in hypothalamus, as well as reducing significantly the levels of serum corticosterone. In conclusion, this study demonstrated that OBX rats treated with SA could significantly improve the depressive-like behaviors. The antidepressant mechanisms of SA might be associated with its anti-inflammatory effects and the regulation of HPA axis activity. Reversal of abnormalities of GR may be partly responsible for those effects. These findings suggested that SA might become a beneficial agent to prevent and treat the depression. Copyright © 2014 Elsevier Inc. All rights reserved.

A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric Aβ and frank neuronal loss

OpenAIRE

Cohen, Robert M.; Rezai-Zadeh, Kavon; Weitz, Tara M.; Rentsendorj, Altan; Gate, David; Spivak, Inna; Bholat, Yasmin; Vasilevko, Vitaly; Glabe, Charles G.; Breunig, Joshua J.; Rakic, Pasko; Davtyan, Hayk; Agadjanyan, Michael G.; Kepe, Vladimir; Barrio, Jorge

2013-01-01

Alzheimer’s disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The ‘amyloid cascade hypothesis’ posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aβ peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing...

Locomotion and physical development in rats treated with ionizing radiation in utero

International Nuclear Information System (INIS)

Zaman, M.S.; Hupp, E.W.; Lancaster, F.E.

1993-01-01

Effects of ionizing radiation on the emergence of locomotor skill, and physical development were studied in laboratory rats (Fisher F-344 inbred strain). Rats were treated with 3 different doses of radiation (150 rad, 15 rad, and 6.8 rad) delivered on the 20th day of prenatal life. Results indicated that relatively moderate (15 rad) to high (150 rad) doses of radiation had effects on certain locomotion and physical development parameters. Exposure to 150 rad delayed pivoting, cliff-avoidance, upper jaw tooth eruption, and decreased body weights. Other parameters, such as negative geotaxis, eye opening, and lower jaw tooth eruption were marginally delayed in the 150 rad treated animals. Exposure to 15 rad delayed pivoting and cliff-avoidance

Olfactory dysfunction in neuromyelitis optica spectrum disorders

NARCIS (Netherlands)

Zhang, L.J.; Zhao, N.; Fu, Y.; Zhang, D.Q.; Wang, J.; Qin, W.; Zhang, N.N.N.; Wood, K.; Liu, Y.; Yu, C.S.; Shi, F.D.; Yang, L.

2015-01-01

Few data were available for the understanding of olfactory function in neuromyelitis optica spectrum disorders (NMOSDs). The aims of our study were to investigate the incidence of olfactory dysfunction and characterize olfactory structures, using MRI, in patients with NMOSDs. Olfactory function was

Olfactory bulb proteins linked to olfactory memory in C57BL/6J mice.

Science.gov (United States)

Li, Lin; Mauric, Veronika; Zheng, Jun-Fang; Kang, Sung Ung; Patil, Sudarshan; Höger, Harald; Lubec, Gert

2010-08-01

Information on systematic analysis of olfactory memory-related proteins is poor. In this study, the odor discrimination task to investigate olfactory recognition memory of adult male C57BL/6J mice was used. Subsequently, olfactory bulbs (OBs) were taken, proteins extracted, and run on two-dimensional gel electrophoresis with in-gel-protein digestion, followed by mass spectrometry and quantification of differentially expressed proteins. Dual specificity mitogen-activated protein kinase kinase 1 (MEK1), dihydropyrimidinase-related protein 1 (DRP1), and fascin are related with Lemon odor memory. Microtubule-associated protein RP/EB family member 3 is related to Rose odor memory. Hypoxanthine-guanine phosphoribosyltransferase is related with both Lemon and Rose odors memory. MEK1 and DRP1 levels were increased, while microtubule-associated protein RP/EB family member 3, fascin and hypoxanthine-guanine phosphoribosyltransferase levels were decreased during olfactory memory. In summary, neurogenesis, signal transduction, cytoskeleton, and nucleotide metabolism are involved in olfactory memory formation and storage of C57BL/6J mice.

Dietary Chemoprevention of PhIP Induced Carcinogenesis in Male Fischer 344 Rats with Tomato and Broccoli

Science.gov (United States)

Canene-Adams, Kirstie; Sfanos, Karen S.; Liang, Chung-Tiang; Yegnasubramanian, Srinivasan; Nelson, William G.; Brayton, Cory; De Marzo, Angelo M.

2013-01-01

The heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-B]pyridine (PhIP), found in meats cooked at high temperatures, has been implicated in epidemiological and rodent studies for causing breast, prostate, and colorectal cancers. A previous animal study using a xenograft model has shown that whole tomato and broccoli, when eaten in combination, exhibit a marked effect on tumor reduction compared to when eaten alone. Our aim was to determine if PhIP-induced carcinogenesis can be prevented by dietary consumption of whole tomato + broccoli powders. Male Fischer 344 rats (n = 45) were randomized into the following treatment groups: control (AIN93G diet), PhIP (200 ppm in AIN93G diet for the first 20 weeks of the study), or tomato + broccoli + PhIP (mixed in AIN93G diet at 10% each and fed with PhIP for 20 weeks, and then without PhIP for 32 weeks). Study animals were monitored for 52 weeks and were euthanized as necessary based on a set of criteria for health status and tumor burden. Although there appeared to be some hepatic and intestinal toxicity due to the combination of PhIP and tomato + broccoli, these rodents had improved survival and reduced incidence and/or severity of PhIP-induced neoplastic lesions compared to the PhIP-alone treated group. Rats eating tomato + broccoli exhibited a marked decrease in the number and size of cribiform prostatic intraepitheilial neoplasia/carcinoma in situ (cribiform PIN/CIS) lesions and in the incidence of invasive intestinal adenocarcinomas and skin carcinomas. Although the apparent toxic effects of combined PhIP and tomato + broccoli need additional study, the results of this study support the hypothesis that a diet rich in tomato and broccoli can reduce or prevent dietary carcinogen-induced cancers. PMID:24312188

Characterization of biological features of a rat F98 GBM model: A PET-MRI study with [18F]FAZA and [18F]FDG

International Nuclear Information System (INIS)

Belloli, Sara; Brioschi, Andrea; Politi, Letterio Salvatore; Ronchetti, Francesca; Calderoni, Sara; Raccagni, Isabella; Pagani, Antonella; Monterisi, Cristina; Zenga, Francesco; Zara, Gianpaolo; Fazio, Ferruccio; Mauro, Alessandro

2013-01-01

Introduction: The prognosis of malignant gliomas remains largely unsatisfactory for the intrinsic characteristics of the pathology and for the delayed diagnosis. Multimodal imaging based on PET and MRI may assess the dynamics of disease onset and progression allowing the validation of preclinical models of glioblastoma multiforme (GBM). The aim of this study was the characterization of a syngeneic rat model of GBM using combined in vivo imaging and immunohistochemistry. Methods: Four groups of Fischer rats were implanted in a subcortical region with increasing concentration of rat glioma F98 cells and weekly monitored with Gd-MR, [ 18 F]FDG- and [ 18 F]FAZA-PET starting one week after surgery. Different targets were evaluated on post mortem brain specimens using immunohistochemistry: VEGF, GFAP, HIF-1α, Ki-67 and nestin. Results: Imaging results indicated that tumor onset but not progression was related to the number of F98 cells. Hypoxic regions identified with [ 18 F]FAZA and high-glucose metabolism regions recognized with [ 18 F]FDG were located respectively in the core and in external areas of the tumor, with partial overlap and remodeling during disease progression. Histological and immunohistochemical analysis confirmed PET/MRI results and revealed that our model resumes biological characteristics of human GBM. IHC and PET studies showed that necrotic regions, defined on the basis of [ 18 F]FDG uptake reduction, may include hypoxic clusters of vital tumor tissue identified with [ 18 F]FAZA. This last information is particularly relevant for the identification of the target volume during image-guided radiotherapy. Conclusions: In conclusion, the combined use of PET and MRI allows in vivo monitoring of the biological modification of F98 lesions during tumor progression

Assessment of pathological changes associated with chronic allograft rejection and tolerance in two experimental models of rat lung transplantation.

Science.gov (United States)

Matsumura, Y; Marchevsky, A; Zuo, X J; Kass, R M; Matloff, J M; Jordan, S C

1995-06-15

Lung transplantation is now routinely performed for a wide range of end-stage cardiopulmonary disorders. Despite overcoming the problems associated with early acute rejection, chronic rejection (CR) in the form of obliterative bronchiolitis has emerged as the primary cause of late graft loss. The mechanisms involved in the development of CR of lung allografts are poorly understood, and no effective therapy is currently available. To better understand the pathological events associated with CR and tolerance, we examined two models of lung allograft rejection established in our laboratory. First, we exchanged left lung allografts between moderately histoincompatible inbred rat strains (WKY-->F344: n = 42 and F344-->WKY: n = 40). The WKY-->F344 model was previously shown to develop spontaneous tolerance, while the converse model (F344-->WKY) showed persistent acute rejection. The purpose of this investigation was to assess histopathological changes associated with long-term grafts left in place up to 140 days after transplant. To confirm that tolerance had developed, skin-grafting experiments were performed. Five skin grafts from each strain were placed on lung allograft recipients on day 35 after transplant and skin allograft survival was assessed and compared with controls. Acute rejection (AR) was graded histologically (stage O-IV) and the pathologic intensity of inflammation and CR were graded (0-4: 0 = 0%, 1 = 1-25%, 2 = 26-50%, 3 = 51-75%, and 4 = 76-100%) on percentage of involvement with the following categories being examined: (a) lymphocytic infiltration (perivascular, peribronchial, and peribronchiolar) and (b) vasculitis, edema, hemorrhage, and necrosis. Finally, chronic rejection was diagnosed by the presence of intimal hyperplasia, interstitial fibrosis, peribronchiolar fibrosis, bronchiolitis obliterans, and bronchiectasis. The WKY-->F344 animals showed progressive AR (stage III, day 21). Thereafter, the AR subsided spontaneously and was stage 0 on day

Effects of Caloric Restriction and Exercise Training on Skeletal Muscle Histochemistry in Aging Fischer 344 Rats

Directory of Open Access Journals (Sweden)

David T. Lowenthal

2006-01-01

Full Text Available The purpose of this study was to determine the effects of calorie restriction and exercise on hindlimb histochemistry and fiber type in Fischer 344 rats as they advanced from adulthood through senescence. At 10 months of age, animals were divided into sedentary fed ad libitum, exercise (18 m/min, 8% grade, 20 min/day, 5 days/week fed ad libitum, and calorie restricted by alternate days of feeding. Succinic dehydrogenase, myosin adenosine triphosphatase (mATPase at pH 9.4, nicotine adenonine dinucleotide reductase, and Periodic Acid Shiff histochemical stains were performed on plantaris and soleus muscles. The results indicated that aging resulted in a progressive decline in plantaris Type I muscle fiber in sedentary animals, while exercise resulted in maintenance of these fibers. The percent of plantaris Type II fibers increased between 10 and 24 months of age. Exercise also resulted in a small, but significant, increase in the percentage of plantaris Type IIa fibers at 24 months of age. The soleus fiber distribution for Type I fibers was unaffected by increasing age in all groups of animals. The implications of these results suggest the implementation of exercise as a lifestyle modification as early as possible.

18 CFR 344.2 - Manner of submitting quotations.

Science.gov (United States)

2010-04-01

... quotations. 344.2 Section 344.2 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY REGULATIONS UNDER THE INTERSTATE COMMERCE ACT FILING QUOTATIONS FOR U.S. GOVERNMENT SHIPMENTS AT REDUCED RATES § 344.2 Manner of submitting quotations. (a) The quotation or tender...

Olfactory Memory Impairment in Neurodegenerative Diseases

OpenAIRE

Bahuleyan, Biju; Singh, Satendra

2012-01-01

Olfactory disorders are noted in a majority of neurodegenerative diseases, but they are often misjudged and are rarely rated in the clinical setting. Severe changes in the olfactory tests are observed in Parkinson's disease. Olfactory deficits are an early feature in Alzheimer's disease and they worsen with the disease progression. Alterations in the olfactory function are also noted after severe head injuries, temporal lobe epilepsy, multiple sclerosis, and migraine. The purpose of the prese...

Live attenuated Francisella novicida vaccine protects against Francisella tularensis pulmonary challenge in rats and non-human primates.

Directory of Open Access Journals (Sweden)

Ping Chu

2014-10-01

Full Text Available Francisella tularensis causes the disease tularemia. Human pulmonary exposure to the most virulent form, F. tularensis subsp. tularensis (Ftt, leads to high morbidity and mortality, resulting in this bacterium being classified as a potential biothreat agent. However, a closely-related species, F. novicida, is avirulent in healthy humans. No tularemia vaccine is currently approved for human use. We demonstrate that a single dose vaccine of a live attenuated F. novicida strain (Fn iglD protects against subsequent pulmonary challenge with Ftt using two different animal models, Fischer 344 rats and cynomolgus macaques (NHP. The Fn iglD vaccine showed protective efficacy in rats, as did a Ftt iglD vaccine, suggesting no disadvantage to utilizing the low human virulent Francisella species to induce protective immunity. Comparison of specific antibody profiles in vaccinated rat and NHP sera by proteome array identified a core set of immunodominant antigens in vaccinated animals. This is the first report of a defined live attenuated vaccine that demonstrates efficacy against pulmonary tularemia in a NHP, and indicates that the low human virulence F. novicida functions as an effective tularemia vaccine platform.

Traumatic brain injury and olfactory deficits

DEFF Research Database (Denmark)

Fortin, Audrey; Lefebvre, Mathilde Beaulieu; Ptito, Maurice

2010-01-01

. Between 40-44% of the patients showing olfactory impairments were not aware of their deficit. CONCLUSIONS: Since a significant proportion of the patients showing olfactory impairments were not aware of their deficit, it is recommended than clinicians systematically evaluate olfactory functions using...

Radiosynthesis and initial evaluation of [{sup 18}F]-FEPPA for PET imaging of peripheral benzodiazepine receptors

Energy Technology Data Exchange (ETDEWEB)

Wilson, Alan A. [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8 (Canada)], E-mail: alan.wilson@camhpet.ca; Garcia, Armando; Parkes, Jun [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); McCormick, Patrick [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Institute of Medical Science, University of Toronto, Toronto, Ontario, M5S 1A8 (Canada); Stephenson, Karin A. [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Houle, Sylvain; Vasdev, Neil [PET Centre, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8 (Canada); Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8 (Canada)

2008-04-15

Introduction: A novel [{sup 18}F]-radiolabelled phenoxyanilide, [{sup 18}F]-FEPPA, has been synthesized and evaluated, in vitro and ex vivo, as a potential positron emission tomography imaging agent for the peripheral benzodiazepine receptor (PBR). Methods: [{sup 18}F]-FEPPA and two other radiotracers for imaging PBR, namely [{sup 11}C]-PBR28 and [{sup 11}C]-PBR28-d3, were synthesised and evaluated in vitro and ex vivo as potential PBR imaging agents. Results: [{sup 18}F]-FEPPA is efficiently prepared in one step from its tosylate precursor and [{sup 18}F]-fluoride in high radiochemical yields and at high specific activity. FEPPA displayed a K{sub i} of 0.07 nM for PBR in rat mitochondrial membrane preparations and a suitable lipophilicity for brain penetration (log P of 2.99 at pH 7.4). Upon intravenous injection into rats, [{sup 18}F]-FEPPA showed moderate brain uptake [standard uptake value (SUV) of 0.6 at 5 min] and a slow washout (SUV of 0.35 after 60 min). Highest uptake of radioactivity was seen in the hypothalamus and olfactory bulb, regions previously reported to be enriched in PBR in rat brain. Analysis of plasma and brain extracts demonstrated that [{sup 18}F]-FEPPA was rapidly metabolized, but no lipophilic metabolites were observed in either preparation and only 5% radioactive metabolites were present in brain tissue extracts. Blocking studies to determine the extent of specific binding of [{sup 18}F]-FEPPA in rat brain were problematic due to large perturbations in circulating radiotracer and the lack of a reference region. Conclusions: Further evaluation of the potential of [{sup 18}F]-FEPPA will require the employment of rigorous kinetic models and/or appropriate animal models.

The effects of the selective 5-HT(2C) receptor antagonist SB 242084 on learned helplessness in male Fischer 344 rats.

Science.gov (United States)

Strong, Paul V; Greenwood, Benjamin N; Fleshner, Monika

2009-05-01

Rats exposed to an uncontrollable stressor demonstrate a constellation of behaviors such as exaggerated freezing and deficits in shuttle box escape learning. These behaviors in rats have been called learned helplessness and have been argued to model human stress-related mood disorders. Learned helplessness is thought to be caused by hyperactivation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) and a subsequent exaggerated release of 5-HT in DRN projection sites. Blocking 5-HT(2C) receptors in the face of an increase in serotonin can alleviate anxiety behaviors in some animal models. However, specific 5-HT receptor subtypes involved in learned helplessness remain unknown. The current experiments tested the hypothesis that 5-HT(2C) receptor activation is necessary and sufficient for the expression of learned helplessness. The selective 5-HT(2C) receptor antagonist SB 242084 (1.0 mg/kg) administered i.p. to adult male Fischer 344 rats prior to shuttle box behavioral testing, but not before stress, blocked stress-induced deficits in escape learning but had no effect on the exaggerated shock-elicited freezing. The selective 5-HT(2C) receptor agonist CP-809101 was sufficient to produce learned helplessness-like behaviors in the absence of prior stress and these effects were blocked by pretreatment with SB 242084. Results implicate the 5-HT(2C) receptor subtype in mediating the shuttle box escape deficits produced by exposure to uncontrollable stress and suggest that different postsynaptic 5-HT receptor subtypes underlie the different learned helplessness behaviors.

A SUBCHRONIC INHALATION STUDY OF FISCHER 344 RATS EXPOSED TO 0, 0.4, 1.4 OR 4.0 PPM ACROLEIN

International Nuclear Information System (INIS)

KUTZMAN, R.S.

1981-01-01

Fischer 344 rats were exposed to 0.0, 0.4, 1.4, or 4.0 ppm acrolein for 62 days. The major objective of the study was to relate the results of a series of pulmonary function tests to biochemical and pathological alterations observed in the lung. Cytological and reproductive potential endpoints were also assessed after acrolein exposure. Rats were exposed to acrolein for 6 hours/day, 5 days/week for 62 days. Mortality was observed only in the 4.0 ppm chamber where 32 of 57 exposed males died; however, none of the 8 exposed females died. Most of the mortality occurred within the first 10 exposure days. Histologic examination indicated that the animals died of acute bronchopneumonia. The surviving males and females exposed to 4.0 ppm acrolein gained weight at a significantly slower rate than control animals. The growth of both sexes in the 0.4 and 1.4 ppm groups was similar to that of their respective controls. Histopathologic examination of animals after 62 days of exposure revealed bronchiolar epithelial necrosis and sloughing, bronchiolar edema with macrophages, and focal pulmonary edema in the 4.0 ppm group. These lesions were, in some cases, associated with edema of the trachea and peribronchial lymph nodes, and acute rhinitis which indicated an upper respiratory tract effect of acrolein. Of particular interest was the variability of response between rats in the 4.0 ppm group, some not affected at all while others were moderately affected. Intragroup variability in toxicity was also apparent in the 1.4 ppm exposure group where only 3 of 31 animals examined had lesions directly related to acrolein exposure. Extra respiratory organs appeared unaffected

Proteomic Analysis of the Human Olfactory Bulb.

Science.gov (United States)

Dammalli, Manjunath; Dey, Gourav; Madugundu, Anil K; Kumar, Manish; Rodrigues, Benvil; Gowda, Harsha; Siddaiah, Bychapur Gowrishankar; Mahadevan, Anita; Shankar, Susarla Krishna; Prasad, Thottethodi Subrahmanya Keshava

2017-08-01

The importance of olfaction to human health and disease is often underappreciated. Olfactory dysfunction has been reported in association with a host of common complex diseases, including neurological diseases such as Alzheimer's disease and Parkinson's disease. For health, olfaction or the sense of smell is also important for most mammals, for optimal engagement with their environment. Indeed, animals have developed sophisticated olfactory systems to detect and interpret the rich information presented to them to assist in day-to-day activities such as locating food sources, differentiating food from poisons, identifying mates, promoting reproduction, avoiding predators, and averting death. In this context, the olfactory bulb is a vital component of the olfactory system receiving sensory information from the axons of the olfactory receptor neurons located in the nasal cavity and the first place that processes the olfactory information. We report in this study original observations on the human olfactory bulb proteome in healthy subjects, using a high-resolution mass spectrometry-based proteomic approach. We identified 7750 nonredundant proteins from human olfactory bulbs. Bioinformatics analysis of these proteins showed their involvement in biological processes associated with signal transduction, metabolism, transport, and olfaction. These new observations provide a crucial baseline molecular profile of the human olfactory bulb proteome, and should assist the future discovery of biomarker proteins and novel diagnostics associated with diseases characterized by olfactory dysfunction.