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Sample records for aged female mice

  1. Testosterone and Dihydrotestosterone Differentially Improve Cognition in Aged Female Mice

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    Benice, Ted S.; Raber, Jacob

    2009-01-01

    Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to…

  2. Effects of Portulaca oleracea ethanolic extract on reproductive system of aging female mice

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    Akram Ahangarpour

    2016-03-01

    Full Text Available Background: Aging contains morphological and functional deterioration in biological systems. D-galactose (D-gal generates free radicals and accelerates aging. Portulaca oleracea (Purslane may have protective effect against oxidative stress. Objective: Purslane ethanolic extract effects were evaluated on antioxidant indices and sex hormone in D-gal aging female mice. Materials and Methods: 48 female NMRI mice (25-35 gr were randomly divided into, 6 groups: 1- control (normal saline for 45 days, 2- Purslane (200 mg/kg for last 3 weeks, 3-D-gal (500 mg/kg for 45 days, 4-D-gal+Purslane, 5- Aging, 6-Aging+Purslane. Sex hormones, antioxidants and malondialdehyde (MDA level of ovary and uterus were measured. Histological assessment was also done. Results: In D-gal treated and aging animals, LH and FSH levels were significantly increased (p<0.001 while estrogen and progesterone levels were significantly reduced (p<0.001 in comparison with control group. MDA contents were significantly increased in ovaries and uterus of D-gal and aging groups (p<0.01. Superoxide dismutase (SOD (p<0.001 and catalase (p<0.01 activities were significantly decreased in both aging and D-gal treated animals. Ovarian follicles were degenerated and atrophy on uterine wall and endometrial glands was observed in D-gal and aging groups. Alteration in hormone levels, MDA contents and antioxidant activity were significantly reversed by Purslane (p<0.05. Purslane could also improve histological changes such as atrophy of endometrium. Conclusion: These findings indicate that Purslane can attenuate aging alternations induced by D-gal and aging in female reproductive system.

  3. Effects of Portulaca oleracea ethanolic extract on reproductive system of aging female mice

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    Ahangarpour, Akram; Lamoochi, Zohreh; Fathi Moghaddam, Hadi; Mansouri, Seyed Mohamad Taghi

    2016-01-01

    Background: Aging contains morphological and functional deterioration in biological systems. D-galactose (D-gal) generates free radicals and accelerates aging. Portulaca oleracea (Purslane) may have protective effect against oxidative stress. Objective: Purslane ethanolic extract effects were evaluated on antioxidant indices and sex hormone in D-gal aging female mice. Materials and Methods: 48 female NMRI mice (25-35 gr) were randomly divided into, 6 groups: 1- control (normal saline for 45 days), 2- Purslane (200 mg/kg for last 3 weeks), 3-D-gal (500 mg/kg for 45 days), 4-D-gal+Purslane, 5- Aging, 6-Aging+Purslane. Sex hormones, antioxidants and malondialdehyde (MDA) level of ovary and uterus were measured. Histological assessment was also done. Results: In D-gal treated and aging animals, LH and FSH levels were significantly increased (p<0.001) while estrogen and progesterone levels were significantly reduced (p<0.001) in comparison with control group. MDA contents were significantly increased in ovaries and uterus of D-gal and aging groups (p<0.01). Superoxide dismutase (SOD) (p<0.001) and catalase (p<0.01) activities were significantly decreased in both aging and D-gal treated animals. Ovarian follicles were degenerated and atrophy on uterine wall and endometrial glands was observed in D-gal and aging groups. Alteration in hormone levels, MDA contents and antioxidant activity were significantly reversed by Purslane (p<0.05). Purslane could also improve histological changes such as atrophy of endometrium. Conclusion: These findings indicate that Purslane can attenuate aging alternations induced by D-gal and aging in female reproductive system. PMID:27294220

  4. Aging rather than stress strongly influences amino acid metabolisms in the brain and genital organs of female mice.

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    Kodaira, Momoko; Nagasawa, Mao; Yamaguchi, Takeshi; Ikeda, Hiromi; Minaminaka, Kimie; Chowdhury, Vishwajit S; Yasuo, Shinobu; Furuse, Mitsuhiro

    2017-03-01

    Aging and stress affect quality of life, and proper nourishment is one of means of preventing this effect. Today, there is a focus on the amount of protein consumed by elderly people; however, changes in the amino acid metabolism of individuals have not been fully considered. In addition, the difference between average life span and healthy life years is larger in females than it is in males. To prolong the healthy life years of females, in the present study we evaluated the influence of stress and aging on metabolism and emotional behavior by comparing young and middle-aged female mice. After 28 consecutive days of immobilization stress, behavioral tests were conducted and tissue sampling was performed. The results showed that the body weight of middle-aged mice was severely lowered by stress, but emotional behaviors were hardly influenced by either aging or stress. Aging influenced changes in amino acid metabolism in the brain and increased various amino acid levels in the uterus and ovary. In conclusion, we found that aged mice were more susceptible to stress in terms of body-weight reduction, and that amino acid metabolisms in the brain and genital organs were largely influenced by aging rather than by stress. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Diseases of aging untreated virgin female RFM and BALB/c mice

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    Cosgrove, G.E.; Satterfield, L.C.; Bowles, N.D.; Klima, W.C.

    1978-01-01

    Diseases of untreated, virgin female barrier-maintained RFM and BALB/c mice used as controls in a large radiation aging experiment were necropsied after natural death. The spectrum and incidence of neoplastic and nonneoplastic diseases were somewhat different in the two strains. Both strains show a high incidence of neoplasma (largely reticulum cell sarcomas and lung tumors) and of glomerulosclerosis. A wide variety of other diseases was noted in much lower incidence. The findings in the RF were briefly compared with those in earlier experiments with that strain in this laboratory

  6. 17ß-Estradiol Regulates Histone Alterations Associated with Memory Consolidation and Increases "Bdnf" Promoter Acetylation in Middle-Aged Female Mice

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    Fortress, Ashley M.; Kim, Jaekyoon; Poole, Rachel L.; Gould, Thomas J.; Frick, Karyn M.

    2014-01-01

    Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17ß-estradiol…

  7. Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice.

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    Caitlin S Latimer

    Full Text Available Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for six weeks. Exercise decreased hippocampal astrocyte and myelin markers of aging but increased VEGF, a marker of angiogenesis. Brain vascular casts revealed exercise-induced structural modifications associated with improved endothelial function in the periphery. Our results suggest that age-related astrocyte hypertrophy/reactivity and myelin dysregulation are aggravated by a sedentary lifestyle and accompanying reductions in vascular function. However, these effects appear reversible with exercise initiated at mid-age. As this period of the lifespan coincides with the appearance of multiple markers of brain aging, including initial signs of cognitive decline, it may represent a window of opportunity for intervention as the brain appears to still possess significant vascular plasticity. These results may also have particular implications for aging females who are more susceptible than males to certain risk factors which contribute to vascular aging.

  8. Manipulation of Ovarian Function Significantly Influenced Sarcopenia in Postreproductive-Age Mice

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    Rhett L. Peterson

    2016-01-01

    Full Text Available Previously, transplantation of ovaries from young cycling mice into old postreproductive-age mice increased life span. We anticipated that the same factors that increased life span could also influence health span. Female CBA/J mice received new (60 d ovaries at 12 and 17 months of age and were evaluated at 16 and 25 months of age, respectively. There were no significant differences in body weight among any age or treatment group. The percentage of fat mass was significantly increased at 13 and 16 months of age but was reduced by ovarian transplantation in 16-month-old mice. The percentages of lean body mass and total body water were significantly reduced in 13-month-old control mice but were restored in 16- and 25-month-old recipient mice by ovarian transplantation to the levels found in six-month-old control mice. In summary, we have shown that skeletal muscle mass, which is negatively influenced by aging, can be positively influenced or restored by reestablishment of active ovarian function in aged female mice. These findings provide strong incentive for further investigation of the positive influence of young ovaries on restoration of health in postreproductive females.

  9. Age- and region-specific imbalances of basal amino acids and monoamine metabolism in limbic regions of female Fmr1 knock-out mice.

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    Gruss, Michael; Braun, Katharina

    2004-07-01

    The Fragile X syndrome, a common form of mental retardation in humans, originates from the loss of expression of the Fragile X mental retardation gene leading to the absence of the encoded Fragile X mental retardation protein 1 (FMRP). A broad pattern of morphological and behavioral abnormalities is well described for affected humans as well as Fmr1 knock-out mice, a transgenic animal model for the human Fragile X syndrome. In the present study, we examined neurochemical differences between female Fmr1 knock-out and wildtype mice with particular focus on neurotransmission. Significant age- and region-specific differences of basal tissue neurotransmitter and metabolite levels measured by high performance liquid chromatography were found. Those differences were more numerous in juvenile animals (postnatal day (PND) 28-31) compared to adults (postnatal day 209-221). In juvenile female knock-out mice, especially aspartate and taurine were increased in cortical regions, striatum, cerebellum, and brainstem. Furthermore, compared to the wildtype animals, the juvenile knock-out mice displayed an increased level of neuronal inhibition in the hippocampus and brainstem reflected by decreased ratios of (aspartate + glutamate)/(taurine + GABA), as well as an increased dopamine (DA) turnover in cortical regions, striatum, and hippocampus. These results provide the first evidence that the lack of FMRP expression in female Fmr1 knock-out mice is accompanied by age-dependent, region-specific alterations in brain amino acids, and monoamine turnover, which might be related to the reported synaptical and behavioural alterations in these animals.

  10. Lack of effect on the chromosomal non-disjunction in aged female mice after low dose x-irradiation

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    Strausmanis, R; Hendrikson, I B; Holmberg, M; Roennbaeck, C [Research Inst. of National Defence, Sundbyberg (Sweden). Dept. 4

    1978-02-01

    Karyotypes were determined in 1064 embryos of aged C57/BL mothers. The virgin female mice were irradiated with 0, 4, 8 or 16 R of X-rays, respectively, and placed with young untreated males 5 days after irradiation. 10.5-days old embryos were recovered from the uterus. Aneuploid embryos classified as alive (heart beats observed at the dissection) were 1 monosomic in the control group (496 embryos) and 2 trisomics in the irradiated group (568 embryos). The number of aneuploid embryos classified as dead was 4 trisomic cases in the control group and 3 trisomics in the irradiated group. The data indicate that trisomic embryos are not uncommon in the mouse but are eliminated in post-implantation death. In contrast to the results of Yamamoto et al. the present data do not demonstrate an increased frequency of chromosome abnormalities in embryos of aged mice X-irradiated before mating as compared to non-irradiated ones.

  11. Lack of effect on the chromosomal non-disjunction in aged female mice after low dose x-irradiation

    International Nuclear Information System (INIS)

    Strausmanis, R.; Hendrikson, I.-B.; Holmberg, M.; Roennbaeck, C.

    1978-01-01

    Karyotypes were determined in 1064 embryos of aged C57/BL mothers. The virgin female mice were irradiated with 0, 4, 8 or 16 R of X-rays, respectively, and placed with young untreated males 5 days after irradiation. 10.5-days old embryos were recovered from the uterus. Aneuploid embryos classified as alive (heart beats observed at the dissection) were 1 monosomic in the control group (496 embryos) and 2 trisomics in the irradiated group (568 embryos). The number of aneuploid embryos classified as dead was 4 trisomic cases in the control group and 3 trisomics in the irradiated group. The data indicate that trisomic embryos are not uncommon in the mouse but are eliminated in post-implantation death. In contrast to the results of Yamamoto et al. the present data do not demonstrate an increased frequency of chromosome abnormalities in embryos of aged mice X-irradiated before mating as compared to non-irradiated ones

  12. Effects of hydro-alcoholic extract of Vitex agnus-castus fruit on kidney of D-galactose-induced aging model in female mice.

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    Oroojan, A A; Ahangarpour, A; Khorsandi, L; Najimi, S A

    2016-01-01

    The aim of the present study was to evaluate the effect of a hydro-alcoholic extract of Vitex agnus-castus (VAC) fruit on blood urea nitrogen (BUN), creatinine (Cr) and, kidney histology of a female mouse model of D-galactose induced aging. In this experimental study, 72 NMRI mice were divided into 6 groups: control, VAC, D-galactose, D-galactose+VAC, aging, and aging+VAC. D-galactose was injected for 45 days and, VAC extract administered in the last 7 days, twice a day. Serum BUN and Cr levels were not significantly changed in the D-galactose and natural aged animals in comparison to control group. Histological changes such as nuclear pyknosis, proximal cell swelling, infiltration of inflammatory cells, tubular dilatation and, vasodilatation were observed in both D-galactose and natural aged mice. Further, glomerules diameter was decreased in them. Administration of VAC could attenuate the histological alterations. These results indicate that VAC may have beneficial effects on aging and aging related kidney disease.

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

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    Gasco Manuel

    2005-05-01

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

  14. Urethral dysfunction in female mice with estrogen receptor β deficiency.

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    Yung-Hsiang Chen

    Full Text Available Estrogen has various regulatory functions in the growth, development, and differentiation of the female urogenital system. This study investigated the roles of ERβ in stress urinary incontinence (SUI. Wild-type (ERβ(+/+ and knockout (ERβ(-/- female mice were generated (aged 6-8 weeks, n = 6 and urethral function and protein expression were measured. Leak point pressures (LPP and maximum urethral closure pressure (MUCP were assessed in mice under urethane anesthesia. After the measurements, the urethras were removed for proteomic analysis using label-free quantitative proteomics by nano-liquid chromatography-mass spectrometry (LC-MS/MS analysis. The interaction between these proteins was further analysed using MetaCore. Lastly, Western blot was used to confirm the candidate proteins. Compared with the ERβ(+/+ group, the LPP and MUCP values of the ERβ(-/- group were significantly decreased. Additionally, we identified 85 differentially expressed proteins in the urethra of ERβ(-/- female mice; 57 proteins were up-regulated and 28 were down-regulated. The majority of the ERβ knockout-modified proteins were involved in cell-matrix adhesion, metabolism, immune response, signal transduction, nuclear receptor translational regelation, and muscle contraction and development. Western blot confirmed the up-regulation of myosin and collagen in urethra. By contrast, elastin was down-regulated in the ERβ(-/- mice. This study is the first study to estimate protein expression changes in urethras from ERβ(-/- female mice. These changes could be related to the molecular mechanism of ERβ in SUI.

  15. Influence of Sex and Age on Natural Resistance to St. Louis Encephalitis Virus Infection in Mice

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    Andersen, Arthur A.; Hanson, Robert P.

    1974-01-01

    A difference was observed in susceptibility of adult male and female mice to St. Louis encephalitis (SLE) virus as measured by the death rate after intravenous challenge. Female mice that had susceptibility similar to that of males at 2 months of age had increased resistance to SLE virus at 3 and 4 months of age. The increased resistance occurred after sexual maturity, indicating that the resistance factor possibly was related to an aging process in the female. The susceptibility of male mice remained unchanged over the 2- to 4-month period. Neither pregnancy nor castration had any effect on resistance of adult mice to St. Louis encephalitis virus. PMID:4857422

  16. Social isolation during puberty affects female sexual behavior in mice

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    Jasmina eKercmar

    2014-09-01

    Full Text Available Exposure to stress during puberty can lead to long-term behavioral alterations in adult rodents coincident with sex steroid hormone-dependent brain remodeling and reorganization. Social isolation is a stress for social animals like mice, but little is known about the effects of such stress during adolescence on later reproductive behaviors. The present study examined sexual behavior of ovariectomized, estradiol and progesterone primed female mice that were individually housed from 25 days of age until testing at approximately 95 days, or individually housed from day 25 until day 60 (during puberty, followed by housing in social groups. Mice in these isolated groups were compared to females that were group housed throughout the experiment. Receptive sexual behaviors of females and behaviors of stimulus males were recorded. Females housed in social groups displayed greater levels of receptive behaviors in comparison to both socially isolated groups. Namely, social females had higher lordosis quotients and more often displayed stronger lordosis postures in comparison to isolated females. No differences between female groups were observed in stimulus male sexual behavior suggesting that female ’attractiveness’ was not affected by their social isolation. Females housed in social groups had fewer cells containing immunoreactive estrogen receptor (ER α in the anteroventral periventricular nucleus (AVPV and in the ventromedial nucleus of the hypothalamus (VMH than both isolated groups. These results suggest that isolation during adolescence affects female sexual behavior and re-socialization for one month in adulthood is insufficient to rescue lordosis behavior from the effects of social isolation during the pubertal period.

  17. Room temperature housing results in premature cancellous bone loss in growing female mice: implications for the mouse as a preclinical model for age-related bone loss.

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    Iwaniec, U T; Philbrick, K A; Wong, C P; Gordon, J L; Kahler-Quesada, A M; Olson, D A; Branscum, A J; Sargent, J L; DeMambro, V E; Rosen, C J; Turner, R T

    2016-10-01

    Room temperature housing (22 °C) results in premature cancellous bone loss in female mice. The bone loss was prevented by housing mice at thermoneutral temperature (32 °C). Thermogenesis differs markedly between mice and humans and mild cold stress induced by standard room temperature housing may introduce an unrecognized confounding variable into preclinical studies. Female mice are often used as preclinical models for osteoporosis but, in contrast to humans, mice exhibit cancellous bone loss during growth. Mice are routinely housed at room temperature (18-23 °C), a strategy that exaggerates physiological differences in thermoregulation between mice (obligatory daily heterotherms) and humans (homeotherms). The purpose of this investigation was to assess whether housing female mice at thermoneutral (temperature range where the basal rate of energy production is at equilibrium with heat loss) alters bone growth, turnover and microarchitecture. Growing (4-week-old) female C57BL/6J and C3H/HeJ mice were housed at either 22 or 32 °C for up to 18 weeks. C57BL/6J mice housed at 22 °C experienced a 62 % cancellous bone loss from the distal femur metaphysis during the interval from 8 to 18 weeks of age and lesser bone loss from the distal femur epiphysis, whereas cancellous and cortical bone mass in 32 °C-housed mice were unchanged or increased. The impact of thermoneutral housing on cancellous bone was not limited to C57BL/6J mice as C3H/HeJ mice exhibited a similar skeletal response. The beneficial effects of thermoneutral housing on cancellous bone were associated with decreased Ucp1 gene expression in brown adipose tissue, increased bone marrow adiposity, higher rates of bone formation, higher expression levels of osteogenic genes and locally decreased bone resorption. Housing female mice at 22 °C resulted in premature cancellous bone loss. Failure to account for species differences in thermoregulation may seriously confound interpretation of studies

  18. Crybb2 deficiency impairs fertility in female mice

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    Gao, Qian; Sun, Li-Li; Xiang, Fen-Fen; Gao, Li; Jia, Yin; Zhang, Jian-Rong; Tao, Hai-Bo; Zhang, Jun-Jie; Li, Wen-Jie

    2014-01-01

    Highlights: • Crybb2 deletion impaired female fertility. • Crybb2 deletion dramatically affected the production of reproduction-related hormones and hormone response. • Crybb2 deletion impaired follicular development and inhibited the proliferation of granulosa cells. • Crybb2 deletion promoted follicular atresia and apoptosis in granulosa cells. - Abstract: Beta-B2-crystallin (CRYBB2), encoded by Crybb2 gene, is a major protein in the mammalian eye lens that plays an important role in maintaining the transparency of the ocular lens. However, CRYBB2 also plays important roles in many extra-lenticular tissues and organs such as the retina, brain and testis. Our previous studies demonstrated that male Crybb2 deficient (Crybb2 −/− ) mice have reduced fertility compared with wild-type (WT) mice, while female Crybb2 −/− mice exhibited reduced ovary weights and shorter estrous cycle percentages. Here we specifically investigated the role of CRYBB2 in the female reproductive system. Our studies revealed that ovaries from female Crybb2 −/− mice exhibited significantly reduced numbers of primordial, secondary and pre-ovulatory follicles when compared with WT mice, while the rate of atretic follicles was also increased. Additionally, fewer eggs were collected from the oviduct of Crybb2 −/− female mice after superovulation. Estrogen levels were higher in the metestrus and diestrus cycles of female Crybb2 −/− mice, while progesterone levels were lower in diestrus cycles. Furthermore, the expression of survival and cell cycle genes, Bcl-2, Cdk4 and Ccnd2, were significantly decreased in granulosa cells isolated from female Crybb2 −/− mice, consistent with the predominant expression of CRYBB2 in ovarian granulosa cells. Our results reveal a critical role for CRYBB2 in female fertility and specific effects on the proliferation and survival status of ovarian granulosa cells

  19. Crybb2 deficiency impairs fertility in female mice

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    Gao, Qian [Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Sun, Li-Li [Aviation Medical Evaluation and Training Center of Airforce in Dalian, Dalian, Liaoning Province 116013 (China); Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Xiang, Fen-Fen [Department of Laboratory Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062 (China); Gao, Li [Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Jia, Yin; Zhang, Jian-Rong; Tao, Hai-Bo [Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Zhang, Jun-Jie, E-mail: zhangjj910@163.com [Department of Obstetrics and Gynecology, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Li, Wen-Jie, E-mail: wenjieli@pku.org.cn [Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China)

    2014-10-10

    Highlights: • Crybb2 deletion impaired female fertility. • Crybb2 deletion dramatically affected the production of reproduction-related hormones and hormone response. • Crybb2 deletion impaired follicular development and inhibited the proliferation of granulosa cells. • Crybb2 deletion promoted follicular atresia and apoptosis in granulosa cells. - Abstract: Beta-B2-crystallin (CRYBB2), encoded by Crybb2 gene, is a major protein in the mammalian eye lens that plays an important role in maintaining the transparency of the ocular lens. However, CRYBB2 also plays important roles in many extra-lenticular tissues and organs such as the retina, brain and testis. Our previous studies demonstrated that male Crybb2 deficient (Crybb2{sup −/−}) mice have reduced fertility compared with wild-type (WT) mice, while female Crybb2{sup −/−} mice exhibited reduced ovary weights and shorter estrous cycle percentages. Here we specifically investigated the role of CRYBB2 in the female reproductive system. Our studies revealed that ovaries from female Crybb2{sup −/−} mice exhibited significantly reduced numbers of primordial, secondary and pre-ovulatory follicles when compared with WT mice, while the rate of atretic follicles was also increased. Additionally, fewer eggs were collected from the oviduct of Crybb2{sup −/−} female mice after superovulation. Estrogen levels were higher in the metestrus and diestrus cycles of female Crybb2{sup −/−} mice, while progesterone levels were lower in diestrus cycles. Furthermore, the expression of survival and cell cycle genes, Bcl-2, Cdk4 and Ccnd2, were significantly decreased in granulosa cells isolated from female Crybb2{sup −/−} mice, consistent with the predominant expression of CRYBB2 in ovarian granulosa cells. Our results reveal a critical role for CRYBB2 in female fertility and specific effects on the proliferation and survival status of ovarian granulosa cells.

  20. Effects of Altered Levels of Extracellular Superoxide Dismutase and Irradiation on Hippocampal Neurogenesis in Female Mice

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    Zou, Yani; Leu, David; Chui, Jennifer; Fike, John R.; Huang, Ting-Ting

    2013-01-01

    Purpose: Altered levels of extracellular superoxide dismutase (EC-SOD) and cranial irradiation have been shown to affect hippocampal neurogenesis. However, previous studies were only conducted in male mice, and it was not clear if there was a difference between males and females. Therefore, female mice were studied and the results compared with those generated in male mice from an earlier study. Methods and Materials: Female wild-type, EC-SOD-null (KO), and EC-SOD bigenic mice with neuronal-specific expression of EC-SOD (OE) were subjected to a single dose of 5-Gy gamma rays to the head at 8 weeks of age. Progenitor cell proliferation, differentiation, and long-term survival of newborn neurons were determined. Results: Similar to results from male mice, EC-SOD deficiency and irradiation both resulted in significant reductions in mature newborn neurons in female mice. EC-SOD deficiency reduced long-term survival of newborn neurons whereas irradiation reduced progenitor cell proliferation. Overexpression of EC-SOD corrected the negative impacts from EC-SOD deficiency and irradiation and normalized the production of newborn neurons in OE mice. Expression of neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 were significantly reduced by irradiation in wild-type mice, but the levels were not changed in KO and OE mice even though both cohorts started out with a lower baseline level. Conclusion: In terms of hippocampal neurogenesis, EC-SOD deficiency and irradiation have the same overall effects in males and females at the age the studies were conducted

  1. Influence of sex and age on the biological half-life of cadmium in mice

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    Taguchi, T.; Suzuki, S.

    1981-01-01

    The influence of age on the whole-body biological half-life of 109 Cd was studied in male mice following ip injection. The influence of sex on whole-body and organ retention was ascertained after sc injection. The whole-body biological half-life of 109 Cd of the older mice was more than twice that of the younger mice, and that of the female mice was longer than that of the males. These differences demonstrate a biological difference between males and females with respect to whole-body half-life of 109 Cd. The effects of age and sex on the biological half-life of Cd in mice are assessed quantitatively

  2. Effects of hydro-alcoholic extract of Vitex agnus-castus fruit on kidney of D-galactose-induced aging model in female mice

    OpenAIRE

    Oroojan, A. A.; Ahangarpour, A.; Khorsandi, L.; Najimi, S. A.

    2016-01-01

    The aim of the present study was to evaluate the effect of a hydro-alcoholic extract of Vitex agnus-castus (VAC) fruit on blood urea nitrogen (BUN), creatinine (Cr) and, kidney histology of a female mouse model of D-galactose induced aging. In this experimental study, 72 NMRI mice were divided into 6 groups: control, VAC, D-galactose, D-galactose+VAC, aging, and aging+VAC. D-galactose was injected for 45 days and, VAC extract administered in the last 7 days, twice a day. Serum BUN and Cr leve...

  3. Gender-specific effects of endogenous testosterone: female alpha-estrogen receptor-deficient C57Bl/6J mice develop glomerulosclerosis.

    Science.gov (United States)

    Elliot, S J; Berho, M; Korach, K; Doublier, S; Lupia, E; Striker, G E; Karl, M

    2007-08-01

    Young female mice on a C57Bl/6J (B6) background are considered glomerulosclerosis (GS)-resistant but aging B6 mice develop mild GS. Estrogen deficiency accelerates while estrogen replacement retards GS in young sclerosis-prone oligosyndactyly mutant mice on an ROP background. To explore the effects of sex hormones on glomerular structure and function in the context of gender and genetic background, we studied mice in which the estrogen-receptor (ER) genes alpha- or -beta were deleted (alpha- or betaER knockout (KO)) and crossed into the B6 background. We also studied ovariectomized (Ovx) B6 mice given testosterone. Male and female betaERKO and male alphaERKO mice had no glomerular dysfunction at 9 months of age; however, alphaERKO female mice displayed albuminuria and GS. Ovx prevented glomerular dysfunction in alphaERKO female mice by eliminating endogenous testosterone production while exogenous testosterone induced GS in Ovx B6 mice. Androgen receptor (AR) expression and function was found in microdissected glomeruli and cultured mesangial cells. Testosterone compared to placebo increased both AR expression and TGF-beta1 mRNA levels in glomeruli isolated from female B6 mice. Estrogen deficiency had no deleterious effects on the glomeruli in B6 mice. Our study shows that genetic traits strongly influence the GS-promoting effects of estrogen deficiency while testosterone induces GS in a gender-specific manner.

  4. Age- and sex-related disturbance in a battery of sensorimotor and cognitive tasks in Kunming mice.

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    Chen, Gui-Hai; Wang, Yue-Ju; Zhang, Li-Qun; Zhou, Jiang-Ning

    2004-12-15

    A battery of tasks, i.e. beam walking, open field, tightrope, radial six-arm water maze (RAWM), novel-object recognition and olfactory discrimination, was used to determine whether there was age- and sex-related memory deterioration in Kunming (KM) mice, and whether these tasks are independent or correlated with each other. Two age groups of KM mice were used: a younger group (7-8 months old, 12 males and 11 females) and an older group (17-18 months old, 12 males and 12 females). The results showed that the spatial learning ability and memory in the RAWM were lower in older female KM mice relative to younger female mice and older male mice. Consistent with this, in the novel-object recognition task, a non-spatial cognitive task, older female mice but not older male mice had impairment of short-term memory. In olfactory discrimination, another non-spatial task, the older mice retained this ability. Interestingly, female mice performed better than males, especially in the younger group. The older females exhibited sensorimotor impairment in the tightrope task and low locomotor activity in the open-field task. Moreover, older mice spent a longer time in the peripheral squares of the open-field than younger ones. The non-spatial cognitive performance in the novel-object recognition and olfactory discrimination tasks was related to performance in the open-field, whereas the spatial cognitive performance in the RAWM was not related to performance in any of the three sensorimotor tasks. These results suggest that disturbance of spatial learning and memory, as well as selective impairment of non-spatial learning and memory, existed in older female KM mice.

  5. Amiloride Improves Endothelial Function and Reduces Vascular Stiffness in Female Mice Fed a Western Diet

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    Luis A. Martinez-Lemus

    2017-06-01

    Full Text Available Obese premenopausal women lose their sex related cardiovascular disease protection and develop greater arterial stiffening than age matched men. In female mice, we have shown that consumption of a Western diet (WD, high in fat and refined sugars, is associated with endothelial dysfunction and vascular stiffening, which occur via activation of mineralocorticoid receptors and associated increases in epithelial Na+ channel (ENaC activity on endothelial cells (EnNaC. Herein our aim was to determine the effect that reducing EnNaC activity with a very-low-dose of amiloride would have on decreasing endothelial and arterial stiffness in young female mice consuming a WD. To this end, we fed female mice either a WD or control diet and treated them with or without a very-low-dose of the ENaC-inhibitor amiloride (1 mg/kg/day in the drinking water for 20 weeks beginning at 4 weeks of age. Mice consuming a WD were heavier and had greater percent body fat, proteinuria, and aortic stiffness as assessed by pulse-wave velocity than those fed control diet. Treatment with amiloride did not affect body weight, body composition, blood pressure, urinary sodium excretion, or insulin sensitivity, but significantly reduced the development of endothelial and aortic stiffness, aortic fibrosis, aortic oxidative stress, and mesenteric resistance artery EnNaC abundance and proteinuria in WD-fed mice. Amiloride also improved endothelial-dependent vasodilatory responses in the resistance arteries of WD-fed mice. These results indicate that a very-low-dose of amiloride, not affecting blood pressure, is sufficient to improve endothelial function and reduce aortic stiffness in female mice fed a WD, and suggest that EnNaC-inhibition may be sufficient to ameliorate the pathological vascular stiffening effects of WD-induced obesity in females.

  6. β-cell serotonin production is associated with female sex, old age, and diabetes-free condition.

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    Kim, Yeong Gi; Moon, Joon Ho; Kim, Kyuho; Kim, Hyeongseok; Kim, Juok; Jeong, Ji-Seon; Lee, Junguee; Kang, Shinae; Park, Joon Seong; Kim, Hail

    2017-11-25

    Serotonin is known to be present in pancreatic β-cells and to play several physiological roles, including insulin secretion, β-cell proliferation, and paracrine inhibition of α-cells. However, the serotonin production of different cell lines and islets has not been compared based on age, sex, and diabetes related conditions. Here, we directly compared the serotonin concentrations in βTC and MIN6 cell lines, as well as in islets from mice using ultra-performance liquid chromatography tandem mass spectrometry. The average serotonin concentration was 5-10 ng/mg protein in the islets of male and non-pregnant female mice. The serotonin level was higher in females than males at 8 weeks, although there was no difference at 1 year. Furthermore, we observed serotonin by immunofluorescence staining in the pancreatic tissues of mice and human. Serotonin was detected by immunofluorescence staining in a portion of β-cells from islets of old female mice, but not of male or young female mice. A similar pattern was observed in human pancreas as well. In humans, serotonin production in β-cells was associated with a diabetes-free condition. Thus, serotonin production in β-cells was associated with old age, female sex, and diabetes-free condition. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Experimental Tityus serrulatus scorpion envenomation: age- and sex-related differences in symptoms and mortality in mice

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    Pucca MB

    2011-01-01

    Full Text Available Among the various methods for evaluating animal venom toxicity, the calculation of the median lethal dose (LD50 is the most widely used. Although different protocols can be used to calculate the LD50, the source of the venom and the method of extraction, as well as the strain, age, and sex of the animal model employed, should be taken into consideration. The objective of the present study was to evaluate the influence of sex and age on the toxicity of Tityus serrulatus scorpion venom in Swiss mice. Although the symptoms of envenomation were similar in male and female animals, female mice proved to be more resistant to the venom. In females, age had no impact on the susceptibility to scorpion envenomation. Male mice were more sensitive to T. serrulatus venom. Moreover, in males, age was an important parameter since sensitivity to the venom increased with age.

  8. Tibial loading increases osteogenic gene expression and cortical bone volume in mature and middle-aged mice.

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    Matthew J Silva

    Full Text Available There are conflicting data on whether age reduces the response of the skeleton to mechanical stimuli. We examined this question in female BALB/c mice of different ages, ranging from young to middle-aged (2, 4, 7, 12 months. We first assessed markers of bone turnover in control (non-loaded mice. Serum osteocalcin and CTX declined significantly from 2 to 4 months (p<0.001. There were similar age-related declines in tibial mRNA expression of osteoblast- and osteoclast-related genes, most notably in late osteoblast/matrix genes. For example, Col1a1 expression declined 90% from 2 to 7 months (p<0.001. We then assessed tibial responses to mechanical loading using age-specific forces to produce similar peak strains (-1300 µε endocortical; -2350 µε periosteal. Axial tibial compression was applied to the right leg for 60 cycles/day on alternate days for 1 or 6 weeks. qPCR after 1 week revealed no effect of loading in young (2-month mice, but significant increases in osteoblast/matrix genes in older mice. For example, in 12-month old mice Col1a1 was increased 6-fold in loaded tibias vs. controls (p = 0.001. In vivo microCT after 6 weeks revealed that loaded tibias in each age group had greater cortical bone volume (BV than contralateral control tibias (p<0.05, due to relative periosteal expansion. The loading-induced increase in cortical BV was greatest in 4-month old mice (+13%; p<0.05 vs. other ages. In summary, non-loaded female BALB/c mice exhibit an age-related decline in measures related to bone formation. Yet when subjected to tibial compression, mice from 2-12 months have an increase in cortical bone volume. Older mice respond with an upregulation of osteoblast/matrix genes, which increase to levels comparable to young mice. We conclude that mechanical loading of the tibia is anabolic for cortical bone in young and middle-aged female BALB/c mice.

  9. The carcinogenic effects of fetal and postnatal radiation in female mice

    International Nuclear Information System (INIS)

    Kusama, Tomoko; Yoshizawa, Yasuo

    1982-01-01

    The present study was designed to investigate the carcinogenic effects of fetal and postnatal irradiation in female mice. The C57BL/6J mice were subjected to whole-body exposure to 1-Gy or 4-Gy 137 Cs γ-ray irradiation on the 15th fetal day or the 30th postnatal day. Following this, all mice were observed throughout their respective life spans under conventional rearing conditions. The tumor incidence rate, average latent period and distributions of various tumors were used as the quantitative parameters of radiation-induced carcinogenesis. The following conclusions can be draw: (1) The mean life span of mice that underwent 4-Gy irradiation at the age of 30 days was shorter than that of non-irradiated control mice. (2) In control mice, the tumor incidence was 75.7%. (3) In order to estimate the mean age and tumor incidence, an adjustment for competing death is necessary. (4) The adjusted tumor incidences of thymic lymphoma and breast tumor of the irradiated groups were not different from those of control group. On the other hand, there was a significant difference between the two in the adjusted incidence of reticular tissue neoplasm. (author)

  10. Inducible knockdown of pregnancy-associated plasma protein-A gene expression in adult female mice extends life span.

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    Bale, Laurie K; West, Sally A; Conover, Cheryl A

    2017-08-01

    Pregnancy-associated plasma protein-A (PAPP-A) knockout (KO) mice, generated through homologous recombination in embryonic stem cells, have a significantly increased lifespan compared to wild-type littermates. However, it is unknown whether this longevity advantage would pertain to PAPP-A gene deletion in adult animals. In the present study, we used tamoxifen (Tam)-inducible Cre recombinase-mediated excision of the floxed PAPP-A (fPAPP-A) gene in mice at 5 months of age. fPAPP-A mice, which were either positive (pos) or negative (neg) for Tam-Cre, received Tam treatment with quarterly boosters. Only female mice could be used with this experimental design. fPAPP-A/neg and fPAPP-A/pos mice had similar weights at the start of the experiment and showed equivalent weight gain. We found that fPAPP-A/pos mice had a significant extension of life span (P = 0.005). The median life span was increased by 21% for fPAPP-A/pos compared to fPAPP-A/neg mice. Analysis of mortality in life span quartiles indicated that the proportion of deaths of fPAPP-A/pos mice were lower than fPAPP-A/neg mice at young adult ages (P = 0.002 for 601-800 days) and higher than fPAPP-A/neg mice at older ages (P = 0.004 for >1000 days). Thus, survival curves and age-specific mortality indicate that female mice with knockdown of PAPP-A gene expression as adults have an extended healthy life span. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  11. Effects of Vitex agnus-castus fruit on sex hormones and antioxidant indices in a d-galactose-induced aging female mouse model.

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    Ahangarpour, Akram; Najimi, Seyedeh Asma; Farbood, Yaghoob

    2016-11-01

    Aging is associated with the loss of endocrine function. In this study, Vitex agnus-castus (Vitex), which has antioxidant effects and high levels of phytoestrogen, was investigated with regard to the hypothalamic-pituitary-gonadal axis and antioxidant indices in natural aging and in a d-galactose induced aging model in female mice. The mice were subcutaneously injected with d-galactose (500 mg/kg/d for 45 days). Extract of Vitex (600 mg/kg/bid for 7 days by gavage) was used to treat d-galactose-induced aging and natural aging in mice. Seventy-two female NMRI mice (48 3-month-old normal mice and 24 18-24-month-old mice), weighing 30-35 g were randomly divided into six groups: control, Vitex, d-galactose, Vitex + d-galactose, Aging, and Vitex + Aging. The antioxidant indices and sex hormone levels were subsequently measured by enzyme-linked immunosorbent assay kits. Body weight and the levels of malondialdehyde (MDA), follicle-stimulating hormone, and luteinizing hormone levels were significantly increased in the d-galactose aging and natural aging groups, whereas catalase and superoxide dismutase (SOD) activity and estrogen level were significantly decreased in these same groups. d-Galactose can also disrupt the estrous cycle and damage the uterus and ovarian tissues. Vitex could effectively attenuate these alterations. Vitex improved some aging events in the reproductive system of female mice. Therefore, because of its apparent antiaging effects, Vitex can be suitable for some aging problems such as oxidative stress, female sex hormone deficiency, and an atrophic endometrium. Copyright © 2016. Published by Elsevier Taiwan LLC.

  12. Exposure to Alumina Nanoparticles in Female Mice During Pregnancy Induces Neurodevelopmental Toxicity in the Offspring.

    Science.gov (United States)

    Zhang, Qinli; Ding, Yong; He, Kaihong; Li, Huan; Gao, Fuping; Moehling, Taylor J; Wu, Xiaohong; Duncan, Jeremy; Niu, Qiao

    2018-01-01

    Alumina nanoparticles (AlNP) have been shown to accumulate in organs and penetrate biological barriers which lead to toxic effects in many organ systems. However, it is not known whether AlNP exposure to female mice during pregnancy can affect the development of the central nervous system or induce neurodevelopmental toxicity in the offspring. The present study aims to examine the effect of AlNP on neurodevelopment and associated underlying mechanism. ICR strain adult female mice were randomly divided into four groups, which were treated with normal saline (control), 10 μm particle size of alumina (bulk-Al), and 50 and 13 nm AlNP during entire pregnancy period. Aluminum contents in the hippocampus of newborns were measured and neurodevelopmental behaviors were tracked in the offspring from birth to 1 month of age. Furthermore, oxidative stress and neurotransmitter levels were measured in the cerebral cortex of the adolescents. Our results showed that aluminum contents in the hippocampus of newborns in AlNP-treated groups were significantly higher than those in bulk-Al and controls. Moreover, the offspring delivered by AlNP-treated female mice displayed stunted neurodevelopmental behaviors. Finally, the offspring of AlNP-treated mice demonstrated significantly increased anxiety-like behavior with impaired learning and memory performance at 1 month of age. The underlying mechanism could be related to increased oxidative stress and decreased neurotransmitter levels in the cerebral cortex. We therefore conclude that AlNP exposure of female mice during pregnancy can induce neurodevelopmental toxicity in offspring.

  13. Identification of novel genes associated with renal tertiary lymphoid organ formation in aging mice.

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    Huang, Yuan; Caputo, Christina R; Noordmans, Gerda A; Yazdani, Saleh; Monteiro, Luiz Henrique; van den Born, Jaap; van Goor, Harry; Heeringa, Peter; Korstanje, Ron; Hillebrands, Jan-Luuk

    2014-01-01

    A hallmark of aging-related organ deterioration is a dysregulated immune response characterized by pathologic leukocyte infiltration of affected tissues. Mechanisms and genes involved are as yet unknown. To identify genes associated with aging-related renal infiltration, we analyzed kidneys from aged mice (≥20 strains) for infiltrating leukocytes followed by Haplotype Association Mapping (HAM) analysis. Immunohistochemistry revealed CD45+ cell clusters (predominantly T and B cells) in perivascular areas coinciding with PNAd+ high endothelial venules and podoplanin+ lymph vessels indicative of tertiary lymphoid organs. Cumulative cluster size increased with age (analyzed at 6, 12 and 20 months). Based on the presence or absence of clusters in male and female mice at 20 months, HAM analysis revealed significant associations with loci on Chr1, Chr2, Chr8 and Chr14 in male mice, and with loci on Chr4, Chr7, Chr13 and Chr14 in female mice. Wisp2 (Chr2) showed the strongest association (P = 5.00×10(-137)) in male mice; Ctnnbip1 (P = 6.42×10(-267)) and Tnfrsf8 (P = 5.42×10(-245)) (both on Chr4) showed the strongest association in female mice. Both Wisp2 and Ctnnbip1 are part of the Wnt-signaling pathway and the encoded proteins were expressed within the tertiary lymphoid organs. In conclusion, this study revealed differential lymphocytic infiltration and tertiary lymphoid organ formation in aged mouse kidneys across different inbred mouse strains. HAM analysis identified candidate genes involved in the Wnt-signaling pathway that may be causally linked to tertiary lymphoid organ formation.

  14. Apolipoprotein E4 Causes Age- and Sex-Dependent Impairments of Hilar GABAergic Interneurons and Learning and Memory Deficits in Mice

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    Leung, Laura; Andrews-Zwilling, Yaisa; Yoon, Seo Yeon; Jain, Sachi; Ring, Karen; Dai, Jessica; Wang, Max Mu; Tong, Leslie; Walker, David; Huang, Yadong

    2012-01-01

    Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). ApoE4 has sex-dependent effects, whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic interneurons, whereby GAD67- or somatostatin-positive–but not NPY- or parvalbumin-positive–interneuron loss was exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at 16 months of age in female apoE4-KI mice; however, this effect was not observed in female apoE3-KI mice. In contrast, we found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated by apoE genotype. PMID:23300939

  15. Associations between tumor types in irradiated BALB/c female mice

    International Nuclear Information System (INIS)

    Storer, J.B.

    1982-01-01

    Associations between pairs of 12 different tumor types were estimated for a population of over 3800 irradiated BALB/c female mice. The associations were adjusted for age and radiation dose. Of the 66 pairs of tumor types, 21 showed significant positive or negative associations. Of these, 8 were considered to be spurious, principally because one or both of the tumors was rapidly lethal, leading to an apparent negative association. Six of the remaining 13 significant associations involed tumors of endocrine organs or tumors known to be endocrine related. Six others involved associations between lung, vascular tissue, or reticular tissue tumors, and tumors of endocrine organs. The remaining and highly negative association was between reticulum cell sarcomas and other lymphomas and leukemias. It was concluded that in irradiated female mice of this strain, at least, tumors are not independent and that alterations in host factors (principally endocrine) lead to animals developing both tumors (positive associations) or to one tumor but not the other (negative associations)

  16. Proteomic study on gender differences in aging kidney of mice

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    Cristobal Susana

    2009-04-01

    Full Text Available Abstract Background This study aims to analyze sex differences in mice aging kidney. We applied a proteomic technique based on subfractionation, and liquid chromatography coupled with 2-DE. Samples from male and female CD1-Swiss outbred mice from 28 weeks, 52 weeks, and 76 weeks were analysed by 2-DE, and selected proteins were identified by matrix assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS. Results This proteomic analysis detected age-related changes in protein expression in 55 protein-spots, corresponding to 22 spots in males and 33 spots in females. We found a protein expression signature (PES of aging composed by 8 spots, common for both genders. The identified proteins indicated increases in oxidative and proteolytic proteins and decreases in glycolytic proteins, and antioxidant enzymes. Conclusion Our results provide insights into the gender differences associated to the decline of kidney function in aging. Thus, we show that proteomics can provide valuable information on age-related changes in expression levels of proteins and related modifications. This pilot study is still far from providing candidates for aging-biomarkers. However, we suggest that the analysis of these proteins could suggest mechanisms of cellular aging in kidney, and improve the kidney selection for transplantation.

  17. Absence of ERRalpha in female mice confers resistance to bone loss induced by age or estrogen-deficiency.

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    Catherine Teyssier

    Full Text Available BACKGROUND: ERRalpha is an orphan member of the nuclear hormone receptor superfamily, which acts as a transcription factor and is involved in various metabolic processes. ERRalpha is also highly expressed in ossification zones during mouse development as well as in human bones and cell lines. Previous data have shown that this receptor up-modulates the expression of osteopontin, which acts as an inhibitor of bone mineralization and whose absence results in resistance to ovariectomy-induced bone loss. Altogether this suggests that ERRalpha may negatively regulate bone mass and could impact on bone fragility that occurs in the absence of estrogens. METHODS/PRINCIPAL FINDINGS: In this report, we have determined the in vivo effect of ERRalpha on bone, using knock-out mice. Relative to wild type animals, female ERRalphaKO bones do not age and are resistant to bone loss induced by estrogen-withdrawal. Strikingly male ERRalphaKO mice are indistinguishable from their wild type counterparts, both at the unchallenged or gonadectomized state. Using primary cell cultures originating from ERRalphaKO bone marrow, we also show that ERRalpha acts as an inhibitor of osteoblast differentiation. CONCLUSION/SIGNIFICANCE: Down-regulating ERRalpha could thus be beneficial against osteoporosis.

  18. Female mice deficient in alpha-fetoprotein show female-typical neural responses to conspecific-derived pheromones.

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    Olivier Brock

    Full Text Available The neural mechanisms controlling sexual behavior are sexually differentiated by the perinatal actions of sex steroid hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO and which lack the protective actions of AFP against maternal estradiol, that exposure to prenatal estradiol completely defeminized the potential to show lordosis behavior in adulthood. Furthermore, AFP-KO females failed to show any male-directed mate preferences following treatment with estradiol and progesterone, indicating a reduced sexual motivation to seek out the male. In the present study, we asked whether neural responses to male- and female-derived odors are also affected in AFP-KO female mice. Therefore, we compared patterns of Fos, the protein product of the immediate early gene, c-fos, commonly used as a marker of neuronal activation, between wild-type (WT and AFP-KO female mice following exposure to male or estrous female urine. We also tested WT males to confirm the previously observed sex differences in neural responses to male urinary odors. Interestingly, AFP-KO females showed normal, female-like Fos responses, i.e. exposure to urinary odors from male but not estrous female mice induced equivalent levels of Fos protein in the accessory olfactory pathways (e.g. the medial part of the preoptic nucleus, the bed nucleus of the stria terminalis, the amygdala, and the lateral part of the ventromedial hypothalamic nucleus as well as in the main olfactory pathways (e.g. the piriform cortex and the anterior cortical amygdaloid nucleus, as WT females. By contrast, WT males did not show any significant induction of Fos protein in these brain areas upon exposure to either male or estrous female urinary odors. These results thus suggest that prenatal estradiol is not involved in the sexual differentiation of neural Fos responses to male-derived odors.

  19. Male mice ultrasonic vocalizations enhance female sexual approach and hypothalamic kisspeptin neuron activity.

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    Asaba, Akari; Osakada, Takuya; Touhara, Kazushige; Kato, Masahiro; Mogi, Kazutaka; Kikusui, Takefumi

    2017-08-01

    Vocal communication in animals is important for ensuring reproductive success. Male mice emit song-like "ultrasonic vocalizations (USVs)" when they encounter female mice, and females show approach to the USVs. However, it is unclear whether USVs of male mice trigger female behavioral and endocrine responses in reproduction. In this study, we first investigated the relationship between the number of deliveries in breeding pairs for 4months and USVs syllables emitted from those paired males during 3min of sexual encounter with unfamiliar female mice. There was a positive correlation between these two indices, which suggests that breeding pairs in which males could emit USVs more frequently had more offspring. Further, we examined the effect of USVs of male mice on female sexual behavior. Female mice showed more approach behavior towards vocalizing males than devocalized males. Finally, to determine whether USVs of male mice could activate the neural system governing reproductive function in female mice, the activation of kisspeptin neurons, key neurons to drive gonadotropin-releasing hormone neurons in the hypothalamus, was examined using dual-label immunocytochemistry with cAMP response element-binding protein phosphorylation (pCREB). In the arcuate nucleus (Arc), the number of kisspeptin neurons expressing pCREB significantly increased after exposure to USVs of male as compared with noise exposure group. In conclusion, our results suggest that USVs of male mice promote fertility in female mice by activating both their approaching behavior and central kisspeptin neurons. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Effect of Sex Differences on Brain Mitochondrial Function and Its Suppression by Ovariectomy and in Aged Mice.

    Science.gov (United States)

    Gaignard, Pauline; Savouroux, Stéphane; Liere, Philippe; Pianos, Antoine; Thérond, Patrice; Schumacher, Michael; Slama, Abdelhamid; Guennoun, Rachida

    2015-08-01

    Sex steroids regulate brain function in both normal and pathological states. Mitochondria are an essential target of steroids, as demonstrated by the experimental administration of 17β-estradiol or progesterone (PROG) to ovariectomized female rodents, but the influence of endogenous sex steroids remains understudied. To address this issue, mitochondrial oxidative stress, the oxidative phosphorylation system, and brain steroid levels were analyzed under 3 different experimental sets of endocrine conditions. The first set was designed to study steroid-mediated sex differences in young male and female mice, intact and after gonadectomy. The second set concerned young female mice at 3 time points of the estrous cycle in order to analyze the influence of transient variations in steroid levels. The third set involved the evaluation of the effects of a permanent decrease in gonadal steroids in aged male and female mice. Our results show that young adult females have lower oxidative stress and a higher reduced nicotinamide adenine dinucleotide (NADH)-linked respiration rate, which is related to a higher pyruvate dehydrogenase complex activity as compared with young adult males. This sex difference did not depend on phases of the estrous cycle, was suppressed by ovariectomy but not by orchidectomy, and no longer existed in aged mice. Concomitant analysis of brain steroids showed that pregnenolone and PROG brain levels were higher in females during the reproductive period than in males and decreased with aging in females. These findings suggest that the major male/female differences in brain pregnenolone and PROG levels may contribute to the sex differences observed in brain mitochondrial function.

  1. The influence of enriched environment on spatial memory in Swiss mice of different ages

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    Alessandra Fernandes Druzian

    2015-08-01

    Full Text Available The objective of this study was to evaluate the influence of enriched environment on spatial memory acquisition in mice of three different age groups. Weanling, young, and young adult female Swiss mice were housed in a standard control or enriched environment for 50 days, and their spatial memory was tested with the Morris Water Maze. We did not observe an experimental effect for spatial memory acquisition, and there was neither an effect of time of analysis nor an interaction between experimental group and time of analysis. Regarding effects of experimental group and training day in relation to latency in finding the hidden platform, we did find an effect in the experimental young adult mice group (p = 0.027, but there was no interaction between these factors in all three groups. Based on these findings environmental enrichment did not enhance spatial memory acquisition in female Swiss mice in the tested age groups.

  2. Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome

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    Bianca De Filippis

    2015-01-01

    Full Text Available Rett syndrome (RTT is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2 cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by the in vivo magnetic resonance spectroscopy (MRS analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag test and Capellini handling task. A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested.

  3. Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder

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    Claudia Fuchs

    2018-01-01

    Full Text Available CDKL5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 (cyclin-dependent kinase-like five gene. CDKL5 disorder primarily affects girls and is characterized by early-onset epileptic seizures, gross motor impairment, intellectual disability, and autistic features. Although all CDKL5 female patients are heterozygous, the most valid disease-related model, the heterozygous female Cdkl5 knockout (Cdkl5 +/− mouse, has been little characterized. The lack of detailed behavioral profiling of this model remains a crucial gap that must be addressed in order to advance preclinical studies. Here, we provide a behavioral and molecular characterization of heterozygous Cdkl5 +/− mice. We found that Cdkl5 +/− mice reliably recapitulate several aspects of CDKL5 disorder, including autistic-like behaviors, defects in motor coordination and memory performance, and breathing abnormalities. These defects are associated with neuroanatomical alterations, such as reduced dendritic arborization and spine density of hippocampal neurons. Interestingly, Cdkl5 +/− mice show age-related alterations in protein kinase B (AKT and extracellular signal-regulated kinase (ERK signaling, two crucial signaling pathways involved in many neurodevelopmental processes. In conclusion, our study provides a comprehensive overview of neurobehavioral phenotypes of heterozygous female Cdkl5 +/− mice and demonstrates that the heterozygous female might be a valuable animal model in preclinical studies on CDKL5 disorder.

  4. Female scent signals enhance the resistance of male mice to influenza.

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    Ekaterina A Litvinova

    Full Text Available BACKGROUND: The scent from receptive female mice functions as a signal, which stimulates male mice to search for potential mating partners. This searching behavior is coupled with infection risk due to sniffing both scent marks as well as nasal and anogenital areas of females, which harbor bacteria and viruses. Consideration of host evolution under unavoidable parasitic pressures, including helminthes, bacteria, viruses, etc., predicts adaptations that help protect hosts against the parasites associated with mating. METHODS AND FINDINGS: We propose that the perception of female signals by BALB/c male mice leads to adaptive redistribution of the immune defense directed to protection against respiratory infection risks. Our results demonstrate migration of macrophages and neutrophils to the upper airways upon exposure to female odor stimuli, which results in an increased resistance of the males to experimental influenza virus infection. This moderate leukocyte intervention had no negative effect on the aerobic performance in male mice. CONCLUSIONS: Our data provide the first demonstration of the adaptive immunological response to female odor stimuli through induction of nonspecific immune responses in the upper respiratory tract.

  5. Age-related changes in body composition of bovine growth hormone transgenic mice.

    Science.gov (United States)

    Palmer, Amanda J; Chung, Min-Yu; List, Edward O; Walker, Jennifer; Okada, Shigeru; Kopchick, John J; Berryman, Darlene E

    2009-03-01

    GH has a significant impact on body composition due to distinct anabolic and catabolic effects on lean and fat mass, respectively. Several studies have assessed body composition in mice expressing a GH transgene. Whereas all studies report enhanced growth of transgenic mice as compared with littermate controls, there are inconsistencies in terms of the relative proportion of lean mass to fat mass in these animals. The purpose of this study was to characterize the accumulation of adipose and lean mass with age and according to gender in a bovine (b) GH transgenic mouse line. Weight and body composition measurements were assessed in male and female bGH mice with corresponding littermate controls in the C57BL/6J genetic background. Body composition measurements began at 6 wk and continued through 1 yr of age. At the conclusion of the study, tissue weights were determined and triglyceride content was quantified in liver and kidney. Although body weights for bGH mice were significantly greater than their corresponding littermate controls at all time points, body composition measurements revealed an unexpected transition midway through analyses. That is, younger bGH mice had relatively more fat mass than nontransgenic littermates, whereas bGH mice became significantly leaner than controls by 4 months in males and 6 months in females. These results reveal the importance in timing and gender when conducting studies related to body composition or lean and fat tissue in GH transgenic mice or in other genetically manipulated mouse strains in which body composition may be impacted.

  6. Prevention of neuromusculoskeletal frailty in slow-aging ames dwarf mice: longitudinal investigation of interaction of longevity genes and caloric restriction.

    Directory of Open Access Journals (Sweden)

    Oge Arum

    Full Text Available Ames dwarf (Prop1 (df/df mice are remarkably long-lived and exhibit many characteristics of delayed aging and extended healthspan. Caloric restriction (CR has similar effects on healthspan and lifespan, and causes an extension of longevity in Ames dwarf mice. Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old or old (128 ± 14 w.o. mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age. This study serves as a particularly important example of knowledge related to addressing aging-associated diseases and disorders that results from studies in long-lived mammals.

  7. Prevention of neuromusculoskeletal frailty in slow-aging ames dwarf mice: longitudinal investigation of interaction of longevity genes and caloric restriction.

    Science.gov (United States)

    Arum, Oge; Rasche, Zachary Andrew; Rickman, Dustin John; Bartke, Andrzej

    2013-01-01

    Ames dwarf (Prop1 (df/df) ) mice are remarkably long-lived and exhibit many characteristics of delayed aging and extended healthspan. Caloric restriction (CR) has similar effects on healthspan and lifespan, and causes an extension of longevity in Ames dwarf mice. Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old) or old (128 ± 14 w.o.) mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age. This study serves as a particularly important example of knowledge related to addressing aging-associated diseases and disorders that results from studies in long-lived mammals.

  8. Endothelial dysfunction of resistance vessels in female apolipoprotein E-deficient mice

    Directory of Open Access Journals (Sweden)

    Vasquez Elisardo C

    2010-05-01

    Full Text Available Abstract Background The effects of hypercholesterolemia on vasomotricity in apolipoprotein E-deficient (ApoE mice, a murine model of spontaneous atherosclerosis, are still unclear. The studies were mostly performed in conductance vessels from male mice fed a high-fat diet. In the present study, we evaluated the endothelial function of resistance vessels from normal C57BL/6 (C57 and hypercholesterolemic (ApoE female mice in both normal and ovariectomized conditions. Methods Twenty week-old C57 and ApoE mice underwent ovariectomy or sham surgery and were studied 30 days later. The vascular reactivities to norepinephrine (NE, 10-9 to 2 × 10-3 mol/L, acetylcholine (ACh and sodium nitroprusside (SNP (10-10 to 10-3 mol/L were evaluated in the isolated mesenteric arteriolar bed through dose-response curves. Results ACh-induced relaxation was significantly reduced (P 50 (-5.67 ± 0.18 vs. -6.23 ± 0.09 mol/L. Ovariectomy caused a significant impairment in ACh-induced relaxation in the C57 group (maximal response: 61 ± 4% but did not worsen the deficient state of relaxation in ApoE animals (maximal response: 39 ± 5%. SNP-induced vasorelaxation and NE-induced vasoconstriction were similar in ApoE and C57 female mice. Conclusion These data show an impairment of endothelial function in the resistance vessels of spontaneously atherosclerotic (ApoE-deficient female mice compared with normal (C57 female mice. The endothelial dysfunction in hypercholesterolemic animals was so marked that ovariectomy, which impaired endothelial function in C57 mice, did not cause additional vascular damage in ApoE-deficient mice.

  9. Effects of Vitex agnus-castus fruit on sex hormones and antioxidant indices in a d-galactose-induced aging female mouse model

    Directory of Open Access Journals (Sweden)

    Akram Ahangarpour

    2016-11-01

    Conclusion: Vitex improved some aging events in the reproductive system of female mice. Therefore, because of its apparent antiaging effects, Vitex can be suitable for some aging problems such as oxidative stress, female sex hormone deficiency, and an atrophic endometrium.

  10. Cardiac autonomic modulation by estrogen in female mice undergoing ambulatory monitoring and in vivo electrophysiologic testing.

    Science.gov (United States)

    Saba, Samir; Shusterman, Vladimir; Usiene, Irmute; London, Barry

    2004-04-01

    Estrogen is an important modulator of cardiovascular risk, but its mechanism of action is not fully understood. We investigated the effect of ovariectomy and its timing on the cardiac electrophysiology in mice. Thirty female mice (age 18.8 +/- 3.1 weeks) underwent in vivo electrophysiologic testing before and after autonomic blockade. Fifteen mice were ovariectomized prepuberty (PRE) and ten postpuberty (POST), 2 weeks prior to electrophysiologic testing. Five age-matched sham-operated female mice (Control) served as controls. A subset of 13 mice (5 PRE, 3 POST, and 5 Controls) underwent 24-hour ambulatory monitoring. With ambulatory monitoring, the average (668 +/- 28 vs 769 +/- 52 b/min, P = 0.008) and minimum (485 +/- 47 vs 587 +/- 53 b/min, P = 0.02) heart rates were significantly slower in the ovariectomized mice (PRE and POST groups) compared to the Control group. At baseline electrophysiologic testing, there were no significant differences among the ovariectomized and intact mice in any of the measured parameters. With autonomic blockade, the Control group had a significantly larger change (delta) in the atrioventricular (AV) nodal Wenckebach (AVW) periodicity (deltaAVW = 11.3 +/- 2.9 vs 2.1 +/- 7.3 ms, P = 0.05) and functional refractory period (deltaFRP = 11.3 +/- 2.1 vs 1.25 +/- 6.8 ms, P = 0.02) compared to the ovariectomized mice. These results were not altered by the time of ovariectomy (PRE vs POST groups). Our results suggest that estrogen modulates the autonomic inputs into the murine sinus and AV nodes. These findings, if replicated in humans, might underlie the observed clustering of certain arrhythmias around menstruation and explain the higher incidence of arrhythmias in men and postmenopausal women.

  11. Effects of a single bout of strenuous exercise on platelet activation in female ApoE/LDLR-/- mice.

    Science.gov (United States)

    Przyborowski, K; Kassassir, H; Wojewoda, M; Kmiecik, K; Sitek, B; Siewiera, K; Zakrzewska, A; Rudolf, A M; Kostogrys, R; Watala, C; Zoladz, J A; Chlopicki, S

    2017-11-01

    Strenuous physical exercise leads to platelet activation that is normally counterbalanced by the production of endothelium-derived anti-platelet mediators, including prostacyclin (PGI 2 ) and nitric oxide (NO). However, in the case of endothelial dysfunction, e.g. in atherosclerosis, there exists an increased risk for intravascular thrombosis during exercise that might be due to an impairment in endothelial anti-platelet mechanisms. In the present work, we evaluated platelet activation at rest and following a single bout of strenuous treadmill exercise in female ApoE/LDLR - /- mice with early (3-month-old) and advanced (7-month-old) atherosclerosis compared to female age-matched WT mice. In sedentary and post-exercise groups of animals, we analyzed TXB 2 generation and the expression of platelet activation markers in the whole blood ex vivo assay. We also measured pre- and post-exercise plasma concentration of 6-keto-PGF 1α , nitrite/nitrate, lipid profile, and blood cell count. Sedentary 3- and 7-month-old ApoE/LDLR - /- mice displayed significantly higher activation of platelets compared to age-matched wild-type (WT) mice, as evidenced by increased TXB 2 production, expression of P-selectin, and activation of GPIIb/IIIa receptors, as well as increased fibrinogen and von Willebrand factor (vWf) binding. Interestingly, in ApoE/LDLR - /- but not in WT mice, strenuous exercise partially inhibited TXB 2 production, the expression of activated GPIIb/IIIa receptors, and fibrinogen binding, with no effect on the P-selectin expression and vWf binding. Post-exercise down-regulation of the activated GPIIb/IIIa receptor expression and fibrinogen binding was not significantly different between 3- and 7-month-old ApoE/LDLR - /- mice; however, only 7-month-old ApoE/LDLR - /- mice showed lower TXB 2 production after exercise. In female 4-6-month-old ApoE/LDLR - /- but not in WT mice, an elevated pre- and post-exercise plasma concentration of 6-keto-PGF 1α was observed. In turn

  12. Dim Light at Night Increases Body Mass of Female Mice

    OpenAIRE

    Aubrecht, Taryn G.; Jenkins, Richelle; Nelson, Randy J.

    2014-01-01

    During the past century the prevalence of light at night has increased in parallel with obesity rates. Dim light at night (dLAN) increases body mass in male mice. However, the effects of light at night on female body mass remain unspecified. Thus, female mice were exposed to a standard light/dark (LD; 16h light at ~150 lux/8h dark at ~0 lux) cycle or to light/dim light at night (dLAN; 16h light at ~150 lux/8h dim light at ~5 lux) cycles for six weeks. Females exposed to dLAN increased the rat...

  13. Dim light at night increases body mass of female mice.

    Science.gov (United States)

    Aubrecht, Taryn G; Jenkins, Richelle; Nelson, Randy J

    2015-05-01

    During the past century, the prevalence of light at night has increased in parallel with obesity rates. Dim light at night (dLAN) increases body mass in male mice. However, the effects of light at night on female body mass remain unspecified. Thus, female mice were exposed to a standard light/dark (LD; 16 h light at ∼150 lux/8 h dark at ∼0 lux) cycle or to light/dim light at night (dLAN; 16 h light at ∼150 lux/8 h dim light at ∼5 lux) cycles for six weeks. Females exposed to dLAN increased the rate of change in body mass compared to LD mice despite reduced total food intake during weeks five and six, suggesting that dLAN disrupted circadian rhythms resulting in deranged metabolism.

  14. Papain-induced experimental pulmonary emphysema in male and female mice.

    Science.gov (United States)

    Machado, Mariana Nascimento; Figueirôa, Silviane Fernandes da Silva; Mazzoli-Rocha, Flavia; Valença, Samuel dos Santos; Zin, Walter Araújo

    2014-08-15

    In papain-induced models of emphysema, despite the existing extensive description of the cellular and molecular aspects therein involved, sexual hormones may play a complex and still not fully understood role. Hence, we aimed at exploring the putative gender-related differences in lung mechanics, histology and oxidative stress in papain-exposed mice. Thirty adult BALB/c mice received intratracheally either saline (50 μL) or papain (10 U/50 μL saline) once a week for 2 weeks. In males papain increased lung resistive and viscoelastic/inhomogeneous pressures, static elastance, and viscoelastic component of elastance, while females showed higher static elastance and resistive pressure only. Both genders presented similar higher parenchymal cellularity and mean alveolar diameter, and less collagen-elastic fiber content and body weight gain than their respective controls. Increased functional residual capacity was more prominent in males. Female papain-treated mice were more susceptible to oxidative stress. Thus, male and female papain-exposed mice respond differently, which should be carefully considered to avoid confounding results. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Men and mice: Relating their ages.

    Science.gov (United States)

    Dutta, Sulagna; Sengupta, Pallav

    2016-05-01

    Since the late 18th century, the murine model has been widely used in biomedical research (about 59% of total animals used) as it is compact, cost-effective, and easily available, conserving almost 99% of human genes and physiologically resembling humans. Despite the similarities, mice have a diminutive lifespan compared to humans. In this study, we found that one human year is equivalent to nine mice days, although this is not the case when comparing the lifespan of mice versus humans taking the entire life at the same time without considering each phase separately. Therefore, the precise correlation of age at every point in their lifespan must be determined. Determining the age relation between mice and humans is necessary for setting up experimental murine models more analogous in age to humans. Thus, more accuracy can be obtained in the research outcome for humans of a specific age group, although current outcomes are based on mice of an approximate age. To fill this gap between approximation and accuracy, this review article is the first to establish a precise relation between mice age and human age, following our previous article, which explained the relation in ages of laboratory rats with humans in detail. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Neonatal exposure to daidzein, genistein, or the combination modulates bone development in female CD-1 mice.

    Science.gov (United States)

    Kaludjerovic, Jovana; Ward, Wendy E

    2009-03-01

    Neonatal exposure to genistein (GEN), an isoflavone abundant in soy, favorably modulates bone mineral density (BMD) and bone strength in mice at adulthood. The study objective was to determine whether early exposure to a combination of the soy isoflavones daidzein (DAI) and GEN that naturally exists in soy protein-based infant formula results in greater benefits to bone at adulthood than either treatment alone. Male and female CD-1 mice (n = 8-16 pups per group per gender) were randomized to subcutaneous injections of DAI (2 mg x kg body weight(-1) x d(-1)), GEN (5 mg x kg body weight(-1) x d(-1)), DAI+GEN (7 mg x kg body weight(-1) x d(-1)), diethylstilbesterol (DES; positive control) (2 mg x kg body weight(-1) x d(-1)), or control (CON) from postnatal d 1-5 and were studied to 4 mo of age. BMD, biomechanical bone strength, and bone microarchitecture were assessed at the femur and lumbar vertebrae (LV). Females treated with DAI, GEN, DAI+GEN, or DES had greater (P GEN resulted in greater (P GEN had a positive effect on the skeleton of female mice at adulthood, but, compared with individual treatments, DAI+GEN did not have a greater benefit to bone in females or males.

  17. CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity.

    Science.gov (United States)

    Cappel, David A; Lantier, Louise; Palmisano, Brian T; Wasserman, David H; Stafford, John M

    2015-01-01

    Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD). Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP) is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD) feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.

  18. CETP Expression Protects Female Mice from Obesity-Induced Decline in Exercise Capacity.

    Directory of Open Access Journals (Sweden)

    David A Cappel

    Full Text Available Pharmacological approaches to reduce obesity have not resulted in dramatic reductions in the risk of coronary heart disease (CHD. Exercise, in contrast, reduces CHD risk even in the setting of obesity. Cholesteryl Ester Transfer Protein (CETP is a lipid transfer protein that shuttles lipids between serum lipoproteins and tissues. There are sexual-dimorphisms in the effects of CETP in humans. Mice naturally lack CETP, but we previously reported that transgenic expression of CETP increases muscle glycolysis in fasting and protects against insulin resistance with high-fat diet (HFD feeding in female but not male mice. Since glycolysis provides an important energy source for working muscle, we aimed to define if CETP expression protects against the decline in exercise capacity associated with obesity. We measured exercise capacity in female mice that were fed a chow diet and then switched to a HFD. There was no difference in exercise capacity between lean, chow-fed CETP female mice and their non-transgenic littermates. Female CETP transgenic mice were relatively protected against the decline in exercise capacity caused by obesity compared to WT. Despite gaining similar fat mass after 6 weeks of HFD-feeding, female CETP mice showed a nearly two-fold increase in run distance compared to WT. After an additional 6 weeks of HFD-feeding, mice were subjected to a final exercise bout and muscle mitochondria were isolated. We found that improved exercise capacity in CETP mice corresponded with increased muscle mitochondrial oxidative capacity, and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α. These results suggest that CETP can protect against the obesity-induced impairment in exercise capacity and may be a target to improve exercise capacity in the context of obesity.

  19. Retaining Residual Ovarian Tissue following Ovarian Failure Has Limited Influence on Bone Loss in Aged Mice

    Directory of Open Access Journals (Sweden)

    Zelieann R. Craig

    2010-01-01

    Full Text Available Previous work showed that retaining residual ovarian tissue protects young mice from accelerated bone loss following ovarian failure. The present study was designed to determine whether this protection is also present in aged animals. Aged (9–12 months C57BL/6Hsd female mice were divided into: CON (vehicle, VCD (160 mg/kg; 15d, or OVX (ovariectomized. Lumbar BMD was monitored by DXA and μCT used to assess vertebral microarchitecture. BMD was not different between VCD and CON at any time point but was lower (P<.05 than baseline, starting 1 month after ovarian failure in VCD and OVX mice. Following μCT analysis there were no differences between CON and VCD, but OVX mice had lower bone volume fraction, trabecular thickness, and a trend for decreased connectivity density. These findings provide evidence that retention of residual ovarian tissue may protect aged follicle-depleted mice from accelerated bone loss to a lesser extent than that observed in young mice.

  20. Macrophage overexpression of matrix metalloproteinase-9 in aged mice improves diastolic physiology and cardiac wound healing after myocardial infarction.

    Science.gov (United States)

    Meschiari, Cesar A; Jung, Mira; Iyer, Rugmani Padmanabhan; Yabluchanskiy, Andriy; Toba, Hiroe; Garrett, Michael R; Lindsey, Merry L

    2018-02-01

    Matrix metalloproteinase (MMP)-9 increases in the myocardium with advanced age and after myocardial infarction (MI). Because young transgenic (TG) mice overexpressing human MMP-9 only in macrophages show better outcomes post-MI, whereas aged TG mice show a worse aging phenotype, we wanted to evaluate the effect of aging superimposed on MI to see if the detrimental effect of aging counteracted the benefits of macrophage MMP-9 overexpression. We used 17- to 28-mo-old male and female C57BL/6J wild-type (WT) and TG mice ( n = 10-21 mice/group) to evaluate the effects of aging superimposed on MI. Despite similar infarct areas and mortality rates at day 7 post-MI, aging TG mice showed improved diastolic properties and remodeling index compared with WT mice (both P wound healing through direct and indirect mechanisms to improve diastolic physiology and remodeling. NEW & NOTEWORTHY Aging mice with macrophage overexpression of matrix metalloproteinase-9 have increased macrophage numbers 7 days after myocardial infarction, resulting in improved diastolic physiology and left ventricular remodeling through effects on cardiac wound healing.

  1. Prenatal exposure to an environmentally relevant phthalate mixture disrupts reproduction in F1 female mice

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Changqing; Gao, Liying; Flaws, Jodi A., E-mail: jflaws@illinois.edu

    2017-03-01

    Phthalates are used in a large variety of products, such as building materials, medical devices, and personal care products. Most previous studies on the toxicity of phthalates have focused on single phthalates, but it is also important to study the effects of phthalate mixtures because humans are exposed to phthalate mixtures. Thus, we tested the hypothesis that prenatal exposure to an environmentally relevant phthalate mixture adversely affects female reproduction in mice. To test this hypothesis, pregnant CD-1 dams were orally dosed with vehicle (tocopherol-stripped corn oil) or a phthalate mixture (20 and 200 μg/kg/day, 200 and 500 mg/kg/day) daily from gestational day 10 to birth. The mixture was based on the composition of phthalates detected in urine samples from pregnant women in Illinois. The mixture included 35% diethyl phthalate, 21% di(2-ethylhexyl) phthalate, 15% dibutyl phthalate, 15% diisononyl phthalate, 8% diisobutyl phthalate, and 5% benzylbutyl phthalate. Female mice born to the exposed dams were subjected to tissue collections and fertility tests at different ages. Our results indicate that prenatal exposure to the phthalate mixture significantly increased uterine weight and decreased anogenital distance on postnatal days 8 and 60, induced cystic ovaries at 13 months, disrupted estrous cyclicity, reduced fertility-related indices, and caused some breeding complications at 3, 6, and 9 months of age. Collectively, our data suggest that prenatal exposure to an environmentally relevant phthalate mixture disrupts aspects of female reproduction in mice. - Highlights: • Prenatal exposure to a phthalate mixture disrupts F1 estrous cyclicity. • Prenatal exposure to a phthalate mixture induces F1 ovarian cysts. • Prenatal exposure to a phthalate mixture decreases F1 female fertility-related indices. • Prenatal exposure to a phthalate mixture induces F1 breeding complications.

  2. Altered gut microbiota in female mice with persistent low body weights following removal of post-weaning chronic dietary restriction.

    Science.gov (United States)

    Chen, Jun; Toyomasu, Yoshitaka; Hayashi, Yujiro; Linden, David R; Szurszewski, Joseph H; Nelson, Heidi; Farrugia, Gianrico; Kashyap, Purna C; Chia, Nicholas; Ordog, Tamas

    2016-10-03

    Nutritional interventions often fail to prevent growth failure in childhood and adolescent malnutrition and the mechanisms remain unclear. Recent studies revealed altered microbiota in malnourished children and anorexia nervosa. To facilitate mechanistic studies under physiologically relevant conditions, we established a mouse model of growth failure following chronic dietary restriction and examined microbiota in relation to age, diet, body weight, and anabolic treatment. Four-week-old female BALB/c mice (n = 12/group) were fed ad libitum (AL) or offered limited food to abolish weight gain (LF). A subset of restricted mice was treated with an insulin-like growth factor 1 (IGF1) analog. Food access was restored in a subset of untreated LF (LF-RF) and IGF1-treated LF mice (TLF-RF) on day 97. Gut microbiota were determined on days 69, 96-99 and 120 by next generation sequencing of the V3-5 region of the 16S rRNA gene. Microbiota-host factor associations were analyzed by distance-based PERMANOVA and quantified by the coefficient of determination R 2 for age, diet, and normalized body weight change (Δbwt). Microbial taxa on day 120 were compared following fitting with an overdispersed Poisson regression model. The machine learning algorithm Random Forests was used to predict age based on the microbiota. On day 120, Δbwt in AL, LF, LF-RF, and TLF-RF mice was 52 ± 3, -6 ± 1*, 40 ± 3*, and 46 ± 2 % (*, P < 0.05 versus AL). Age and diet, but not Δbwt, were associated with gut microbiota composition. Age explained a larger proportion of the microbiota variability than diet or Δbwt. Random Forests predicted chronological age based on the microbiota and indicated microbiota immaturity in the LF mice before, but not after, refeeding. However, on day 120, the microbiota community structure of LF-RF mice was significantly different from that of both AL and LF mice. IGF1 mitigated the difference from the AL group. Refed groups had a higher

  3. 17β-Estradiol administration promotes delayed cutaneous wound healing in 40-week ovariectomised female mice.

    Science.gov (United States)

    Mukai, Kanae; Nakajima, Yukari; Urai, Tamae; Komatsu, Emi; Nasruddin; Sugama, Junko; Nakatani, Toshio

    2016-10-01

    This study investigated the effect of 17β-estradiol on wound healing in 40-week ovariectomised female mice. Thirty-six-week-old female mice were divided into three groups: medication with 17β-estradiol after ovariectomy (OVX + 17β-estradiol), ovariectomy (OVX) and sham (SHAM). The mice received two full-thickness wounds, and the OVX + 17β-estradiol group was administered 17β-estradiol at 0·01 g/day until healing. In the OVX + 17β-estradiol group, the ratio of wound area was significantly smaller than those of the OVX and SHAM groups on days 1-3, 5, 6, 8-12 and 9-12, respectively, the numbers of neutrophils and macrophages were significantly smaller than those on days 3 and 7, the ratio of re-epithelialisation was significantly higher than those on days 3 and 11, the ratio of myofibroblasts was significantly higher than those on day 11 and smaller on day 14, and the ratio of collagen fibres was significantly larger than that of the OVX group on days 7-14. We found that 17β-estradiol administration promotes cutaneous wound healing in 40-week female mice by reducing wound area, shortening inflammatory response, and promoting re-epithelialisation, collagen deposition and wound contraction. Our results suggest that cutaneous wound healing that is delayed because of ageing is promoted by exogenous and continuous 17β-estradiol administration. © 2014 The Authors. International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

  4. Age- and gender-dependent impairments of neurobehaviors in mice whose mothers were exposed to lipopolysaccharide during pregnancy.

    Science.gov (United States)

    Wang, Hua; Meng, Xiu-Hong; Ning, Huan; Zhao, Xian-Feng; Wang, Qun; Liu, Ping; Zhang, Heng; Zhang, Cheng; Chen, Gui-Hai; Xu, De-Xiang

    2010-02-01

    Lipopolysaccharide (LPS)-induced intrauterine infection has been associated with neurodevelopmental injury in rodents. The purpose of the present study was to analyze the dynamic changes of neurobehaviors in mice whose mothers were exposed to LPS during pregnancy. The pregnant mice were intraperitoneally (i.p.) injected with LPS (8 microg/kg) daily from gestational day (gd) 8 to gd 15. A battery of neurobehavioral tasks was performed in mice at postnatal day (PND) 70, 200, 400 and 600. Results showed that the spatial learning and memory ability, determined by radial six-arm water maze (RAWM), were obviously impaired in two hundred-day-old female mice and four hundred-day-old male mice whose mothers were exposed to LPS during pregnancy. Open field test showed that the number of squares crossed and peripheral time, a marker of anxiety and exploration activity, were markedly increased in two hundred-day-old female mice following prenatal LPS exposure. In addition, prenatal LPS exposure significantly shortened the latency to the first grid crossing in six hundred-day-old female offspring. Moreover, sensorimotor impairment in the beam walking was observed in two hundred-day-old female mice whose mothers were exposed to LPS during pregnancy. Species-typical behavior examination showed that prenatal LPS exposure markedly increased weight burrowed in seventy-day-old male offspring and six hundred-day-old female offspring. Correspondingly, prenatal LPS exposure significantly reduced weight hoarded in two hundred-day-old female offspring. Taken together, these results suggest that prenatal LPS exposure induces neurobehavioral impairments at adulthood in an age- and gender-dependent manner. 2009 Elsevier Ireland Ltd. All rights reserved.

  5. Voluntary resistance wheel exercise from mid-life prevents sarcopenia and increases markers of mitochondrial function and autophagy in muscles of old male and female C57BL/6J mice.

    Science.gov (United States)

    White, Zoe; Terrill, Jessica; White, Robert B; McMahon, Christopher; Sheard, Phillip; Grounds, Miranda D; Shavlakadze, Tea

    2016-12-13

    There is much interest in the capacity of resistance exercise to prevent the age-related loss of skeletal muscle mass and function, known as sarcopenia. This study investigates the molecular basis underlying the benefits of resistance exercise in aging C57BL/6J mice of both sexes. This study is the first to demonstrate that long-term (34 weeks) voluntary resistance wheel exercise (RWE) initiated at middle age, from 15 months, prevents sarcopenia in selected hindlimb muscles and causes hypertrophy in soleus, by 23 months of age in both male and female C57BL/6J mice. Compared with 23-month-old sedentary (SED) controls, RWE (0-6 g of resistance) increased intramuscular mitochondrial density and oxidative capacity (measured by citrate synthase and NADH-TR) and increased LC3II/I ratios (a marker of autophagy) in exercised mice of both sexes. RWE also reduced mRNA expression of Gadd45α (males only) and Runx1 (females only) but had no effect on other markers of denervation including Chrng, Chrnd, Musk, and Myog. RWE increased heart mass in all mice, with a more pronounced increase in females. Significant sex differences were also noted among SED mice, with Murf1 mRNA levels increasing in male, but decreasing in old female mice between 15 and 23 months. Overall, long-term RWE initiated from 15 month of age significantly improved some markers of the mitochondrial and autophagosomal pathways and prevented age-related muscle wasting.

  6. Heterozygosity for a Bub1 mutation causes female-specific germ cell aneuploidy in mice

    Energy Technology Data Exchange (ETDEWEB)

    Leland, Shawn; Nagarajan, Prabakaran; Polyzos, Aris; Thomas, Sharon; Samaan, George; Donnell, Robert; Marchetti, Francesco; Venkatachalam, Sundaresan

    2009-06-24

    Aneuploidy, the most common chromosomal abnormality at birth and the main ascertained cause of pregnancy loss in humans, originates primarily from chromosome segregation errors during oogenesis. Here we report that heterozygosity for a mutation in the mitotic checkpoint kinase gene, Bub1, induces aneuploidy in female germ cells of mice, and that the effect increases with advancing maternal age. Analysis of Bub1 heterozygous oocytes showed that aneuploidy occurred primarily during the first meiotic division and involved premature sister chromatid separation. Furthermore, aneuploidy was inherited in zygotes and resulted in the loss of embryos after implantation. The incidence of aneuploidy in zygotes was sufficient to explain the reduced litter size in matings with Bub1 heterozygous females. No effects were seen in germ cells from heterozygous males. These findings show that Bub1 dysfunction is linked to inherited aneuploidy in female germ cells and may contribute to the maternal age-related increase in aneuploidy and pregnancy loss.

  7. Compared to sucrose, previous consumption of fructose and glucose monosaccharides reduces survival and fitness of female mice.

    Science.gov (United States)

    Ruff, James S; Hugentobler, Sara A; Suchy, Amanda K; Sosa, Mirtha M; Tanner, Ruth E; Hite, Megumi E; Morrison, Linda C; Gieng, Sin H; Shigenaga, Mark K; Potts, Wayne K

    2015-03-01

    Intake of added sugar has been shown to correlate with many human metabolic diseases, and rodent models have characterized numerous aspects of the resulting disease phenotypes. However, there is a controversy about whether differential health effects occur because of the consumption of either of the two common types of added sugar-high-fructose corn syrup (fructose and glucose monosaccharides; F/G) or table sugar (sucrose, a fructose and glucose disaccharide). We tested the equivalence of sucrose- vs. F/G-containing diets on mouse (Mus musculus) longevity, reproductive success, and social dominance. We fed wild-derived mice, outbred mice descended from wild-caught ancestors, a diet in which 25% of the calories came from either an equal ratio of F/G or an isocaloric amount of sucrose (both diets had 63% of total calories as carbohydrates). Exposure lasted 40 wk, starting at weaning (21 d of age), and then mice (104 females and 56 males) were released into organismal performances assays-seminatural enclosures where mice competed for territories, resources, and mates for 32 wk. Within enclosures all mice consumed the F/G diet. Females initially fed the F/G diet experienced a mortality rate 1.9 times the rate (P = 0.012) and produced 26.4% fewer offspring than females initially fed sucrose (P = 0.001). This reproductive deficiency was present before mortality differences, suggesting the F/G diet was causing physiologic performance deficits prior to mortality. No differential patterns in survival, reproduction, or social dominance were observed in males, indicating a sex-specific outcome of exposure. This study provides experimental evidence that the consumption of human-relevant levels of F/G is more deleterious than an isocaloric amount of sucrose for key organism-level health measures in female mice. © 2015 American Society for Nutrition.

  8. Role of the vomeronasal system in intersexual attraction in female mice.

    Science.gov (United States)

    Martínez-Ricós, J; Agustín-Pavón, C; Lanuza, E; Martínez-García, F

    2008-05-02

    Although it is generally accepted that rodents' sociosexual behavior relies mainly on chemosignals, the specific roles played by the vomeronasal and olfactory systems in detecting these signals are presently unclear. This work reports the results of three experiments aimed at clarifying the role of the vomeronasal system on gender recognition and intersexual attraction, by analyzing the effects of lesions of the accessory olfactory bulbs (AOB) in chemically naïve female mice. The first experiment demonstrates that lesions of the AOB abolish the preference that females show for male-soiled bedding in tests in which the females can contact the bedding, thus having access to both volatile and involatile male chemosignals. The second experiment shows that airborne male-derived chemosignals are not attractive to intact, chemically naïve females but tend to be preferentially explored by females whose AOB has been lesioned. However, repeated exposure to male-soiled bedding has opposite effects in sham-operated and AOB-lesioned female mice. Whereas after this experience sham-operated females show an (acquired) attraction toward male airborne chemosignals, in AOB-lesioned females the same experience makes male-derived volatiles aversive. Finally, in the third experiment we have confirmed that our AOB-lesioned females are able to detect urine-borne male odorants, as well as to discriminate them from the synthetic terpene geraniol. These findings strongly suggest that in mice, the involatile male sexual pheromone that is intrinsically attractive is detected by the vomeronasal system of the females. In addition, the repeated experience of females with male-soiled bedding would probably allow the association of this pheromone, acting as unconditioned stimulus, with olfactory stimuli (odorants) that therefore would become conditioned attractors to the females.

  9. Mammary tumorigenesis in APCmin/+ mice is enhanced by X-irradiation with a characteristic age dependence

    International Nuclear Information System (INIS)

    Tatsuhiko, Imaoka; Mayumi, Nishimura; Shizuko, Kakinuma; Yoshiya, Shimada; Mieko, Okamoto

    2006-01-01

    The ApcM min/+ (Min) mouse is a genetically predisposed model of both intestinal and mammary tumorigenesis. We investigated age-related changes in the susceptibility of mice (before, during and after puberty) to radiation-induced mammary tumorigenesis using this model. Female Min and wild-type mice having the C57BL/6J background were irradiated with 2 Gy of X-rays at 2, 5, 7 and 10 weeks and sacrificed at 18 weeks of age. Min mice irradiated at 7 to 10 weeks of age (after puberty) developed mammary tumors with squamous metaplasia, whereas their wild-type litter-mates did not. Interestingly, irradiation of Min mice at 2 to 5 weeks (before and during puberty, respectively) did not induce mammary tumors but rather cystic nodules with metaplasia. The mammary tumors exhibited increased nuclear beta-catenin protein and loss of the wild-type Apc allele. Our results show that susceptibility to radiation-induced mammary tumorigenesis increases after puberty in Min mice, suggesting that the tumorigenic effect of ionizing radiation targets the lobular-alveolar progenitor cells, which increase in number with age and are controlled by beta-catenin signaling. (author)

  10. Female preproenkephalin-knockout mice display altered emotional responses

    Science.gov (United States)

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

    2001-01-01

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

  11. Impact of β-hydroxy β-methylbutyrate (HMB) on age-related functional deficits in mice.

    Science.gov (United States)

    Munroe, Michael; Pincu, Yair; Merritt, Jennifer; Cobert, Adam; Brander, Ryan; Jensen, Tor; Rhodes, Justin; Boppart, Marni D

    2017-01-01

    β-Hydroxy β-methylbutyrate (HMB) is a metabolite of the essential amino acid leucine. Recent studies demonstrate a decline in plasma HMB concentrations in humans across the lifespan, and HMB supplementation may be able to preserve muscle mass and strength in older adults. However, the impact of HMB supplementation on hippocampal neurogenesis and cognition remains largely unexplored. The purpose of this study was to simultaneously evaluate the impact of HMB on muscle strength, neurogenesis and cognition in young and aged mice. In addition, we evaluated the influence of HMB on muscle-resident mesenchymal stem/stromal cell (Sca-1 + CD45 - ; mMSC) function to address these cells potential to regulate physiological outcomes. Three month-old (n=20) and 24 month-old (n=18) female C57BL/6 mice were provided with either Ca-HMB or Ca-Lactate in a sucrose solution twice per day for 5.5weeks at a dose of 450mg/kg body weight. Significant decreases in relative peak and mean force, balance, and neurogenesis were observed in aged mice compared to young (age main effects, p≤0.05). Short-term HMB supplementation did not alter activity, balance, neurogenesis, or cognitive function in young or aged mice, yet HMB preserved relative peak force in aged mice. mMSC gene expression was significantly reduced with age, but HMB supplementation was able to recover expression of select growth factors known to stimulate muscle repair (HGF, LIF). Overall, our findings demonstrate that while short-term HMB supplementation does not appear to affect neurogenesis or cognitive function in young or aged mice, HMB may maintain muscle strength in aged mice in a manner dependent on mMSC function. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Dopamine D5 receptor modulates male and female sexual behavior in mice.

    Science.gov (United States)

    Kudwa, A E; Dominguez-Salazar, E; Cabrera, D M; Sibley, D R; Rissman, E F

    2005-07-01

    Dopamine exerts its actions through at least five receptor (DAR) isoforms. In female rats, D5 DAR may be involved in expression of sexual behavior. We used a D5 knockout (D5KO) mouse to assess the role of D5 DAR in mouse sexual behavior. Both sexes of D5KO mice are fertile and exhibit only minor disruptions in exploratory locomotion, startle, and prepulse inhibition responses. This study was conducted to characterize the sexual behavior of male and female D5KO mice relative to their WT littermates. Female WT and D5KO littermates were ovariectomized and given a series of sexual behavior tests after treatment with estradiol benzoate (EB) and progesterone (P). Once sexual performance was optimal the dopamine agonist, apomorphine (APO), was substituted for P. Male mice were observed in pair- and trio- sexual behavior tests. To assess whether the D5 DAR is involved in rewarding aspects of sexual behavior, WT and D5KO male mice were tested for conditioned place preference. Both WT and D5KO females can display receptivity after treatment with EB and P, but APO was only able to facilitate receptivity in EB-primed WT, not in D5KO, mice. Male D5KO mice display normal masculine sexual behavior in mating tests. In conditioned preference tests, WT males formed a conditioned preference for context associated with either intromissions alone or ejaculation as the unconditioned stimulus. In contrast, D5KO males only showed a place preference when ejaculation was paired with the context. In females, the D5 DAR is essential for the actions of dopamine on receptivity. In males, D5 DAR influences rewarding aspects of intromissions. Taken together, the work suggests that the D5 receptor mediates dopamine's action on sexual behavior in both sexes, perhaps via a reward pathway.

  13. Augmented healing process in female mice with acute myocardial infarction.

    Science.gov (United States)

    Wang, Fangfei; Keimig, Thomas; He, Quan; Ding, Jennifer; Zhang, Zhenggang; Pourabdollah-Nejad, Siamak; Yang, Xiao-Ping

    2007-09-01

    It is well established that premenopausal women are protected from cardiovascular disease. This gender difference in favor of females is also demonstrated in animal studies. Our research group previously found that female mice had much lower incidence of cardiac rupture and mortality than did males during the acute phase of myocardial infarction (MI); however, the mechanisms responsible for such protection are not fully understood. The aim of this study was to determine whether the favorable cardiac effect observed in female mice with MI is due to an augmented healing process that includes less inflammation, reduced matrix degradation, and enhanced neovascularization. Twelve-week-old male and female C57BL/6J mice were subjected to MI by ligating the left anterior descending coronary artery and then euthanized at 1, 4, 7, or 14 days post-MI. Inflammatory cell infiltration and myofibroblast transformation, matrix metalloproteinase (MMP)-2 and MMP-9 activity, tissue inhibitor of metalloproteinase (TIMP)-I expression, and neovascularization were examined by immunohistochemistry, zymography, Western blot, and laser scanning confocal microscopy, respectively. Cardiac function was evaluated by echocardiography on day 14. We found that: (1) neutrophil infiltration during the early phase of MI (1-4 days) was much lower in females than in males and was associated with lower MMP-9 activity and higher TIMP-1 protein expression, indicating less-exaggerated inflammation and extracellular matrix degradation in females; (2) myofibroblast transformation, as indicated by expression of alpha-smooth muscle actin, was significantly greater in females than in males at day 7 of MI (Pvascular area in the infarct border) was markedly increased in females, and was associated with better preserved cardiac function and less left ventricular dilatation. Our data suggest that less-exaggerated early inflammation and augmented reparative fibrotic response, indicated by enhanced myofibroblast

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

    Directory of Open Access Journals (Sweden)

    Mandy Sawitzky

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

  15. Influence of Ovarian Hormones on Strength Loss in Healthy and Dystrophic Female Mice

    Science.gov (United States)

    Kosir, Allison M.; Mader, Tara L.; Greising, Angela G.; Novotny, Susan A.; Baltgalvis, Kristen A.; Lowe, Dawn A.

    2014-01-01

    Purpose The primary objective of this study was to determine if strength loss and recovery following eccentric contractions is impaired in healthy and dystrophic female mice with low levels of ovarian hormones. Methods Female C57BL/6 (wildtype) or mdx mice were randomly assigned to ovarian-intact (Sham) and ovariectomized (Ovx) groups. Anterior crural muscles were tested for susceptibility to injury from 150 or 50 eccentric contractions in wildtype and mdx mice, respectively. An additional experiment challenged mdx mice with a 2-wk treadmill running protocol followed by an eccentric contraction injury to posterior crural muscles. Functional recovery from injury was evaluated in wildtype mice by measuring isometric torque 3, 7, 14, or 21 days following injury. Results Ovarian hormone deficiency in wildtype mice did not impact susceptibility to injury as the ~50% isometric torque loss following eccentric contractions did not differ between Sham and Ovx mice (p=0.121). Similarly in mdx mice, hormone deficiency did not affect percent of pre injury isometric torque lost by anterior crural muscles following eccentric contractions (p=0.952), but the percent of pre injury torque in posterior crural muscles was lower in Ovx compared to Sham mice (p=0.014). Recovery from injury in wildtype mice was affected by hormone deficiency. Sham mice recovered pre injury isometric strength by 14 days (96 ± 2%) while Ovx mice maintained deficits at 14 and 21 days post injury (80 ± 3% and 84 ± 2%; phormone status did not impact the vulnerability of skeletal muscle to strength loss following eccentric contractions. However, ovarian hormone deficiency did impair the recovery of muscle strength in female mice. PMID:25255128

  16. Endothelial Estrogen Receptor-α Does Not Protect Against Vascular Stiffness Induced by Western Diet in Female Mice.

    Science.gov (United States)

    Manrique, Camila; Lastra, Guido; Ramirez-Perez, Francisco I; Haertling, Dominic; DeMarco, Vincent G; Aroor, Annayya R; Jia, Guanghong; Chen, Dongqing; Barron, Brady J; Garro, Mona; Padilla, Jaume; Martinez-Lemus, Luis A; Sowers, James R

    2016-04-01

    Consumption of a diet high in fat and refined carbohydrates (Western diet [WD]) is associated with obesity and insulin resistance, both major risk factors for cardiovascular disease (CVD). In women, obesity and insulin resistance abrogate the protection against CVD likely afforded by estrogen signaling through estrogen receptor (ER)α. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ERα signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ERα knockout (EC-ERαKO), obtained after sequential crossing of the ERα double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ERαKO and aged-matched genopairs were fed either a regular chow diet (control diet) or WD for 8 weeks. Vascular stiffness was measured in vivo by pulse wave velocity and ex vivo in aortic explants by atomic force microscopy. In addition, vascular reactivity was assessed in isolated aortic rings. Initial characterization of the model fed a control diet did not reveal changes in whole-body insulin sensitivity, aortic vasoreactivity, or vascular stiffness in the EC-ERαKO mice. Interestingly, ablation of ERα in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ERα signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ERα in the setting of a WD remain to be elucidated.

  17. Compared to Sucrose, Previous Consumption of Fructose and Glucose Monosaccharides Reduces Survival and Fitness of Female Mice123

    Science.gov (United States)

    Ruff, James S; Hugentobler, Sara A; Suchy, Amanda K; Sosa, Mirtha M; Tanner, Ruth E; Hite, Megumi E; Morrison, Linda C; Gieng, Sin H; Shigenaga, Mark K; Potts, Wayne K

    2015-01-01

    Background: Intake of added sugar has been shown to correlate with many human metabolic diseases, and rodent models have characterized numerous aspects of the resulting disease phenotypes. However, there is a controversy about whether differential health effects occur because of the consumption of either of the two common types of added sugar—high-fructose corn syrup (fructose and glucose monosaccharides; F/G) or table sugar (sucrose, a fructose and glucose disaccharide). Objectives: We tested the equivalence of sucrose- vs. F/G-containing diets on mouse (Mus musculus) longevity, reproductive success, and social dominance. Methods: We fed wild-derived mice, outbred mice descended from wild-caught ancestors, a diet in which 25% of the calories came from either an equal ratio of F/G or an isocaloric amount of sucrose (both diets had 63% of total calories as carbohydrates). Exposure lasted 40 wk, starting at weaning (21 d of age), and then mice (104 females and 56 males) were released into organismal performances assays—seminatural enclosures where mice competed for territories, resources, and mates for 32 wk. Within enclosures all mice consumed the F/G diet. Results: Females initially fed the F/G diet experienced a mortality rate 1.9 times the rate (P = 0.012) and produced 26.4% fewer offspring than females initially fed sucrose (P = 0.001). This reproductive deficiency was present before mortality differences, suggesting the F/G diet was causing physiologic performance deficits prior to mortality. No differential patterns in survival, reproduction, or social dominance were observed in males, indicating a sex-specific outcome of exposure. Conclusion: This study provides experimental evidence that the consumption of human-relevant levels of F/G is more deleterious than an isocaloric amount of sucrose for key organism-level health measures in female mice. PMID:25733457

  18. Male mice song syntax depends on social contexts and influences female preferences

    Directory of Open Access Journals (Sweden)

    Jonathan eChabout

    2015-04-01

    Full Text Available In 2005 Holy & Guo advanced the idea that male mice produce ultrasonic vocalizations (USV with some features similar to courtship songs of songbirds. Since then, studies showed that male mice emit USV songs in different contexts (sexual and other and possess a multisyllabic repertoire. Debate still exists for and against plasticity in their vocalizations. But the use of a multisyllabic repertoire can increase potential flexibility and information, in how elements are organized and recombined, namely syntax. In many bird species, modulating song syntax has ethological relevance for sexual behavior and mate preferences. In this study we exposed adult male mice to different social contexts and developed a new approach of analyzing their USVs based on songbird syntax analysis. We found that male mice modify their syntax, including specific sequences, length of sequence, repertoire composition, and spectral features, according to stimulus and social context. Males emit longer and simpler syllables and sequences when singing to females, but more complex syllables and sequences in response to fresh female urine. Playback experiments show that the females prefer the complex songs over the simpler ones. We propose the complex songs are to lure females in, whereas the directed simpler sequences are used for direct courtship. These results suggest that although mice have a much more limited ability of song modification, they could still be used as animal models for understanding some vocal communication features that songbirds are used for.

  19. Effectiveness of BCG vaccination to aged mice

    Directory of Open Access Journals (Sweden)

    Ito Tsukasa

    2010-09-01

    Full Text Available Abstract Background The tuberculosis (TB still increases in the number of new cases, which is estimated to approach 10 million in 2010. The number of aged people has been growing all over the world. Ageing is one of risk factors in tuberculosis because of decreased immune responses in aged people. Mycobacterium bovis Bacillus Calmette Guérin (BCG is a sole vaccine currently used for TB, however, the efficacy of BCG in adults is still a matter of debate. Emerging the multidrug resistant Mycobacterium tuberculosis (MDR-TB make us to see the importance of vaccination against TB in new light. In this study, we evaluated the efficacy of BCG vaccination in aged mice. Results The Th1 responses, interferon-γ production and interleukin 2, in BCG inoculated aged mice (24-month-old were comparable to those of young mice (4- to 6-week-old. The protection activity of BCG in aged mice against Mycobacterium tuberculosis H37Rv was also the same as young mice. Conclusion These findings suggest that vaccination in aged generation is still effective for protection against tuberculosis.

  20. High-fat-diet-induced weight gain ameliorates bone loss without exacerbating AβPP processing and cognition in female APP/PS1 mice

    Directory of Open Access Journals (Sweden)

    Yunhua ePeng

    2014-08-01

    Full Text Available Osteoporosis is negatively correlated with body mass, whereas both osteoporosis and weight loss occur at higher incidence during the progression of Alzheimer’s disease (AD than the age-matched non-dementia individuals. Given that there is no evidence that overweight associated with AD-type cognitive dysfunction, we hypothesized that moderate weight gain might have a protective effect on the bone loss in AD without exacerbating cognitive dysfunction. In the present study, feeding a high-fat-diet (HFD, 45% calorie from fat to female APP/PS1 transgenic mice, an AD animal model, induced weight gain. The bone mineral density, microarchitecture, and biomechanical properties of the femurs were then evaluated. The results showed that the middle-aged female APP/PS1 transgenic mice were susceptible to osteoporosis of the femoral bones and that weight gain significantly enhanced bone mass and mechanical properties. Notably, HFD was not detrimental to brain insulin signaling and AβPP processing, as well as to exploration ability and working, learning and memory performance of the transgenic mice measured by T maze and water maze, compared with the mice fed a normal fat diet (10% calorie from fat. In addition, the circulating levels of leptin but not estradiol were remarkably elevated in HFD-treated mice. These results suggest that a body weight gain induced by the HFD feeding regimen significantly improved bone mass in female APP/PS1 mice with no detriments to exploration ability and spatial memory, most likely via the action of elevated circulating leptin.

  1. Effects of transgenic methionine sulfoxide reductase A (MsrA expression on lifespan and age-dependent changes in metabolic function in mice

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    Adam B. Salmon

    2016-12-01

    Full Text Available Mechanisms that preserve and maintain the cellular proteome are associated with long life and healthy aging. Oxidative damage is a significant contributor to perturbation of proteostasis and is dealt with by the cell through regulation of antioxidants, protein degradation, and repair of oxidized amino acids. Methionine sulfoxide reductase A (MsrA repairs oxidation of free- and protein-bound methionine residues through enzymatic reduction and is found in both the cytosol and the mitochondria. Previous studies in Drosophila have shown that increasing expression of MsrA can extend longevity. Here we test the effects of increasing MsrA on longevity and healthy aging in two transgenic mouse models. We show that elevated expression of MsrA targeted specifically to the cytosol reduces the rate of age-related death in female mice when assessed by Gompertz analysis. However, neither cytosolic nor mitochondrial MsrA overexpression extends lifespan when measured by log-rank analysis. In mice with MsrA overexpression targeted to the mitochondria, we see evidence for improved insulin sensitivity in aged female mice. With these and our previous data, we conclude that the increasing MsrA expression in mice has differential effects on aging and healthy aging that are dependent on the target of its subcellular localization.

  2. 2-Methoxyestradiol Reduces Angiotensin II-Induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice.

    Science.gov (United States)

    Pingili, Ajeeth K; Davidge, Karen N; Thirunavukkarasu, Shyamala; Khan, Nayaab S; Katsurada, Akemi; Majid, Dewan S A; Gonzalez, Frank J; Navar, L Gabriel; Malik, Kafait U

    2017-06-01

    Cytochrome P450 1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol. This study was conducted to determine whether 2-methoxyestradiol ameliorates Ang II-induced hypertension, renal dysfunction, and end-organ damage in intact Cyp1b1 -/- , ovariectomized female, and Cyp1b1 +/+ male mice. Ang II or vehicle was infused for 2 weeks and administered concurrently with 2-methoxyestradiol. Mice were placed in metabolic cages on day 12 of Ang II infusion for urine collection for 24 hours. 2-Methoxyestradiol reduced Ang II-induced increases in systolic blood pressure, water consumption, urine output, and proteinuria in intact female Cyp1b1 -/- and ovariectomized mice. 2-Methoxyestradiol also reduced Ang II-induced increase in blood pressure, water intake, urine output, and proteinuria in Cyp1b1 +/+ male mice. Treatment with 2-methoxyestradiol attenuated Ang II-induced end-organ damage in intact Cyp1b1 -/- and ovariectomized Cyp1b1 +/+ and Cyp1b1 -/- female mice and Cyp1b1 +/+ male mice. 2-Methoxyestradiol mitigated Ang II-induced increase in urinary excretion of angiotensinogen in intact Cyp1b1 -/- and ovariectomized Cyp1b1 +/+ and Cyp1b1 -/- female mice but not in Cyp1b1 +/+ male mice. The G protein-coupled estrogen receptor 1 antagonist G-15 failed to alter Ang II-induced increases in blood pressure and renal function in Cyp1b1 +/+ female mice. These data suggest that 2-methoxyestradiol reduces Ang II-induced hypertension and associated end-organ damage in intact Cyp1b1 -/- , ovariectomized Cyp1b1 +/+ and Cyp1b1 -/- female mice, and Cyp1b1 +/+ male mice independent of G protein-coupled estrogen receptor 1. Therefore, 2-methoxyestradiol could serve as a therapeutic agent for treating hypertension and associated pathogenesis in postmenopausal females, and in males. © 2017 American Heart Association, Inc.

  3. A Larger Social Network Enhances Novel Object Location Memory and Reduces Hippocampal Microgliosis in Aged Mice

    Science.gov (United States)

    Smith, Bryon M.; Yao, Xinyue; Chen, Kelly S.; Kirby, Elizabeth D.

    2018-01-01

    The mammalian hippocampus shows marked decline in function with aging across many species, including humans and laboratory rodent models. This decline frequently manifests in memory impairments that occur even in the absence of dementia pathology. In humans, a number of factors correlate with preserved hippocampal memory in aging, such as exercise, cognitive stimulation and number of social ties. While interventional studies and animal models clearly indicate that exercise and cognitive stimulation lead to hippocampal preservation, there is relatively little research on whether a decline in social ties leads to cognitive decline or vice versa. Even in animal studies of environmental enrichment in aging, the focus typically falls on physical enrichment such as a rotating cast of toys, rather than the role of social interactions. The present studies investigated the hypothesis that a greater number of social ties in aging mice would lead to improved hippocampal function. Aged, female C57/Bl6 mice were housed for 3 months in pairs or large groups (7 mice per cage). Group-housed mice showed greater novel object location memory and stronger preference for a spatial navigation strategy in the Barnes maze, though no difference in escape latency, compared to pair-housed mice. Group-housed mice did not differ from pair-housed mice in basal corticosterone levels or adult hippocampal neurogenesis. Group-housed mice did, however, show reduced numbers of Iba1/CD68+ microglia in the hippocampus. These findings suggest that group housing led to better memory function and reduced markers of neuroinflammation in aged mice. More broadly, they support a causative link between social ties and hippocampal function, suggesting that merely having a larger social network can positively influence the aging brain. Future research should address the molecular mechanisms by which a greater number of social ties alters hippocampal function. PMID:29904345

  4. Lef1 haploinsufficient mice display a low turnover and low bone mass phenotype in a gender- and age-specific manner.

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    Tommy Noh

    Full Text Available We investigated the role of Lef1, one of the four transcription factors that transmit Wnt signaling to the genome, in the regulation of bone mass. Microcomputed tomographic analysis of 13- and 17-week-old mice revealed significantly reduced trabecular bone mass in Lef1(+/- females compared to littermate wild-type females. This was attributable to decreased osteoblast activity and bone formation as indicated by histomorphometric analysis of bone remodeling. In contrast to females, bone mass was unaffected by Lef1 haploinsufficiency in males. Similarly, females were substantially more responsive than males to haploinsufficiency in Gsk3beta, a negative regulator of the Wnt pathway, displaying in this case a high bone mass phenotype. Lef1 haploinsufficiency also led to low bone mass in males lacking functional androgen receptor (AR (tfm mutants. The protective skeletal effect of AR against Wnt-related low bone mass is not necessarily a result of direct interaction between the AR and Wnt signaling pathways, because Lef1(+/- female mice had normal bone mass at the age of 34 weeks. Thus, our results indicate an age- and gender-dependent role for Lef1 in regulating bone formation and bone mass in vivo. The resistance to Lef1 haploinsufficiency in males with active AR and in old females could be due to the reduced bone turnover in these mice.

  5. The role of p38 in mitochondrial respiration in male and female mice.

    Science.gov (United States)

    Ju, Xiaohua; Wen, Yi; Metzger, Daniel; Jung, Marianna

    2013-06-07

    p38 is a mitogen-activated protein kinase and mediates cell growth, cell differentiation, and synaptic plasticity. The aim of this study is to determine the extent to which p38 plays a role in maintaining mitochondrial respiration in male and female mice under a normal condition. To achieve this aim, we have generated transgenic mice that lack p38 in cerebellar Purkinje neurons by crossing Pcp2 (Purkinje cell protein 2)-Cre mice with p38(loxP/loxP) mice. Mitochondria from cerebellum were then isolated from the transgenic and wild-type mice to measure mitochondrial respiration using XF24 respirometer. The mRNA and protein expression of cytochrome c oxidase (COX) in cerebellum were also measured using RT-PCR and immunoblot methods. Separately, HT22 cells were used to determine the involvement of 17β-estradiol (E2) and COX in mitochondrial respiration. The genetic knockout of p38 in Purkinje neurons suppressed the mitochondrial respiration only in male mice and increased COX expression only in female mice. The inhibition of COX by sodium azide (SA) sharply suppressed mitochondrial respiration of HT22 cells in a manner that was protected by E2. These data suggest that p38 is required for the mitochondrial respiration of male mice. When p38 is below a normal level, females may maintain mitochondrial respiration through COX up-regulation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  6. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.

    Directory of Open Access Journals (Sweden)

    Jung Yoon Park

    2008-06-01

    Full Text Available Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W, display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.

  7. Effects of Vitex agnus-castus fruit on sex hormones and antioxidant indices in a d-galactose-induced aging female mouse model

    OpenAIRE

    Akram Ahangarpour; Seyedeh Asma Najimi; Yaghoob Farbood

    2016-01-01

    Background: Aging is associated with the loss of endocrine function. In this study, Vitex agnus-castus (Vitex), which has antioxidant effects and high levels of phytoestrogen, was investigated with regard to the hypothalamic-pituitary-gonadal axis and antioxidant indices in natural aging and in a d-galactose induced aging model in female mice. Methods: The mice were subcutaneously injected with d-galactose (500 mg/kg/d for 45 days). Extract of Vitex (600 mg/kg/bid for 7 days by gavage) was...

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

    Science.gov (United States)

    Weisker, S M; Barkley, M

    1991-10-01

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

  9. Nucleus Accumbens Dopamine Signaling Regulates Sexual Preference for Females in Male Mice.

    Science.gov (United States)

    Beny-Shefer, Yamit; Zilkha, Noga; Lavi-Avnon, Yael; Bezalel, Nadav; Rogachev, Ilana; Brandis, Alexander; Dayan, Molly; Kimchi, Tali

    2017-12-12

    Sexual preference for the opposite sex is a fundamental behavior underlying reproductive success, but the neural mechanisms remain unclear. Here, we examined the role of dopamine signaling in the nucleus accumbens core (NAcc) in governing chemosensory-mediated preference for females in TrpC2 -/- and wild-type male mice. TrpC2 -/- males, deficient in VNO-mediated signaling, do not display mating or olfactory preference toward females. We found that, during social interaction with females, TrpC2 -/- males do not show increased NAcc dopamine levels, observed in wild-type males. Optogenetic stimulation of VTA-NAcc dopaminergic neurons in TrpC2 -/- males during exposure to a female promoted preference response to female pheromones and elevated copulatory behavior toward females. Additionally, we found that signaling through the D1 receptor in the NAcc is necessary for the olfactory preference for female-soiled bedding. Our study establishes a critical role for the mesolimbic dopaminergic system in governing pheromone-mediated responses and mate choice in male mice. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Nucleus Accumbens Dopamine Signaling Regulates Sexual Preference for Females in Male Mice

    Directory of Open Access Journals (Sweden)

    Yamit Beny-Shefer

    2017-12-01

    Full Text Available Sexual preference for the opposite sex is a fundamental behavior underlying reproductive success, but the neural mechanisms remain unclear. Here, we examined the role of dopamine signaling in the nucleus accumbens core (NAcc in governing chemosensory-mediated preference for females in TrpC2−/− and wild-type male mice. TrpC2−/− males, deficient in VNO-mediated signaling, do not display mating or olfactory preference toward females. We found that, during social interaction with females, TrpC2−/− males do not show increased NAcc dopamine levels, observed in wild-type males. Optogenetic stimulation of VTA-NAcc dopaminergic neurons in TrpC2−/− males during exposure to a female promoted preference response to female pheromones and elevated copulatory behavior toward females. Additionally, we found that signaling through the D1 receptor in the NAcc is necessary for the olfactory preference for female-soiled bedding. Our study establishes a critical role for the mesolimbic dopaminergic system in governing pheromone-mediated responses and mate choice in male mice.

  11. Mammary tumorigenesis in APC{sup min/+} mice is enhanced by X-irradiation with a characteristic age dependence

    Energy Technology Data Exchange (ETDEWEB)

    Tatsuhiko, Imaoka; Mayumi, Nishimura; Shizuko, Kakinuma; Yoshiya, Shimada [National Institute of Radiological Sciences, Experimental Radiobiology for Children' s Health Research Group, Research, Center for Radiation Protection (Japan); Mieko, Okamoto [Tokyo Metropolitan Institute of Medical Science (Japan)

    2006-07-01

    The ApcM{sup min/+} (Min) mouse is a genetically predisposed model of both intestinal and mammary tumorigenesis. We investigated age-related changes in the susceptibility of mice (before, during and after puberty) to radiation-induced mammary tumorigenesis using this model. Female Min and wild-type mice having the C57BL/6J background were irradiated with 2 Gy of X-rays at 2, 5, 7 and 10 weeks and sacrificed at 18 weeks of age. Min mice irradiated at 7 to 10 weeks of age (after puberty) developed mammary tumors with squamous metaplasia, whereas their wild-type litter-mates did not. Interestingly, irradiation of Min mice at 2 to 5 weeks (before and during puberty, respectively) did not induce mammary tumors but rather cystic nodules with metaplasia. The mammary tumors exhibited increased nuclear beta-catenin protein and loss of the wild-type Apc allele. Our results show that susceptibility to radiation-induced mammary tumorigenesis increases after puberty in Min mice, suggesting that the tumorigenic effect of ionizing radiation targets the lobular-alveolar progenitor cells, which increase in number with age and are controlled by beta-catenin signaling. (author)

  12. Ursodeoxycholic acid decreases age-related adiposity and inflammation in mice

    Science.gov (United States)

    Oh, Ah-Reum; Bae, Jin-Sik; Lee, Junghoon; Shin, Eunji; Oh, Byung-Chul; Park, Sang-Chul; Cha, Ji-Young

    2016-01-01

    Ursodeoxycholic acid (UDCA), a natural, hydrophilic nontoxic bile acid, is clinically effective for treating cholestatic and chronic liver diseases. We investigated the chronic effects of UDCA on age-related lipid homeostasis and underlying molecular mechanisms. Twenty-week-old C57BL/6 male and female mice were fed a diet with or without 0.3% UDCA supplementation for 25 weeks. UDCA significantly reduced weight gain, adiposity, hepatic triglyceride, and hepatic cholesterol without incidental hepatic injury. UDCA-mediated hepatic triglyceride reduction was associated with downregulated hepatic expression of peroxisome proliferator-activated receptor-γ, and of other genes involved in lipogenesis (Chrebp, Acaca, Fasn, Scd1, and Me1) and fatty acid uptake (Ldlr, Cd36). The inflammatory cytokines Tnfa, Ccl2, and Il6 were significantly decreased in liver and/or white adipose tissues of UDCA-fed mice. These data suggest that UDCA exerts beneficial effects on age-related metabolic disorders by lowering the hepatic lipid accumulation, while concurrently reducing hepatocyte and adipocyte susceptibility to inflammatory stimuli. [BMB Reports 2016; 49(2): 105-110] PMID:26350747

  13. AGEMAP: a gene expression database for aging in mice.

    Directory of Open Access Journals (Sweden)

    Jacob M Zahn

    2007-11-01

    Full Text Available We present the AGEMAP (Atlas of Gene Expression in Mouse Aging Project gene expression database, which is a resource that catalogs changes in gene expression as a function of age in mice. The AGEMAP database includes expression changes for 8,932 genes in 16 tissues as a function of age. We found great heterogeneity in the amount of transcriptional changes with age in different tissues. Some tissues displayed large transcriptional differences in old mice, suggesting that these tissues may contribute strongly to organismal decline. Other tissues showed few or no changes in expression with age, indicating strong levels of homeostasis throughout life. Based on the pattern of age-related transcriptional changes, we found that tissues could be classified into one of three aging processes: (1 a pattern common to neural tissues, (2 a pattern for vascular tissues, and (3 a pattern for steroid-responsive tissues. We observed that different tissues age in a coordinated fashion in individual mice, such that certain mice exhibit rapid aging, whereas others exhibit slow aging for multiple tissues. Finally, we compared the transcriptional profiles for aging in mice to those from humans, flies, and worms. We found that genes involved in the electron transport chain show common age regulation in all four species, indicating that these genes may be exceptionally good markers of aging. However, we saw no overall correlation of age regulation between mice and humans, suggesting that aging processes in mice and humans may be fundamentally different.

  14. Improvement of ovarian response and oocyte quality of aged female by administration of bone morphogenetic protein-6 in a mouse model

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    Park Seung S

    2012-12-01

    Full Text Available Abstract Background Advancing female age remains a difficult problem in infertility treatment. Ovarian angiogenesis plays an important role in follicular development and the activation of ovarian angiogenesis has been emerged as a new strategy for the improvement of age-related decline of oocyte quality. BMP-6 affect gonadotropin signals in granulosa cells and it promotes normal fertility by enabling appropriate response to LH and normal oocyte quality. BMP-6 has a potential role in regulation of angiogenesis and regulates the expression of inhibitor of DNA-binding proteins (Ids. Ids involved in the control and timing of follicle selection and granulosa cells differentiation. Especially, Id-1 is well-characterized target of BMP-6 signaling. Therefore, this study investigated whether co-administration of BMP-6 during superovulation process improves ovarian response, oocyte quality and expression of Id-1 and vascular endothelial growth factor (VEGF in the ovary of aged female using a mouse model. Methods Aged C57BL/6 female mice (26–31 weeks old were superovulated by injection with 0.1 mL of 5 IU equine chorionic gonadotropin (eCG containing recombinant mouse BMP-6 at various doses (0, 0.01, 0.1, 1, and 10 ng, followed by injection with 5 IU human chorionic gonadotropin (hCG 48 h later. Then, the mice were immediately paired with an individual male. The aged control group was superovulated without BMP-6. Young mice of 6–9 weeks old were superovulated without BMP-6 as a positive control for superovulation and in vitro culture of embryos. Eighteen hours after hCG injection, zygotes were retrieved and cultured for 4 days. Both ovaries of each mouse were provided in the examination of ovarian expression of Id-1 and VEGF by reverse transcriptase-polymerase chain reaction, western blot, and immunohistochemistry. Results Administration of 0.1 ng BMP-6 significantly increased the number and blastocyst formation rate of oocytes ovulated and ovarian

  15. Vulnerability of female germ cells in developing mice and monkeys to tritium, gamma rays, and polycyclic aromatic hydrocarbons

    International Nuclear Information System (INIS)

    Dobson, R.L.; Koehler, C.G.; Felton, J.S.; Kwan, T.C.; Wuebbles, B.J.; Jones, D.C.L.

    1978-01-01

    During development female germ cells in both mouse and monkey are extremely sensitive to destruction by low-level chronic tritium exposure (via 3 HOH in maternal drinking water). Practical significance of this stems from tritium's importance in nuclear energy production and as an environmental pollutant. In mice exposed from conception to 14 days of age, the LD 50 level for oocytes is only 2 μCi per mililiter of body water. The present studies indicate that, for female germ cells in squirrel monkeys exposed in utero, the LD 50 is even lower, about 0.5 μCi/ml. This striking sensitivity contrasts with reported radioresistance for primate oocytes, chiefly from acute x-irradiation experiments. The discrepancy is reconciled if germ cells in the fetal primate pass through a highly sensitive period of limited duration. In light of other data showing germ-cell loss following repeated semiweekly x-irradiation during late but not during mid gestation, these results indicate that exceedingly high sensitivity occurs probably about the middle of the last trimester, at which time the LD 50 for monkey germ cells is, as for that of the mouse, less than 5 rads. Whereas highest radiosensitivity in primates is before birth, in mice it is after birth. To define the period of sensitivity more sharply, we measured oocyte responses to standard gamma-ray exposures in Swiss-Webster mice at various ages and found them to be maximal between days 5 and 19. Polycyclic aromatic hydrocarbons (PAH's), important as pollutants, also can destroy female germ cells effectively

  16. Female Nur77-deficient mice show increased susceptibility to diet-induced obesity.

    Directory of Open Access Journals (Sweden)

    Sonia Perez-Sieira

    Full Text Available Adipose tissue is essential in the regulation of body weight. The key process in fat catabolism and the provision of energy substrate during times of nutrient deprivation or enhanced energy demand is the hydrolysis of triglycerides and the release of fatty acids and glycerol. Nur77 is a member of the NR4A subfamily of nuclear receptors that plays an important metabolic role, modulating hepatic glucose metabolism and lipolysis in muscle. However, its endogenous role on white adipose tissue, as well as the gender dependency of these mechanisms, remains largely unknown. Male and female wild type and Nur77 deficient mice were fed with a high fat diet (45% calories from fat for 4 months. Mice were analyzed in vivo with the indirect calorimetry system, and tissues were analyzed by real-time PCR and Western blot analysis. Female, but not male Nur77 deficient mice, gained more weight and fat mass when compared to wild type mice fed with high fat diet, which can be explained by decreased energy expenditure. The lack of Nur77 also led to a decreased pHSL/HSL ratio in white adipose tissue and increased expression of CIDEA in brown adipose tissue of female Nur77 deficient mice. Overall, these findings suggest that Nur77 is an important physiological modulator of lipid metabolism in adipose tissue and that there are gender differences in the sensitivity to deletion of the Nur77 signaling. The decreased energy expenditure and the actions of Nur77 on liver, muscle, brown and white adipose tissue contribute to the increased susceptibility to diet-induced obesity in females lacking Nur77.

  17. Effects of age and parity on mammary gland lesions and progenitor cells in the FVB/N-RC mice.

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    Ahmed Raafat

    Full Text Available The FVB/N mouse strain is extensively used in the development of animal models for breast cancer research. Recently it has been reported that the aging FVB/N mice develop spontaneous mammary lesions and tumors accompanied with abnormalities in the pituitary glands. These observations have a great impact on the mouse models of human breast cancer. We have developed a population of inbred FVB/N mice (designated FVB/N-RC that have been genetically isolated for 20 years. To study the effects of age and parity on abnormalities of the mammary glands of FVB/N-RC mice, twenty-five nulliparous and multiparous (3-4 pregnancies females were euthanized at 16-22 months of age. Examination of the mammary glands did not reveal macroscopic evidence of mammary gland tumors in either aged-nulliparous or multiparous FVB/N-RC mice (0/25. However, histological analysis of the mammary glands showed rare focal nodules of squamous changes in 2 of the aged multiparous mice. Mammary gland hyperplasia was detected in 8% and 71% of the aged-nulliparous and aged-multiparous mice, respectively. Epithelial contents and serum levels of triiodothyronine were significantly higher in the experimental groups than the 14-wk-old control mice. Immuno-histochemical staining of the pituitary gland pars distalis showed no difference in prolactin staining between the control and the aged mice. Tissue transplant and dilution studies showed no effect of age and/or parity on the ability of putative progenitor cells present among the injected mammary cells to repopulate a cleared fat pad and develop a full mammary gland outgrowth. This FVB/N-RC mouse substrain is suitable to develop mouse models for breast cancer.

  18. Female Mice Deficient in Alpha-Fetoprotein Show Female-Typical Neural Responses to Conspecific-Derived Pheromones

    NARCIS (Netherlands)

    Brock, O.; Keller, M.; Douhard, Q.; Bakker, J.

    2012-01-01

    The neural mechanisms controlling sexual behavior are sexually differentiated by the perinatal actions of sex steroid hormones. We recently observed using female mice deficient in alpha-fetoprotein (AFP-KO) and which lack the protective actions of AFP against maternal estradiol, that exposure to

  19. Modified forelimb grip strength test detects aging-associated physiological decline in skeletal muscle function in male mice.

    Science.gov (United States)

    Takeshita, Hikari; Yamamoto, Koichi; Nozato, Satoko; Inagaki, Tadakatsu; Tsuchimochi, Hirotsugu; Shirai, Mikiyasu; Yamamoto, Ryohei; Imaizumi, Yuki; Hongyo, Kazuhiro; Yokoyama, Serina; Takeda, Masao; Oguro, Ryosuke; Takami, Yoichi; Itoh, Norihisa; Takeya, Yasushi; Sugimoto, Ken; Fukada, So-Ichiro; Rakugi, Hiromi

    2017-02-08

    The conventional forelimb grip strength test is a widely used method to assess skeletal muscle function in rodents; in this study, we modified this method to improve its variability and consistency. The modified test had lower variability among trials and days than the conventional test in young C57BL6 mice, especially by improving the variabilities in male. The modified test was more sensitive than the conventional test to detect a difference in motor function between female and male mice, or between young and old male mice. When the modified test was performed on male mice during the aging process, reduction of grip strength manifested between 18 and 24 months of age at the group level and at the individual level. The modified test was similar to the conventional test in detecting skeletal muscle dysfunction in young male dystrophic mice. Thus, the modified forelimb grip strength test, with its improved validity and reliability may be an ideal substitute for the conventional method.

  20. Comparison of the course of infection with Giardia muris in male and female mice.

    Science.gov (United States)

    Daniels, C W; Belosevic, M

    1995-01-01

    The infection with Giardia muris in male and female C57BL/6 mice was characterized by enumerating cyst release in the feces and trophozoite burden in the small intestine. Cyst release differed between males and females during the course of the primary and challenge infections. Males and females released similar numbers of cysts in the feces during the acute phase of the infection. However, the trophozoite burden was significantly higher in males during the same period. Males released cysts in their feces longer than females and trophozoites present in their intestines for a longer period than females. From day 18 of infection the females did not release cysts in their feces, while males continued to do so for at least 60 days. Thus, distinct differences exist between male and female mice in their ability to harbor and eliminate this intestinal parasite.

  1. Age-related retinopathy in NRF2-deficient mice.

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    Zhenyang Zhao

    2011-04-01

    Full Text Available Cumulative oxidative damage is implicated in the pathogenesis of age-related macular degeneration (AMD. Nuclear factor erythroid 2-related factor 2 (NRF2 is a transcription factor that plays key roles in retinal antioxidant and detoxification responses. The purposes of this study were to determine whether NRF2-deficient mice would develop AMD-like retinal pathology with aging and to explore the underlying mechanisms.Eyes of both wild type and Nrf2(-/- mice were examined in vivo by fundus photography and electroretinography (ERG. Structural changes of the outer retina in aged animals were examined by light and electron microscopy, and immunofluorescence labeling. Our results showed that Nrf2(-/- mice developed age-dependent degenerative pathology in the retinal pigment epithelium (RPE. Drusen-like deposits, accumulation of lipofuscin, spontaneous choroidal neovascularization (CNV and sub-RPE deposition of inflammatory proteins were present in Nrf2(-/- mice after 12 months. Accumulation of autophagy-related vacuoles and multivesicular bodies was identified by electron microscopy both within the RPE and in Bruch's membrane of aged Nrf2(-/- mice.Our data suggest that disruption of Nfe2l2 gene increased the vulnerability of outer retina to age-related degeneration. NRF2-deficient mice developed ocular pathology similar to cardinal features of human AMD and deregulated autophagy is likely a mechanistic link between oxidative injury and inflammation. The Nrf2(-/- mice can provide a novel model for mechanistic and translational research on AMD.

  2. Cytochrome P450-2E1 is involved in aging-related kidney damage in mice through increased nitroxidative stress.

    Science.gov (United States)

    Abdelmegeed, Mohamed A; Choi, Youngshim; Ha, Seung-Kwoon; Song, Byoung-Joon

    2017-11-01

    The aim of this study was to investigate the role of cytochrome P450-2E1 (CYP2E1) in aging-dependent kidney damage since it is poorly understood. Young (7 weeks) and aged female (16-17 months old) wild-type (WT) and Cyp2e1-null mice were used. Kidney histology showed that aged WT mice exhibited typical signs of kidney aging such as cell vacuolation, inflammatory cell infiltration, cellular apoptosis, glomerulonephropathy, and fibrosis, along with significantly elevated levels of renal TNF-α and serum creatinine than all other groups. Furthermore, the highest levels of renal hydrogen peroxide, protein carbonylation and nitration were observed in aged WT mice. These increases in the aged WT mice were accompanied by increased levels of iNOS and mitochondrial nitroxidative stress through altered amounts and activities of the mitochondrial complex proteins and significantly reduced levels of the antioxidant glutathione (GSH). In contrast, the aged Cyp2e1-null mice exhibited significantly higher antioxidant capacity with elevated heme oxygenase-1 and catalase activities compared to all other groups, while maintaining normal GSH levels with significantly less mitochondrial nitroxidative stress compared to the aged WT mice. Thus, CYP2E1 is important in causing aging-related kidney damage most likely through increasing nitroxidative stress and that CYP2E1 could be a potential target in preventing aging-related kidney diseases. Published by Elsevier Ltd.

  3. Dwarf Mice and Aging.

    Science.gov (United States)

    Masternak, Michal M; Darcy, Justin; Victoria, Berta; Bartke, Andrzej

    2018-01-01

    Dwarf mice have been studied for many decades, however, the focus of these studies shifted in 1996 when it was shown by Brown-Borg and her coworkers that Ames dwarf (Prop1 df ) mice are exceptionally long-lived. Since then, Snell dwarf (Pit1 dw ) and growth hormone receptor knockout (GHR-KO, a.k.a. Laron dwarf) mice were also shown to be exceptionally long-lived, presumably due to their growth hormone (GH)-deficiency or -resistance, respectively. What is of equal importance in these dwarf mice is their extended health span, that is, these animals have a longer period of life lived free of frailty and age-related diseases. This review article focuses on recent studies conducted in these dwarf mice, which concerned brown and white adipose tissue biology, microRNA (miRNA) profiling, as well as early-life dietary and hormonal interventions. Results of these studies identify novel mechanisms linking reduced GH action with extensions of both life span and health span. Copyright © 2017. Published by Elsevier Inc.

  4. Lower susceptibility of female mice to acetaminophen hepatotoxicity: Role of mitochondrial glutathione, oxidant stress and c-jun N-terminal kinase

    International Nuclear Information System (INIS)

    Du, Kuo; Williams, C. David; McGill, Mitchell R.; Jaeschke, Hartmut

    2014-01-01

    Acetaminophen (APAP) overdose causes severe hepatotoxicity in animals and humans. However, the mechanisms underlying the gender differences in susceptibility to APAP overdose in mice have not been clarified. In our study, APAP (300 mg/kg) caused severe liver injury in male mice but 69–77% lower injury in females. No gender difference in metabolic activation of APAP was found. Hepatic glutathione (GSH) was rapidly depleted in both genders, while GSH recovery in female mice was 2.6 fold higher in the mitochondria at 4 h, and 2.5 and 3.3 fold higher in the total liver at 4 h and 6 h, respectively. This faster recovery of GSH, which correlated with greater induction of glutamate-cysteine ligase, attenuated mitochondrial oxidative stress in female mice, as suggested by a lower GSSG/GSH ratio at 6 h (3.8% in males vs. 1.4% in females) and minimal centrilobular nitrotyrosine staining. While c-jun N-terminal kinase (JNK) activation was similar at 2 and 4 h post-APAP, it was 3.1 fold lower at 6 h in female mice. However, female mice were still protected by the JNK inhibitor SP600125. 17β-Estradiol pretreatment moderately decreased liver injury and oxidative stress in male mice without affecting GSH recovery. Conclusion: The lower susceptibility of female mice is achieved by the improved detoxification of reactive oxygen due to accelerated recovery of mitochondrial GSH levels, which attenuates late JNK activation and liver injury. However, even the reduced injury in female mice was still dependent on JNK. While 17β-estradiol partially protects male mice, it does not affect hepatic GSH recovery. - Highlights: • Female mice are less susceptible to acetaminophen overdose than males. • GSH depletion and protein adduct formation are similar in both genders. • Recovery of hepatic GSH levels is faster in females and correlates with Gclc. • Reduced oxidant stress in females leads to reduced JNK activation. • JNK activation and mitochondrial translocation are critical

  5. Activation of PPARα decreases bile acids in livers of female mice while maintaining bile flow and biliary bile acid excretion.

    Science.gov (United States)

    Zhang, Youcai; Lickteig, Andrew J; Csanaky, Iván L; Klaassen, Curtis D

    2018-01-01

    Fibrates are hypolipidemic drugs that act as activators of peroxisome proliferator-activated receptor α (PPARα). In both humans and rodents, females were reported to be less responsive to fibrates than males. Previous studies on fibrates and PPARα usually involved male mice, but little has been done in females. The present study aimed to provide the first comprehensive analysis of the effects of clofibrate (CLOF) and PPARα on bile acid (BA) homeostasis in female mice. Study in WT male mice showed that a 4-day CLOF treatment increased liver weight, bile flow, and biliary BA excretion, but decreased total BAs in both serum and liver. In contrast, WT female mice were less susceptible to these CLOF-mediated responses observed in males. In WT female mice, CLOF decreased total BAs in the liver, but had little effect on the mRNAs of hepatic BA-related genes. Next, a comparative analysis between WT and PPARα-null female mice showed that lack of PPARα in female mice decreased total BAs in serum, but had little effect on total BAs in liver or bile. However, lack of PPARα in female mice increased mRNAs of BA synthetic enzymes (Cyp7a1, Cyp8b1, Cyp27a1, and Cyp7b1) and transporters (Ntcp, Oatp1a1, Oatp1b2, and Mrp3). Furthermore, the increase of Cyp7a1 in PPARα-null female mice was associated with an increase in liver Fxr-Shp-Lrh-1 signaling. In conclusion, female mice are resistant to CLOF-mediated effects on BA metabolism observed in males, which could be attributed to PPARα-mediated suppression in females on genes involved in BA synthesis and transport. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Peptide YY induces characteristic meal patterns of aged mice.

    Science.gov (United States)

    Mogami, Sachiko; Yamada, Chihiro; Fujitsuka, Naoki; Hattori, Tomohisa

    2017-11-01

    Changes in eating behavior occur in the elderly due to oral and swallowing dysfunctions. We aimed to clarify the difference between basal meal patterns of young and aged mice in relation to appetite regulating hormones. Thirty two of young (7-week-old) and aged (23-25-month-old) C57BL/6 male mice were acclimated to a single housing and then transferred to a highly sensitive automated feeding monitoring device. Feeding behavior was monitored from the onset of the dark phase after habituation to the device. Plasma peptide YY (PYY) levels were assessed under the several feeding status or after treatment of PYY. PYY and its receptor (NPY Y2 receptor, Y2R) antagonist were intraperitoneally administered 30min before the monitoring. Although the basal 24-h meal amounts did not differ by age, the total meal time and frequency of minimum feeding activity (bout) were significantly increased and the average bout size and time per bout were significantly decreased in aged mice. PYY dynamics were abnormal and the temporal reduction in food intake by exogenous PYY was more prominent in aged mice than in young mice. PYY administration to young mice induced aged-like meal patterns, and Y2R antagonist administration to aged mice induced young-like meal patterns. Aged mice exhibited characteristic meal patterns probably due to PYY metabolism dysfunction and/or enhanced PYY-Y2R signaling, suggesting a novel method for assessing eating difficulties in aged animals and a potential target for the remedy. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. The ZEB1 transcription factor is a novel repressor of adiposity in female mice.

    Directory of Open Access Journals (Sweden)

    Jessica N Saykally

    Full Text Available BACKGROUND: Four genome-wide association studies mapped an "obesity" gene to human chromosome 10p11-12. As the zinc finger E-box binding homeobox 1 (ZEB1 transcription factor is encoded by the TCF8 gene located in that region, and as it influences the differentiation of various mesodermal lineages, we hypothesized that ZEB1 might also modulate adiposity. The goal of these studies was to test that hypothesis in mice. METHODOLOGY/PRINCIPAL FINDINGS: To ascertain whether fat accumulation affects ZEB1 expression, female C57BL/6 mice were fed a regular chow diet (RCD ad libitum or a 25% calorie-restricted diet from 2.5 to 18.3 months of age. ZEB1 mRNA levels in parametrial fat were six to ten times higher in the obese mice. To determine directly whether ZEB1 affects adiposity, wild type (WT mice and mice heterozygous for TCF8 (TCF8+/- were fed an RCD or a high-fat diet (HFD (60% calories from fat. By two months of age on an HFD and three months on an RCD, TCF8+/- mice were heavier than WT controls, which was attributed by Echo MRI to increased fat mass (at three months on an HFD: 0.517+/-0.081 total fat/lean mass versus 0.313+/-0.036; at three months on an RCD: 0.175+/-0.013 versus 0.124+/-0.012. No differences were observed in food uptake or physical activity, suggesting that the genotypes differ in some aspect of their metabolic activity. ZEB1 expression also increases during adipogenesis in cell culture. CONCLUSION/SIGNIFICANCE: These results show for the first time that the ZEB1 transcription factor regulates the accumulation of adipose tissue. Furthermore, they corroborate the genome-wide association studies that mapped an "obesity" gene at chromosome 10p11-12.

  8. Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.

    Science.gov (United States)

    Yuan, Xidi; Klein, Dennis; Kerscher, Susanne; West, Brian L; Weis, Joachim; Katona, Istvan; Martini, Rudolf

    2018-05-09

    Aging is known as a major risk factor for the structure and function of the nervous system. There is urgent need to overcome such deleterious effects of age-related neurodegeneration. Here we show that peripheral nerves of 24-month-old aging C57BL/6 mice of either sex show similar pathological alterations as nerves from aging human individuals, whereas 12-month-old adult mice lack such alterations. Specifically, nerve fibers showed demyelination, remyelination and axonal lesion. Moreover, in the aging mice, neuromuscular junctions showed features typical for dying-back neuropathies, as revealed by a decline of presynaptic markers, associated with α-bungarotoxin-positive postsynapses. In line with these observations were reduced muscle strengths. These alterations were accompanied by elevated numbers of endoneurial macrophages, partially comprising the features of phagocytosing macrophages. Comparable profiles of macrophages could be identified in peripheral nerve biopsies of aging persons. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by applying an orally administered CSF-1R specific kinase (c-FMS) inhibitor. The 6-month-lasting treatment started before development of degenerative changes at 18 months and reduced macrophage numbers in mice by ∼70%, without side effects. Strikingly, nerve structure was ameliorated and muscle strength preserved. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may pave the way for treating degeneration in the aging peripheral nervous system by targeting macrophages, leading to reduced weakness, improved mobility, and eventually increased quality of life in the elderly. SIGNIFICANCE STATEMENT Aging is a major risk factor for the structure and function of the nervous system. Here we show that peripheral nerves of 24-month-old aging mice show similar degenerative alterations as nerves from aging

  9. Female mucopolysaccharidosis IIIA mice exhibit hyperactivity and a reduced sense of danger in the open field test.

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    Alex Langford-Smith

    Full Text Available Reliable behavioural tests in animal models of neurodegenerative diseases allow us to study the natural history of disease and evaluate the efficacy of novel therapies. Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A, is a severe, neurodegenerative lysosomal storage disorder caused by a deficiency in the heparan sulphate catabolising enzyme, sulfamidase. Undegraded heparan sulphate accumulates, resulting in lysosomal enlargement and cellular dysfunction. Patients suffer a progressive loss of motor and cognitive function with severe behavioural manifestations and premature death. There is currently no treatment. A spontaneously occurring mouse model of the disease has been described, that has approximately 3% of normal enzyme activity levels. Behavioural phenotyping of the MPS IIIA mouse has been previously reported, but the results are conflicting and variable, even after full backcrossing to the C57BL/6 background. Therefore we have independently backcrossed the MPS IIIA model onto the C57BL/6J background and evaluated the behaviour of male and female MPS IIIA mice at 4, 6 and 8 months of age using the open field test, elevated plus maze, inverted screen and horizontal bar crossing at the same circadian time point. Using a 60 minute open field, we have demonstrated that female MPS IIIA mice are hyperactive, have a longer path length, display rapid exploratory behaviour and spend less time immobile than WT mice. Female MPS IIIA mice also display a reduced sense of danger and spend more time in the centre of the open field. There were no significant differences found between male WT and MPS IIIA mice and no differences in neuromuscular strength were seen with either sex. The altered natural history of behaviour that we observe in the MPS IIIA mouse will allow more accurate evaluation of novel therapeutics for MPS IIIA and potentially other neurodegenerative disorders.

  10. Female mucopolysaccharidosis IIIA mice exhibit hyperactivity and a reduced sense of danger in the open field test.

    Science.gov (United States)

    Langford-Smith, Alex; Langford-Smith, Kia J; Jones, Simon A; Wynn, Robert F; Wraith, J E; Wilkinson, Fiona L; Bigger, Brian W

    2011-01-01

    Reliable behavioural tests in animal models of neurodegenerative diseases allow us to study the natural history of disease and evaluate the efficacy of novel therapies. Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A), is a severe, neurodegenerative lysosomal storage disorder caused by a deficiency in the heparan sulphate catabolising enzyme, sulfamidase. Undegraded heparan sulphate accumulates, resulting in lysosomal enlargement and cellular dysfunction. Patients suffer a progressive loss of motor and cognitive function with severe behavioural manifestations and premature death. There is currently no treatment. A spontaneously occurring mouse model of the disease has been described, that has approximately 3% of normal enzyme activity levels. Behavioural phenotyping of the MPS IIIA mouse has been previously reported, but the results are conflicting and variable, even after full backcrossing to the C57BL/6 background. Therefore we have independently backcrossed the MPS IIIA model onto the C57BL/6J background and evaluated the behaviour of male and female MPS IIIA mice at 4, 6 and 8 months of age using the open field test, elevated plus maze, inverted screen and horizontal bar crossing at the same circadian time point. Using a 60 minute open field, we have demonstrated that female MPS IIIA mice are hyperactive, have a longer path length, display rapid exploratory behaviour and spend less time immobile than WT mice. Female MPS IIIA mice also display a reduced sense of danger and spend more time in the centre of the open field. There were no significant differences found between male WT and MPS IIIA mice and no differences in neuromuscular strength were seen with either sex. The altered natural history of behaviour that we observe in the MPS IIIA mouse will allow more accurate evaluation of novel therapeutics for MPS IIIA and potentially other neurodegenerative disorders.

  11. Differentially Severe Cognitive Effects of Compromised Cerebral Blood Flow in Aged Mice: Association with Myelin Degradation and Microglia Activation

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    Gilly Wolf

    2017-06-01

    Full Text Available Bilateral common carotid artery stenosis (BCAS models the effects of compromised cerebral blood flow on brain structure and function in mice. We compared the effects of BCAS in aged (21 month and young adult (3 month female mice, anticipating a differentially more severe effect in the older mice. Four weeks after surgery there was a significant age by time by treatment interaction on the radial-arm water maze (RAWM; p = 0.014: on the first day of the test, latencies of old mice were longer compared to the latencies of young adult mice, independent of BCAS. However, on the second day of the test, latencies of old BCAS mice were significantly longer than old control mice (p = 0.049, while latencies of old controls were similar to those of the young adult mice, indicating more severe impairment of hippocampal dependent learning and working memory by BCAS in the older mice. Fluorescence staining of myelin basic protein (MBP showed that old age and BCAS both induced a significant decrease in fluorescence intensity. Evaluation of the number oligodendrocyte precursor cells demonstrated augmented myelin replacement in old BCAS mice (p < 0.05 compared with young adult BCAS and old control mice. While microglia morphology was assessed as normal in young adult control and young adult BCAS mice, microglia of old BCAS mice exhibited striking activation in the area of degraded myelin compared to young adult BCAS (p < 0.01 and old control mice (p < 0.05. These findings show a differentially more severe effect of cerebral hypoperfusion on cognitive function, myelin integrity and inflammatory processes in aged mice. Hypoperfusion may exacerbate degradation initiated by aging, which may induce more severe neuronal and cognitive phenotypes.

  12. Experimental transmission of M. leprae in the testis of mice, born from 131I-injected females

    International Nuclear Information System (INIS)

    Sushida, Kiyo

    1974-01-01

    Six strains of M. leprae taken from lepromatous leprosy patients were inoculated into the testes of '' 131 I-F 1 '' mice, which were divided into two groups. The first group was born of females which had been subcutaneously injected with 131 I-100 μc during pregnancy; the second group was born of females which had been injected before pregnancy. The '' 131 I-F 1 '' mice which were born of females injected with 131 I-100 μc, during pregnancy were then inoculated with leprous bacilli described above, showed the presence of the so-called ''globi'' in the testes. When samples of leprous bacilli (LL28, LL32, LL33) taken from patients who had not been receiving anti-leprous drug treatments were injected into the 131 I-F 1 mice, globi were also found. When leprous bacilli from leproma removed from patients under treatment were injected into mice born from females which had been injected with 131 I-100 μc either during or before their pregnancy, no globi were found. Even though bacilli (LL32, LL33, LL34) from untreated patients were injected into mice born of females who were injected with 131 I-100 μc before pregnancy, no globi were found. (auth.)

  13. Obesity-induced oxidative stress, accelerated functional decline with age and increased mortality in mice.

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    Zhang, Yiqiang; Fischer, Kathleen E; Soto, Vanessa; Liu, Yuhong; Sosnowska, Danuta; Richardson, Arlan; Salmon, Adam B

    2015-06-15

    Obesity is a serious chronic disease that increases the risk of numerous co-morbidities including metabolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality, leading some to suggest this condition represents accelerated aging. Obesity is associated with significant increases in oxidative stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and assessed both their changes in oxidative stress and in their performance in physiological assays known to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was significantly increased as was oxidative damage in vivo. High fat-feeding significantly accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, we also found that obesity had little effect on other markers of function and actually improved performance in grip strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal, functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some of the aging process. Published by Elsevier Inc.

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

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    Fei He

    Full Text Available Disorders of sexual development (DSD encompass a broad spectrum of urogenital malformations and are amongst the most common congenital birth defects. Although key genetic factors such as the hedgehog (Hh family have been identified, a unifying postnatally viable model displaying the spectrum of male and female urogenital malformations has not yet been reported. Since human cases are diagnosed and treated at various stages postnatally, equivalent mouse models enabling analysis at similar stages are of significant interest. Additionally, all non-Hh based genetic models investigating DSD display normal females, leaving female urogenital development largely unknown. Here, we generated compound mutant mice, Gli2+/-;Gli3Δ699/+, which exhibit a spectrum of urogenital malformations in both males and females upon birth, and also carried them well into adulthood. Analysis of embryonic day (E18.5 and adult mice revealed shortened anogenital distance (AGD, open ventral urethral groove, incomplete fusion of scrotal sac, abnormal penile size and structure, and incomplete testicular descent with hypoplasia in male mice, whereas female mutant mice displayed reduced AGD, urinary incontinence, and a number of uterine anomalies such as vaginal duplication. Male and female fertility was also investigated via breeding cages, and it was identified that male mice were infertile while females were unable to deliver despite becoming impregnated. We propose that Gli2+/-;Gli3Δ699/+ mice can serve as a genetic mouse model for common DSD such as cryptorchidism, hypospadias, and incomplete fusion of the scrotal sac in males, and a spectrum of uterine and vaginal abnormalities along with urinary incontinence in females, which could prove essential in revealing new insights into their equivalent diseases in humans.

  15. Chronic nicotine differentially alters spontaneous recovery of contextual fear in male and female mice.

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    Tumolo, Jessica M; Kutlu, Munir Gunes; Gould, Thomas J

    2018-04-02

    Post-traumatic stress disorder (PTSD) is a devastating disorder with symptoms such as flashbacks, hyperarousal, and avoidance of reminders of the traumatic event. Exposure therapy, which attempts to extinguish fear responses, is a commonly used treatment for PTSD but relapse following successful exposure therapy is a frequent problem. In rodents, spontaneous recovery (SR), where extinguished fear responses resurface following extinction treatment, is used as a model of fear relapse. Previous studies from our lab showed that chronic nicotine impaired fear extinction and acute nicotine enhanced SR of contextual fear in adult male mice. In addition, we showed that acute nicotine's effects were specific to SR as acute nicotine did not affect recall of contextual fear conditioning in the absence of extinction. However, effects of chronic nicotine administration on SR are not known. Therefore, in the present study, we investigated if chronic nicotine administration altered SR or recall of contextual fear in adult male and female C57BL/6J mice. Our results showed that chronic nicotine significantly enhanced SR in female mice and significantly decreased SR in males. Chronic nicotine had no effect on recall of contextual fear in males or females. Female sham mice also had significantly less baseline SR than male sham mice. Overall, these results demonstrate sex differences in SR of fear memories and that chronic nicotine modulates these effects on SR but nicotine does not alter recall of contextual fear. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Cognitive performance of male and female C57BL/6J mice after repetitive concussive brain injuries.

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    Velosky, Alexander G; Tucker, Laura B; Fu, Amanda H; Liu, Jiong; McCabe, Joseph T

    2017-05-01

    In contact sports, repetitive concussive brain injury (rCBI) is the prevalent form of head injury seen in athletes. The need for effective treatment is urgent as rCBI has been associated with a host of cognitive, behavioral and neurological complaints. There has been a growing trend in the use of female animals in pre-clinical research, but few studies have investigated possible sex differences following rCBI. The goal of the current study was to determine any differences between male and female C57BL/6J mice on assessments of learning and memory after repetitive concussive injury. Following rCBI by impact to the scalp, male mice exhibited longer righting reflexes during acute recovery. In both sexes, there were no evident histopathological changes observed in the underlying cerebral cortex or hippocampus. Reactive astrogliosis was elevated in the corpus callosum and optic tract, and astrogliosis was slightly less in the optic tract of female mice. rCBI mice exhibited impairment during the learning phase of the Morris water maze (MWM), but female mice, in comparison to male mice, were observed to have superior spatial memory during standard MWM probe trials. Female mice were overall more active, evidenced by greater distances traveled in the y-maze and greater swim speeds in the MWM. The results of this study demonstrate sex differences in cognitive performance following rCBI and support previous research suggesting the neuroprotective role of sex in brain injury. Published by Elsevier B.V.

  17. Tumor radiation responses and tumor oxygenation in aging mice

    International Nuclear Information System (INIS)

    Rockwell, S.

    1989-01-01

    EMT6 mouse mammary tumors transplanted into aging mice are less sensitive to radiation than tumors growing in young adult animals. The experiments reported here compare the radiation dose-response curves defining the survivals of tumor cells in aging mice and in young adult mice. Cell survival curves were assessed in normal air-breathing mice and in mice asphyxiated with N 2 to produce uniform hypoxia throughout the tumors. Analyses of survival curves revealed that 41% of viable malignant cells were severely hypoxic in tumors in aging mice, while only 19% of the tumor cells in young adult animals were radiobiologically hypoxic. This did not appear to reflect anaemia in the old animals. Treatment of aging animals with a perfluorochemical emulsion plus carbogen (95% O 2 /5% CO 2 ) increased radiation response of the tumors, apparently by improving tumor oxygenation and decreasing the number of severely hypoxic, radiation resistant cells in the tumors. (author)

  18. Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice.

    Science.gov (United States)

    Urzua, Ulises; Chacon, Carlos; Lizama, Luis; Sarmiento, Sebastián; Villalobos, Pía; Kroxato, Belén; Marcelain, Katherine; Gonzalez, María-Julieta

    2017-10-01

    Aging intersects with reproductive senescence in women by promoting a systemic low-grade chronic inflammation that predisposes women to several diseases including ovarian cancer (OC). OC risk at menopause is significantly modified by parity records during prior fertile life. To date, the combined effects of age and parity on the systemic inflammation markers that are particularly relevant to OC initiation and progression at menopause remain largely unknown. Herein, we profiled a panel of circulating cytokines in multiparous versus virgin C57BL/6 female mice at peri-estropausal age and investigated how cytokine levels were modulated by intraperitoneal tumor induction in a syngeneic immunocompetent OC mouse model. Serum FSH, LH and TSH levels increased with age in both groups while prolactin (PRL) was lower in multiparous respect to virgin mice, a finding previously observed in parous women. Serum CCL2, IL-10, IL-5, IL-4, TNF-α, IL1-β and IL-12p70 levels increased with age irrespective of parity status, but were specifically reduced following OC tumor induction only in multiparous mice. Animals developed hemorrhagic ascites and tumor implants in the omental fat band and other intraperitoneal organs by 12 weeks after induction, with multiparous mice showing a significantly extended survival. We conclude that previous parity history counteracts aging-associated systemic inflammation possibly by reducing the immunosuppression that typically allows tumor spread. Results suggest a partial impairment of the M2 shift in tumor-associated macrophages as well as decreased stimulation of regulatory B-cells in aged mice. This long term, tumor-concurrent effect of parity on inflammation markers at menopause would be a contributing factor leading to decreased OC risk.

  19. Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity

    International Nuclear Information System (INIS)

    Kong, Bo; Csanaky, Iván L.; Aleksunes, Lauren M.; Patni, Meghan; Chen, Qi; Ma, Xiaochao; Jaeschke, Hartmut; Weir, Scott; Broward, Melinda; Klaassen, Curtis D.; Guo, Grace L.

    2012-01-01

    Emerging evidence suggests that feeding a high-fat diet (HFD) to rodents affects the expression of genes involved in drug transport. However, gender-specific effects of HFD on drug transport are not known. The multidrug resistance-associated protein 2 (Mrp2, Abcc2) is a transporter highly expressed in the hepatocyte canalicular membrane and is important for biliary excretion of glutathione-conjugated chemicals. The current study showed that hepatic Mrp2 expression was reduced by HFD feeding only in female, but not male, C57BL/6J mice. In order to determine whether down-regulation of Mrp2 in female mice altered chemical disposition and toxicity, the biliary excretion and hepatotoxicity of the Mrp2 substrate, α-naphthylisothiocyanate (ANIT), were assessed in male and female mice fed control diet or HFD for 4 weeks. ANIT-induced biliary injury is a commonly used model of experimental cholestasis and has been shown to be dependent upon Mrp2-mediated efflux of an ANIT glutathione conjugate that selectively injures biliary epithelial cells. Interestingly, HFD feeding significantly reduced early-phase biliary ANIT excretion in female mice and largely protected against ANIT-induced liver injury. In summary, the current study showed that, at least in mice, HFD feeding can differentially regulate Mrp2 expression and function and depending upon the chemical exposure may enhance or reduce susceptibility to toxicity. Taken together, these data provide a novel interaction between diet and gender in regulating hepatobiliary excretion and susceptibility to injury. -- Highlights: ► High-fat diet decreases hepatic Mrp2 expression only in female but not in male mice. ► HFD significantly reduces early-phase biliary ANIT excretion in female mice. ► HFD protects female mice against ANIT-induced liver injury.

  20. Serum antibody responses by male and female C57Bl/6 mice infected with Giardia muris.

    Science.gov (United States)

    Daniels, C W; Belosevic, M

    1994-09-01

    We compared the levels of serum antibodies in male and female C57Bl/6 mice during the primary and after challenge infection with Giardia muris. Male mice began passing cysts in their faeces earlier than females, and were shedding cysts for over 60 days, while females stopped shedding cysts by day 20 after infection. In both males and females there were significant increases in parasite-specific IgM 10 and 20 days after infection. No differences in parasite-specific serum IgA were observed until 40 days after infection. Parasite-specific IgG (whole) levels were elevated on days 20 and 40 in females, while males showed no significant increases. In addition, females had a much stronger IgG2b and IgG3 response than males. After challenge with either cysts or soluble parasite protein only the females had significant increases in specific anti-parasite IgG2b. Our data show differential ability of males and females to control the infection with G. muris is paralleled by a difference in the anti-parasite serum IgG response of the mice.

  1. Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer's disease.

    Science.gov (United States)

    Zhao, Liqin; Mao, Zisu; Woody, Sarah K; Brinton, Roberta D

    2016-06-01

    Despite recent advances in the understanding of clinical aspects of sex differences in Alzheimer's disease (AD), the underlying mechanisms, for instance, how sex modifies AD risk and why the female brain is more susceptible to AD, are not clear. The purpose of this study is to elucidate sex disparities in brain aging profiles focusing on 2 major areas-energy and amyloid metabolism-that are most significantly affected in preclinical development of AD. Total RNA isolated from hippocampal tissues of both female and male 129/C57BL/6 mice at ages of 6, 9, 12, or 15 months were comparatively analyzed by custom-designed Taqman low-density arrays for quantitative real-time polymerase chain reaction detection of a total of 182 genes involved in a broad spectrum of biological processes modulating energy production and amyloid homeostasis. Gene expression profiles revealed substantial differences in the trajectory of aging changes between female and male brains. In female brains, 44.2% of genes were significantly changed from 6 months to 9 months and two-thirds showed downregulation. In contrast, in male brains, only 5.4% of genes were significantly altered at this age transition. Subsequent changes in female brains were at a much smaller magnitude, including 10.9% from 9 months to 12 months and 6.1% from 12 months to 15 months. In male brains, most changes occurred from 12 months to 15 months and the majority were upregulated. Furthermore, gene network analysis revealed that clusterin appeared to serve as a link between the overall decreased bioenergetic metabolism and increased amyloid dyshomeostasis associated with the earliest transition in female brains. Together, results from this study indicate that: (1) female and male brains follow profoundly dissimilar trajectories as they age; (2) female brains undergo age-related changes much earlier than male brains; (3) early changes in female brains signal the onset of a hypometabolic phenotype at risk for AD. These

  2. Efficacy of protocols for induction of chronic hyperthyroidism in male and female mice.

    Science.gov (United States)

    Engels, Kathrin; Rakov, Helena; Zwanziger, Denise; Hönes, Georg Sebastian; Rehders, Maren; Brix, Klaudia; Köhrle, Josef; Möller, Lars Christian; Führer, Dagmar

    2016-10-01

    Protocols for induction of hyperthyroidism in mice are highly variable and mostly involve short-term thyroid hormone (TH) treatment. In addition, little is known about a possible influence of sex on experimental TH manipulation. Here we analyzed the efficacy of intraperitoneal vs. oral levothyroxine (T4) administration to induce chronic hyperthyroidism in male and female mice and asked which T4 dosing intervals are required to achieve stable organ thyrotoxicosis. T4 was administered intraperitoneally or orally over a period of 6/7 weeks. Assessment included monitoring of body weight, TH serum concentrations, and serial quantitative TH target gene expression analysis in liver and heart. Our results show that both intraperitoneal and oral T4 treatment are reliable methods for induction of chronic hyperthyroidism in mice. Thereby T4 injection intervals should not exceed 48 h and oral levothyroxine should be administered continuously during experiments and up to sacrifice to ensure a hyperthyroid organ state. Furthermore, we found a sex-dependent variation in levothyroxine-induced TH serum state, with significantly higher T4 concentrations in female mice, while expression of investigated classical TH responsive genes in liver and heart did not vary with animal's sex. In summary, our study shows that common approaches for rendering rodents thyrotoxic can also be used for induction of chronic hyperthyroidism in male and female mice. Thereby T4 dosing intervals are critical as are read-out parameters to verify a chronic thyrotoxic organ state.

  3. Estradiol replacement enhances fear memory formation, impairs extinction and reduces COMT expression levels in the hippocampus of ovariectomized female mice.

    Science.gov (United States)

    McDermott, Carmel M; Liu, Dan; Ade, Catherine; Schrader, Laura A

    2015-02-01

    Females experience depression, posttraumatic stress disorder (PTSD), and anxiety disorders at approximately twice the rate of males, but the mechanisms underlying this difference remain undefined. The effect of sex hormones on neural substrates presents a possible mechanism. We investigated the effect of ovariectomy at two ages, before puberty and in adulthood, and 17β-estradiol (E2) replacement administered chronically in drinking water on anxiety level, fear memory formation, and extinction. Based on previous studies, we hypothesized that estradiol replacement would impair fear memory formation and enhance extinction rate. Females, age 4 weeks and 10 weeks, were divided randomly into 4 groups; sham surgery, OVX, OVX+low E2 (200nM), and OVX+high E2 (1000nM). Chronic treatment with high levels of E2 significantly increased anxiety levels measured in the elevated plus maze. In both age groups, high levels of E2 significantly increased contextual fear memory but had no effect on cued fear memory. In addition, high E2 decreased the rate of extinction in both ages. Finally, catechol-O-methyltransferase (COMT) is important for regulation of catecholamine levels, which play a role in fear memory formation and extinction. COMT expression in the hippocampus was significantly reduced by high E2 replacement, implying increased catecholamine levels in the hippocampus of high E2 mice. These results suggest that estradiol enhanced fear memory formation, and inhibited fear memory extinction, possibly stabilizing the fear memory in female mice. This study has implications for a neurobiological mechanism for PTSD and anxiety disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Peripheral surgical wounding and age-dependent neuroinflammation in mice.

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    Zhipeng Xu

    Full Text Available Post-operative cognitive dysfunction is associated with morbidity and mortality. However, its neuropathogenesis remains largely to be determined. Neuroinflammation and accumulation of β-amyloid (Aβ have been reported to contribute to cognitive dysfunction in humans and cognitive impairment in animals. Our recent studies have established a pre-clinical model in mice, and have found that the peripheral surgical wounding without the influence of general anesthesia induces an age-dependent Aβ accumulation and cognitive impairment in mice. We therefore set out to assess the effects of peripheral surgical wounding, in the absence of general anesthesia, on neuroinflammation in mice with different ages. Abdominal surgery under local anesthesia was established in 9 and 18 month-old mice. The levels of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, Iba1 positive cells (the marker of microglia activation, CD33, and cognitive function in mice were determined. The peripheral surgical wounding increased the levels of TNF-α, IL-6, and Iba1 positive cells in the hippocampus of both 9 and 18 month-old mice, and age potentiated these effects. The peripheral surgical wounding increased the levels of CD33 in the hippocampus of 18, but not 9, month-old mice. Finally, anti-inflammatory drug ibuprofen ameliorated the peripheral surgical wounding-induced cognitive impairment in 18 month-old mice. These data suggested that the peripheral surgical wounding could induce an age-dependent neuroinflammation and elevation of CD33 levels in the hippocampus of mice, which could lead to cognitive impairment in aged mice. Pending further studies, anti-inflammatory therapies may reduce the risk of postoperative cognitive dysfunction in elderly patients.

  5. Female nursing partner choice in a population of wild house mice (Mus musculus domesticus).

    Science.gov (United States)

    Harrison, Nicola; Lindholm, Anna K; Dobay, Akos; Halloran, Olivia; Manser, Andri; König, Barbara

    2018-01-01

    Communal nursing in house mice is an example of cooperation where females pool litters in the same nest and indiscriminately nurse own and other offspring despite potential exploitation. The direct fitness benefits associated with communal nursing shown in laboratory studies suggest it to be a selected component of female house mice reproductive behaviour. However, past studies on communal nursing in free-living populations have debated whether it is a consequence of sharing the same nest or an active choice. Here using data from a long-term study of free-living, wild house mice we investigated individual nursing decisions and determined what factors influenced a female's decision to nurse communally. Females chose to nurse solitarily more often than expected by chance, but the likelihood of nursing solitarily decreased when females had more partners available. While finding no influence of pairwise relatedness on partner choice, we observed that females shared their social environment with genetically similar individuals, suggesting a female's home area consisted of related females, possibly facilitating the evolution of cooperation. Within such a home area females were more likely to nest communally when the general relatedness of her available options was relatively high. Females formed communal nests with females that were familiar through previous associations and had young pups of usually less than 5 days old. Our findings suggest that communal nursing was not a by-product of sharing the same nesting sites, but females choose communal nursing partners from a group of genetically similar females, and ultimately the decision may then depend on the pool of options available. Social partner choice proved to be an integrated part of cooperation among females, and might allow females to reduce the conflict over number of offspring in a communal nest and milk investment towards own and other offspring. We suggest that social partner choice may be a general

  6. The Effect of a High-Fat Diet on Brain Plasticity, Inflammation and Cognition in Female ApoE4-Knockin and ApoE-Knockout Mice.

    Directory of Open Access Journals (Sweden)

    Carola I F Janssen

    Full Text Available Apolipoprotein E4 (ApoE4, one of three common isoforms of ApoE, is a major risk factor for late-onset Alzheimer disease (AD. ApoE-deficient mice, as well as mice expressing human ApoE4, display impaired learning and memory functions and signs of neurodegeneration. Moreover, ApoE protects against high-fat (HF diet induced neurodegeneration by its role in the maintenance of the integrity of the blood-brain barrier. The influence of a HF diet on the progression of AD-like cognitive and neuropathological changes was assessed in wild-type (WT, human ApoE4 and ApoE-knockout (ApoE-/- mice to evaluate the modulatory role of ApoE in this process. From 12 months of age, female WT, ApoE4, and ApoE-/- mice were fed either a standard or a HF diet (19% butter, 0.5% cholate, 1.25% cholesterol throughout life. At 15 months of age mice performed the Morris water maze, evaluating spatial learning and memory. ApoE-/- showed increased spatial learning compared to WT mice (p = 0.009. HF diet improved spatial learning in WT mice (p = 0.045, but did not affect ApoE4 and ApoE-/- mice. Immunohistochemical analyses of the hippocampus demonstrated increased neuroinflammation (CD68 in the cornu ammonis 1 (CA1 region in ApoE4 (p = 0.001 and in ApoE-/- (p = 0.032 mice on standard diet. HF diet tended to increase CD68 in the CA1 in WT mice (p = 0.052, while it decreased in ApoE4 (p = 0.009, but ApoE-/- remained unaffected. A trend towards increased neurogenesis (DCX was found in both ApoE4 (p = 0.052 and ApoE-/- mice (p = 0.068. In conclusion, these data suggest that HF intake induces different effects in WT mice compared to ApoE4 and ApoE-/- with respect to markers for cognition and neurodegeneration. We propose that HF intake inhibits the compensatory mechanisms of neuroinflammation and neurogenesis in aged female ApoE4 and ApoE-/- mice.

  7. Administration of red ginseng ameliorates memory decline in aged mice.

    Science.gov (United States)

    Lee, Yeonju; Oh, Seikwan

    2015-07-01

    It has been known that ginseng can be applied as a potential nutraceutical for memory impairment; however, experiments with animals of old age are few. To determine the memory enhancing effect of red ginseng, C57BL/6 mice (21 mo old) were given experimental diet pellets containing 0.12% red ginseng extract (approximately 200 mg/kg/d) for 3 mo. Young and old mice (4 mo and 21 mo old, respectively) were used as the control group. The effect of red ginseng, which ameliorated memory impairment in aged mice, was quantified using Y-maze test, novel objective test, and Morris water maze. Red ginseng ameliorated age-related declines in learning and memory in older mice. In addition, red ginseng's effect on the induction of inducible nitric oxide synthase and proinflammatory cytokines was investigated in the hippocampus of aged mice. Red ginseng treatment suppressed the production of age-processed inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-1β expressions. Moreover, it was observed that red ginseng had an antioxidative effect on aged mice. The suppressed glutathione level in aged mice was restored with red ginseng treatment. The antioxidative-related enzymes Nrf2 and HO-1 were increased with red ginseng treatment. The results revealed that when red ginseng is administered over long periods, age-related decline of learning and memory is ameliorated through anti-inflammatory activity.

  8. Potential contribution of progesterone receptors to the development of sexual behavior in male and female mice.

    Science.gov (United States)

    Desroziers, Elodie; Brock, Olivier; Bakker, Julie

    2017-04-01

    We previously showed that estradiol can have both defeminizing and feminizing effects on the developing mouse brain. Pre- and early postnatal estradiol defeminized the ability to show lordosis in adulthood, whereas prepubertal estradiol feminized this ability. Furthermore, we found that estradiol upregulates progesterone receptors (PR) during development, inducing both a male-and female-typical pattern of PR expression in the mouse hypothalamus. In the present study, we took advantage of a newly developed PR antagonist (ZK 137316) to determine whether PR contributes to either male- or female-typical sexual differentiation. Thus groups of male and female C57Bl/6j mice were treated with ZK 137316 or OIL as control: males were treated neonatally (P0-P10), during the critical period for male sexual differentiation, and females were treated prepubertally (P15-P25), during the critical period for female sexual differentiation. In adulthood, mice were tested for sexual behavior. In males, some minor effects of neonatal ZK treatment on sexual behavior were observed: latencies to the first mount, intromission and ejaculation were decreased in neonatally ZK treated males; however, this effect disappeared by the second mating test. By contrast, female mice treated with ZK during the prepubertal period showed significantly less lordosis than OIL-treated females. Mate preferences were not affected in either males or females treated with ZK during development. Taken together, these results suggest a role for PR and thus perhaps progesterone in the development of lordosis behavior in female mice. By contrast, no obvious role for PR can be discerned in the development of male sexual behavior. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. The ZEB1 Transcription Factor Is a Novel Repressor of Adiposity in Female Mice

    Science.gov (United States)

    Saykally, Jessica N.; Dogan, Soner; Cleary, Margot P.; Sanders, Michel M.

    2009-01-01

    Background Four genome-wide association studies mapped an “obesity” gene to human chromosome 10p11–12. As the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor is encoded by the TCF8 gene located in that region, and as it influences the differentiation of various mesodermal lineages, we hypothesized that ZEB1 might also modulate adiposity. The goal of these studies was to test that hypothesis in mice. Methodology/Principal Findings To ascertain whether fat accumulation affects ZEB1 expression, female C57BL/6 mice were fed a regular chow diet (RCD) ad libitum or a 25% calorie-restricted diet from 2.5 to 18.3 months of age. ZEB1 mRNA levels in parametrial fat were six to ten times higher in the obese mice. To determine directly whether ZEB1 affects adiposity, wild type (WT) mice and mice heterozygous for TCF8 (TCF8+/−) were fed an RCD or a high-fat diet (HFD) (60% calories from fat). By two months of age on an HFD and three months on an RCD, TCF8+/− mice were heavier than WT controls, which was attributed by Echo MRI to increased fat mass (at three months on an HFD: 0.517±0.081 total fat/lean mass versus 0.313±0.036; at three months on an RCD: 0.175±0.013 versus 0.124±0.012). No differences were observed in food uptake or physical activity, suggesting that the genotypes differ in some aspect of their metabolic activity. ZEB1 expression also increases during adipogenesis in cell culture. Conclusion/Significance These results show for the first time that the ZEB1 transcription factor regulates the accumulation of adipose tissue. Furthermore, they corroborate the genome-wide association studies that mapped an “obesity” gene at chromosome 10p11–12. PMID:20041147

  10. Age and sex dependence in tumorigenesis in mice by continuous low-dose-rate gamma-ray whole-body irradiation

    International Nuclear Information System (INIS)

    Otsu, Hiroshi; Kobayashi, Shigeru; Furuse, Takeshi; Noda, Yuko; Shiragai, Akihiro; Sato, Fumiaki.

    1992-01-01

    We investigated the dependency of sex and age in mice in the induction of neoplasms by gamma-rays from cesium-137 at a low dose rate of 0.375Gy/22h/day. Thymic lymphomas occurred significantly at the same incidence in both sexes, and more frequently when younger mice were exposed to radiation. Strain C57BL/6J mice were divided into 8 groups, which were whole-body irradiated with a total dose of 39Gy for 105 days each. The exposure was begun at 28 days of age (male:AM1, female:AF1), and then stepwise increasing the starting age by 105 days, i.e., from 133 days (AM2 and AF2), from 238 days (AM3 and AF3), and from 343 days (AM4 and AF4), respectively. Unirradiated mice served as control (UM and UF). The incidence of thymic lymphomas was about 60 % in AM1, AM2, AF1 and AF2, 40 % in AM3 and AF3 and 20 % in AF4 and AF4, demonstrating no sex dependency, but a distinct age dependency, for lymphomogenesis. It was proven that mice showed a tendency to become less susceptible to radiation induced thymic lymphoma with increasing age. Concomitantly, life-shortening also was caused, and the greater the degree of life-shortening was, the younger the mice were the start of exposure. Life-shortening was attributed to thymic lymphoma, and hemorrhage and infectious diseases due to the depletion of bone marrow cells. (author)

  11. Comparison of Neurological Function in Males and Females from Two Substrains of C57BL/6 Mice

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    Amy Ashworth

    2014-12-01

    Full Text Available The C57BL/6 (B6 mouse is the background strain most frequently used for genetically-modified mice. Previous studies have found significant behavioral and genetic differences between the B6J (The Jackson Laboratory and B6N substrains (National Institutes of Health; however, most studies employed only male mice. We performed a comprehensive battery of motor function and learning and memory tests on male and female mice from both substrains. The B6N male mice had greater improvement in the rotarod test. In contrast, B6J female mice had longer latencies to falling from the rotarod. In the Morris water maze (MWM, B6J males had significantly shorter latencies to finding the hidden platform. However, B6N females had significantly shorter path lengths in the reversal and shifted-reduced phases. In open field locomotor activity, B6J males had higher activity levels, whereas B6N females took longer to habituate. In the fear conditioning test, B6N males had a significantly longer time freezing in the new context compared with B6J males, but no significant differences were found in contextual or cued tests. In summary, our findings demonstrate the importance of testing both males and females in neurobehavioral studies. Both factors (sex and substrain must be taken into account when designing developmental neurotoxicology studies.

  12. Male mice emit distinct ultrasonic vocalizations when the female leaves the social interaction arena

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    Mu eYang

    2013-11-01

    Full Text Available Adult male mice emit large number of complex ultrasonic vocalizations (USVs when interacting with adult females. Call numbers and call categories differ greatly among inbred mouse strains. Little is known about USV emissions when the social partner departs. To investigate whether call repertoires and call rates are different when the male is interacting with a female and after the removal of the female, we designed a novel male-female social interaction test in which vocalizations were recorded across three phases. During phase 1, the male subject freely interacts with an unfamiliar estrus female mouse in a clean cage for 5 minutes. During phase 2, the female is removed while the male remains in the cage for 3 minutes. During phase 3, the same female is returned to the cage to rejoin the male subject mouse for 3 minutes. C57BL/6J (B6, FVB.129P2-Pde6b(+ Tyr(c-ch/Ant (FVB, and BTBR T+ tf/J (BTBR male subject mice were tested in this paradigm. All three strains emitted USVs during the absence of the estrous female, although at lower rates. When the female was reintroduced in phase 3, numbers of USVs were similar to the initial introductory phase 1. Strain comparisons indicated fewer calls in pairs of BTBR males and stimulus females than in pairs of B6 males and stimulus females and pairs of FVB males and stimulus females. In the absence of the female, all FVB males vocalized, while only one third of B6 males and one third of BTBR males vocalized. In all three strains, changes in call repertoires were detected after the female was removed. Call categories reverted to the phase 1 pattern when the female was returned in phase 3. Present findings indicate that males of commonly used inbred strains emit USVs when a partner female leaves the testing arena, suggesting that removing a salient social stimulus may be a unique approach to elicit USVs from mice. Our three-phase paradigm may also be useful for studying attention to social cues, and qualitative

  13. The Effects of Dietary Macronutrient Balance on Skin Structure in Aging Male and Female Mice

    Science.gov (United States)

    McMahon, Aisling C.; Ruohonen, Kari; Raubenheimer, David; Ballard, J. William O.; Le Couteur, David G.; Nicholls, Caroline; Li, Zhe; Maitz, Peter K. M.; Wang, Yiwei; Simpson, Stephen J.

    2016-01-01

    Nutrition influences skin structure; however, a systematic investigation into how energy and macronutrients (protein, carbohydrate and fat) affects the skin has yet to be conducted. We evaluated the associations between macronutrients, energy intake and skin structure in mice fed 25 experimental diets and a control diet for 15 months using the Geometric Framework, a novel method of nutritional analysis. Skin structure was associated with the ratio of dietary macronutrients eaten, not energy intake, and the nature of the effect differed between the sexes. In males, skin structure was primarily associated with protein intake, whereas in females carbohydrate intake was the primary correlate. In both sexes, the dermis and subcutaneous fat thicknesses were inversely proportional. Subcutaneous fat thickness varied positively with fat intake, due to enlarged adipocytes rather than increased adipocyte number. We therefore demonstrated clear interactions between skin structure and macronutrient intakes, with the associations being sex-specific and dependent on dietary macronutrient balance. PMID:27832138

  14. Citalopram Ameliorates Impairments in Spatial Memory and Synaptic Plasticity in Female 3xTgAD Mice

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    Zhang Wei

    2017-01-01

    Full Text Available Alzheimer’s disease (AD is the primary cause of dementia. There is no effective treatment. Amyloid-β peptide (Aβ plays an important role in the pathogenesis and thus strategies suppressing Aβ production and accumulation seem promising. Citalopram is an antidepressant drug and can decrease Aβ production and amyloid plaques in transgenic mice of AD and humans. Whether citalopram can ameliorate memory deficit was not known yet. We tested the effects of citalopram on behavioral performance and synaptic plasticity in female 3xTgAD mice, a well-characterized model of AD. Mice were treated with citalopram or water from 5 months of age for 3 months. Citalopram treatment at approximately 10 mg/kg/day significantly improved spatial memory in the Morris water maze (MWM test, while not affecting anxiety-like and depression-like behavior in 3xTgAD mice. Further, hippocampal long-term potentiation (LTP impairment in 3xTgAD mice was reversed by citalopram treatment. Citalopram treatment also significantly decreased the levels of insoluble Aβ40 in hippocampal and cortical tissues in 3xTgAD mice, accompanied with a reduced amyloid precursor protein (APP. Together, citalopram treatment may be a promising strategy for AD and further clinical trials should be conducted to verify the effect of citalopram on cognition in patients with AD or mild cognitive impairment.

  15. DEHP exposure in utero disturbs sex determination and is potentially linked with precocious puberty in female mice

    International Nuclear Information System (INIS)

    Wang, Yongan; Yang, Qing; Liu, Wei; Yu, Mingxi; Zhang, Zhou; Cui, Xiaoyu

    2016-01-01

    Human's ubiquitous exposure to di (2-ethylhexyl) phthalate (DEHP) is thought to be associated with female reproductive toxicity. Previous studies found that DEHP inhibited follicle growth and decreased estradiol levels in adult female mice. However, limited information is available on the link between in utero DEHP exposure and ovarian development in female mouse offspring. The present study evaluates the disturbances in regulatory genes involved in female sex determination and the ovarian outcomes in fetal and postnatal female mice treated with in utero DEHP exposure. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposure levels. After in utero DEHP exposure, increased follicular atresia was observed in the female pups at postnatal days (PND) 21. Foxl2 expression was significantly upregulated, and Fst was significantly downregulated by DEHP above 2 mg/kg/d at PND 1 and 21. This suggests that lesion of granulosa cell differentiation and disturbance of follicle development in postnatal female mice. The expression of Cyp11a1 and Star were significantly downregulated by in utero DEHP exposure, indicating effects on estradiol biosynthesis. The female sex determination pathway was disturbed in fetus by DEHP at 2 mg/kg/d and above during the critical time window of sex determination causing significant upregulation of Foxl2, Wnt4, β-catenin and Fst. Furthermore, the increased expression of Wnt4 was supported by whole-mount in situ hybridization (WISH). These results suggest a possible association between in utero DEHP exposure and precocious puberty in the postnatal life of mice offspring, where disturbance of the sex determination regulating pathway acted as an important mechanism. - Highlights: • Maternal exposure to di (2-ethylhexyl) phthalate disturbs fetus sex determination. • DEHP upregulated Foxl2 expression potentially disturbs postnatal granulosa cell differentiation. • DEHP accelerated medulla

  16. DEHP exposure in utero disturbs sex determination and is potentially linked with precocious puberty in female mice

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yongan [Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024 (China); Yang, Qing [School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024 (China); Liu, Wei, E-mail: liu_wei@dlut.edu.cn [Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024 (China); Yu, Mingxi; Zhang, Zhou; Cui, Xiaoyu [Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024 (China)

    2016-09-15

    Human's ubiquitous exposure to di (2-ethylhexyl) phthalate (DEHP) is thought to be associated with female reproductive toxicity. Previous studies found that DEHP inhibited follicle growth and decreased estradiol levels in adult female mice. However, limited information is available on the link between in utero DEHP exposure and ovarian development in female mouse offspring. The present study evaluates the disturbances in regulatory genes involved in female sex determination and the ovarian outcomes in fetal and postnatal female mice treated with in utero DEHP exposure. Pregnant mice were exposed to DEHP by gavage, with the dosage regime beginning at human relevant exposure levels. After in utero DEHP exposure, increased follicular atresia was observed in the female pups at postnatal days (PND) 21. Foxl2 expression was significantly upregulated, and Fst was significantly downregulated by DEHP above 2 mg/kg/d at PND 1 and 21. This suggests that lesion of granulosa cell differentiation and disturbance of follicle development in postnatal female mice. The expression of Cyp11a1 and Star were significantly downregulated by in utero DEHP exposure, indicating effects on estradiol biosynthesis. The female sex determination pathway was disturbed in fetus by DEHP at 2 mg/kg/d and above during the critical time window of sex determination causing significant upregulation of Foxl2, Wnt4, β-catenin and Fst. Furthermore, the increased expression of Wnt4 was supported by whole-mount in situ hybridization (WISH). These results suggest a possible association between in utero DEHP exposure and precocious puberty in the postnatal life of mice offspring, where disturbance of the sex determination regulating pathway acted as an important mechanism. - Highlights: • Maternal exposure to di (2-ethylhexyl) phthalate disturbs fetus sex determination. • DEHP upregulated Foxl2 expression potentially disturbs postnatal granulosa cell differentiation. • DEHP accelerated medulla

  17. Analysis of mice radiosensitivity depending on age

    International Nuclear Information System (INIS)

    Bogatyrev, A.V.; Timoshenko, S.I.; Nikanorova, N.G.; Sverdlov, A.G.

    1979-01-01

    In order to elucidate mechanisms of age variations in radiosensitivity of mice a study was made of the sensitivity of in vitro irradiated bone marrow stem cells, taken from animals of different age, and postradiation recovery of leukocyte content of peripheral blood and cellularity of bone marrow and spleen. Using the method of spleen colonies similar affections were revealed in bone marrow cells of animals of different age. The degree of recovery of the hemopoietic cell pool was significantly lower in newborn mice than in adults after exposure to a dose (LDsub(50/30)) equally effective with respect to mortality

  18. Reduced anxiety-like behavior and altered hippocampal morphology in female p75NTR exon IV-/- mice.

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    Zoe ePuschban

    2016-06-01

    Full Text Available The presence of the neurotrophin receptor p75NTR in adult basal forebrain cholinergic neurons, precursor cells in the subventricular cell layer and the subgranular cell layer of the hippocampus has been linked to alterations in learning as well as anxiety- and depression- related behaviors. In contrast to previous studies performed in a p75NTR exonIII-/- model still expressing the short isoform of the p75NTR, we focused on locomotor and anxiety–associated behavior in p75NTR exonIV-/- mice lacking both p75NTR isoforms. Comparing p75NTR exonIV-/- and wildtype mice for both male and female animals showed an anxiolytic-like behavior as evidenced by increased central activities in the open field paradigm and flex field activity system as well as higher numbers of open arm entries in the elevated plus maze test in female p75NTR knockout mice.Morphometrical analyses of dorsal and ventral hippocampus revealed a reduction of width of the dentate gyrus and the granular cell layer in the dorsal but not ventral hippocampus in male and female p75NTR exonIV -/- mice. We conclude that germ-line deletion of p75NTR seems to differentially affect morphometry of dorsal and ventral dentate gyrus and that p75NTR may play a role in anxiety-like behavior, specifically in female mice.

  19. Association between Diastolic Dysfunction with Inflammation and Oxidative Stress in Females ob/ob Mice

    Science.gov (United States)

    Sartori, Michelle; Conti, Filipe F.; Dias, Danielle da Silva; dos Santos, Fernando; Machi, Jacqueline F.; Palomino, Zaira; Casarini, Dulce E.; Rodrigues, Bruno; De Angelis, Kátia; Irigoyen, Maria-Claudia

    2017-01-01

    Objective: To evaluate autonomic and cardiovascular function, as well as inflammatory and oxidative stress markers in ob/ob female mice. Methods: Metabolic parameters, cardiac function, arterial pressure (AP), autonomic, hormonal, inflammatory, and oxidative stress markers were evaluated in 12-weeks female wild-type (WT group) and ob/ob mice (OB group). Results: OB animals showed increased body weight, blood glucose, and triglyceride levels, along with glucose intolerance, when compared to WT animals. Ejection fraction (EF) and AP were similar between groups; however, the OB group presented diastolic dysfunction, as well as an impairment on myocardial performance index. Moreover, the OB group exhibited important autonomic dysfunction and baroreflex sensitivity impairment, when compared to WT group. OB group showed increased Angiotensin II levels in heart and renal tissues; decreased adiponectin and increased inflammatory markers in adipose tissue and spleen. Additionally, OB mice presented a higher damage to proteins and lipoperoxidation and lower activity of antioxidant enzymes in kidney and heart. Correlations were found between autonomic dysfunction with angiotensin II and inflammatory mediators, as well as between inflammation and oxidative stress. Conclusions: Our results showed that female adult ob/ob mice presented discrete diastolic dysfunction accompanied by autonomic disorder, which is associated with inflammation and oxidative stress in these animals. PMID:28878683

  20. Association between Diastolic Dysfunction with Inflammation and Oxidative Stress in Females ob/ob Mice

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    Michelle Sartori

    2017-08-01

    Full Text Available Objective: To evaluate autonomic and cardiovascular function, as well as inflammatory and oxidative stress markers in ob/ob female mice.Methods: Metabolic parameters, cardiac function, arterial pressure (AP, autonomic, hormonal, inflammatory, and oxidative stress markers were evaluated in 12-weeks female wild-type (WT group and ob/ob mice (OB group.Results: OB animals showed increased body weight, blood glucose, and triglyceride levels, along with glucose intolerance, when compared to WT animals. Ejection fraction (EF and AP were similar between groups; however, the OB group presented diastolic dysfunction, as well as an impairment on myocardial performance index. Moreover, the OB group exhibited important autonomic dysfunction and baroreflex sensitivity impairment, when compared to WT group. OB group showed increased Angiotensin II levels in heart and renal tissues; decreased adiponectin and increased inflammatory markers in adipose tissue and spleen. Additionally, OB mice presented a higher damage to proteins and lipoperoxidation and lower activity of antioxidant enzymes in kidney and heart. Correlations were found between autonomic dysfunction with angiotensin II and inflammatory mediators, as well as between inflammation and oxidative stress.Conclusions: Our results showed that female adult ob/ob mice presented discrete diastolic dysfunction accompanied by autonomic disorder, which is associated with inflammation and oxidative stress in these animals.

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

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    Michele La Merrill

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

  2. Perinatal Exposure of Mice to the Pesticide DDT Impairs Energy Expenditure and Metabolism in Adult Female Offspring

    Science.gov (United States)

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

    2014-01-01

    Dichlorodiphenyltrichloroethane (DDT) has been used extensively to control malaria, typhus, body lice and bubonic plague worldwide, until countries began restricting its use in the 1970s. Its use in malaria control continues in some countries according to recommendation by the World Health Organization. Individuals exposed to elevated levels of DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) have an increased prevalence of diabetes and insulin resistance. Here we hypothesize that perinatal exposure to DDT disrupts metabolic programming leading to impaired metabolism in adult offspring. To test this, we administered DDT to C57BL/6J mice from gestational day 11.5 to postnatal day 5 and studied their metabolic phenotype at several ages up to nine months. Perinatal DDT exposure reduced core body temperature, impaired cold tolerance, decreased energy expenditure, and produced a transient early-life increase in body fat in female offspring. When challenged with a high fat diet for 12 weeks in adulthood, female offspring perinatally exposed to DDT developed glucose intolerance, hyperinsulinemia, dyslipidemia, and altered bile acid metabolism. Perinatal DDT exposure combined with high fat feeding in adulthood further impaired thermogenesis as evidenced by reductions in core temperature and in the expression of numerous RNA that promote thermogenesis and substrate utilization in the brown adipose tissue of adult female mice. These observations suggest that perinatal DDT exposure impairs thermogenesis and the metabolism of carbohydrates and lipids which may increase susceptibility to the metabolic syndrome in adult female offspring. PMID:25076055

  3. Efficacy of Tramadol as a Sole Analgesic for Postoperative Pain in Male and Female Mice.

    Science.gov (United States)

    Wolfe, A Marissa; Kennedy, Lucy H; Na, Jane J; Nemzek-Hamlin, Jean A

    2015-07-01

    Tramadol is a centrally acting weak μ opioid agonist that has few of the adverse side effects common to other opioids. Little work has been done to establish an effective analgesic dose of tramadol specific for surgical laparotomy and visceral manipulation in mice. We used general appearance parameters to score positive indicators of pain including posture, coat condition, activity, breathing, and interactions with other mice, activity events (that is, the number of times each mouse stretched up in a 3-min period) used as an indicator of decreased pain, von Frey fibers, and plasma levels of corticosterone to determine whether tramadol at 20, 40, or 80 mg/kg prevented postoperative pain in male and female C57BL/6 mice. A ventral midline laparotomy with typhlectomy was used as a model of postoperative pain. In male mice, none of the markers differed between groups that received tramadol (regardless of dose) and the saline-treated controls. However, general appearance scores and plasma corticosterone levels were lower in female mice that received 80 mg/kg tramadol compared with saline. In summary, for severe postoperative pain after laparotomy and aseptic typhlectomy, tramadol was ineffective in male C57BL/6 mice at all doses tested. Although 80 mg/kg ameliorated postoperative pain in female C57BL/6 mice, this dose is very close to the threshold reported to cause toxic side effects, such as tremors and seizures. Therefore, we do not recommend the use of tramadol as a sole analgesic in this mouse model of postoperative pain.

  4. Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice.

    Science.gov (United States)

    Liang, Zhe; Xie, Yan; Dominguez, Jessica A; Breed, Elise R; Yoseph, Benyam P; Burd, Eileen M; Farris, Alton B; Davidson, Nicholas O; Coopersmith, Craig M

    2014-01-01

    Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO) exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8-10 week) Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis. Aged (20-24 months) Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival. In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005). Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice. Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.

  5. Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice.

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    Zhe Liang

    Full Text Available Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8-10 week Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis.Aged (20-24 months Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival.In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005. Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice.Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.

  6. Exercise capacity and cardiac hemodynamic response in female ApoE/LDLR−/− mice: a paradox of preserved V’O2max and exercise capacity despite coronary atherosclerosis

    Science.gov (United States)

    Wojewoda, M.; Tyrankiewicz, U.; Gwozdz, P.; Skorka, T.; Jablonska, M.; Orzylowska, A.; Jasinski, K.; Jasztal, A.; Przyborowski, K.; Kostogrys, R. B.; Zoladz, J. A.; Chlopicki, S.

    2016-01-01

    We assessed exercise performance, coronary blood flow and cardiac reserve of female ApoE/LDLR−/− mice with advanced atherosclerosis compared with age-matched, wild-type C57BL6/J mice. Exercise capacity was assessed as whole body maximal oxygen consumption (V’O2max), maximum running velocity (vmax) and maximum distance (DISTmax) during treadmill exercise. Cardiac systolic and diastolic function in basal conditions and in response to dobutamine (mimicking exercise-induced cardiac stress) were assessed by Magnetic Resonance Imaging (MRI) in vivo. Function of coronary circulation was assessed in isolated perfused hearts. In female ApoE/LDLR−/− mice V’O2max, vmax and DISTmax were not impaired as compared with C57BL6/J mice. Cardiac function at rest and systolic and diastolic cardiac reserve were also preserved in female ApoE/LDLR−/− mice as evidenced by preserved fractional area change and similar fall in systolic and end diastolic area after dobutamine. Moreover, endothelium-dependent responses of coronary circulation induced by bradykinin (Bk) and acetylcholine (ACh) were preserved, while endothelium-independent responses induced by NO-donors were augmented in female ApoE/LDLR−/− mice. Basal COX-2-dependent production of 6-keto-PGF1α was increased. Concluding, we suggest that robust compensatory mechanisms in coronary circulation involving PGI2- and NO-pathways may efficiently counterbalance coronary atherosclerosis-induced impairment in V’O2max and exercise capacity. PMID:27108697

  7. Interaction between Sex Hormones and Matricaria Chamomilla Hydroalcholic Extract on Motor Activity Behavior in Gonadectomized Male and Female Mice

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    H. Raie

    2006-04-01

    Full Text Available Introduction & Objective: Locomotor activity is an important physiologic phenomenon that is influenced by several factors. In previous study we showed that the matricaria chamomilla (chamomile hydroalcholic extract acts differently in male and female mice. Therefore in this study, the role of sex hormones and chamomile hydroalcholic extract were investigated on motor activity behavior in absence of sex glands in adult male and female NMRI mice. Materials and Methods: Gonadectomized male and female mice were divided into groups (seven mice in each group including: receiving testosterone (2 mg/kg S.C., estradiol benzoate (0.1 mg/kg S.C., and progesterone (0.5 mg/kg S.C. with and without hydroalcholic extract of chamomile (50 mg/kg i.p. Motor activity monitor system was used to evaluate locomotor activity parameters (fast and slow activity, fast and slow stereotype activity, fast and slow rearing in all groups. Results: 1 Testosterone had no any effect on motor activity parameters, but extract of chamomile with and without testosterone decreased motor activity parameters in male mice. 2 Estradiol benzoate and chamomile hydroalcholic extract in presence and absence of each other increased locomotor activity parameters in female mice. 3 Progesterone also did not change motor activity parameters in presence and absence of chamomile hydroalcholic extract in female mice. 4 Administration of Estradiol benzoate with progestrone in presence and absence of chamomile hydroalcholic extract did not alter motor activity parameters in female mice. Conclusion: It seems both of the chamomile hydroalcholic extract and estradiol enhance motor activity and probably act through same system and potentiate the effect of each other. Also it seems there are interaction between estradiol and progesterone and also between chamomile extract and progesterone. Testosterone probably did not have any interaction with chamomile extract in locomotor activity.

  8. Age-dependent Changes in the Articular Cartilage and Subchondral Bone of C57BL/6 Mice after Surgical Destabilization of Medial Meniscus.

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    Huang, Henry; Skelly, Jordan D; Ayers, David C; Song, Jie

    2017-02-09

    Age is the primary risk factor for osteoarthritis (OA), yet surgical OA mouse models such as destabilization of the medial meniscus (DMM) used for evaluating disease-modifying OA targets are frequently performed on young adult mice only. This study investigates how age affects cartilage and subchondral bone changes in mouse joints following DMM. DMM was performed on male C57BL/6 mice at 4 months (4 M), 12 months (12 M) and 19+ months (19 M+) and on females at 12 M and 18 M+. Two months after surgery, operated and unoperated contralateral knees were harvested and evaluated using cartilage histology scores and μCT quantification of subchondral bone plate thickness and osteophyte formation. The 12 M and 19 M+ male mice developed more cartilage erosions and thicker subchondral bone plates after DMM than 4 M males. The size of osteophytes trended up with age, while the bone volume fraction was significantly higher in the 19 M+ group. Furthermore, 12 M females developed milder OA than males as indicated by less cartilage degradation, less subchondral bone plate sclerosis and smaller osteophytes. Our results reveal distinct age/gender-dependent structural changes in joint cartilage and subchondral bone post-DMM, facilitating more thoughtful selection of murine age/gender when using this surgical technique for translational OA research.

  9. Age-dependent Changes in the Articular Cartilage and Subchondral Bone of C57BL/6 Mice after Surgical Destabilization of Medial Meniscus

    Science.gov (United States)

    Huang, Henry; Skelly, Jordan D.; Ayers, David C.; Song, Jie

    2017-01-01

    Age is the primary risk factor for osteoarthritis (OA), yet surgical OA mouse models such as destabilization of the medial meniscus (DMM) used for evaluating disease-modifying OA targets are frequently performed on young adult mice only. This study investigates how age affects cartilage and subchondral bone changes in mouse joints following DMM. DMM was performed on male C57BL/6 mice at 4 months (4 M), 12 months (12 M) and 19+ months (19 M+) and on females at 12 M and 18 M+. Two months after surgery, operated and unoperated contralateral knees were harvested and evaluated using cartilage histology scores and μCT quantification of subchondral bone plate thickness and osteophyte formation. The 12 M and 19 M+ male mice developed more cartilage erosions and thicker subchondral bone plates after DMM than 4 M males. The size of osteophytes trended up with age, while the bone volume fraction was significantly higher in the 19 M+ group. Furthermore, 12 M females developed milder OA than males as indicated by less cartilage degradation, less subchondral bone plate sclerosis and smaller osteophytes. Our results reveal distinct age/gender-dependent structural changes in joint cartilage and subchondral bone post-DMM, facilitating more thoughtful selection of murine age/gender when using this surgical technique for translational OA research. PMID:28181577

  10. Long-term exercise in mice has sex-dependent benefits on body composition and metabolism during aging.

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    McMullan, Rachel C; Kelly, Scott A; Hua, Kunjie; Buckley, Brian K; Faber, James E; Pardo-Manuel de Villena, Fernando; Pomp, Daniel

    2016-11-01

    Aging is associated with declining exercise and unhealthy changes in body composition. Exercise ameliorates certain adverse age-related physiological changes and protects against many chronic diseases. Despite these benefits, willingness to exercise and physiological responses to exercise vary widely, and long-term exercise and its benefits are difficult and costly to measure in humans. Furthermore, physiological effects of aging in humans are confounded with changes in lifestyle and environment. We used C57BL/6J mice to examine long-term patterns of exercise during aging and its physiological effects in a well-controlled environment. One-year-old male (n = 30) and female (n = 30) mice were divided into equal size cohorts and aged for an additional year. One cohort was given access to voluntary running wheels while another was denied exercise other than home cage movement. Body mass, composition, and metabolic traits were measured before, throughout, and after 1 year of treatment. Long-term exercise significantly prevented gains in body mass and body fat, while preventing loss of lean mass. We observed sex-dependent differences in body mass and composition trajectories during aging. Wheel running (distance, speed, duration) was greater in females than males and declined with age. We conclude that long-term exercise may serve as a preventive measure against age-related weight gain and body composition changes, and that mouse inbred strains can be used to characterize effects of long-term exercise and factors (e.g. sex, age) modulating these effects. These findings will facilitate studies on relationships between exercise and health in aging populations, including genetic predisposition and genotype-by-environment interactions. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  11. A mineral-rich extract from the red marine algae Lithothamnion calcareum preserves bone structure and function in female mice on a Western-style diet.

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    Aslam, Muhammad Nadeem; Kreider, Jaclynn M; Paruchuri, Tejaswi; Bhagavathula, Narasimharao; DaSilva, Marissa; Zernicke, Ronald F; Goldstein, Steven A; Varani, James

    2010-04-01

    The purpose of this study was to determine whether a mineral-rich extract derived from the red marine algae Lithothamnion calcareum could be used as a dietary supplement for prevention of bone mineral loss. Sixty C57BL/6 mice were divided into three groups based on diet: the first group received a high-fat Western-style diet (HFWD), the second group was fed the same HFWD along with the mineral-rich extract included as a dietary supplement, and the third group was used as a control and was fed a low-fat rodent chow diet (AIN76A). Mice were maintained on the respective diets for 15 months. Then, long bones (femora and tibiae) from both males and females were analyzed by three-dimensional micro-computed tomography (micro-CT) and (bones from female mice) concomitantly assessed in bone strength studies. Tartrate-resistant acid phosphatase (TRAP), osteocalcin, and N-terminal peptide of type I procollagen (PINP) were assessed in plasma samples obtained from female mice at the time of sacrifice. To summarize, female mice on the HFWD had reduced bone mineralization and reduced bone strength relative to female mice on the low-fat chow diet. The bone defects in female mice on the HFWD were overcome in the presence of the mineral-rich supplement. In fact, female mice receiving the mineral-rich supplement in the HFWD had better bone structure/function than did female mice on the low-fat chow diet. Female mice on the mineral-supplemented HFWD had higher plasma levels of TRAP than mice of the other groups. There were no differences in the other two markers. Male mice showed little diet-specific differences by micro-CT.

  12. Running rescues a fear-based contextual discrimination deficit in aged mice

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    Melody V. Wu

    2015-08-01

    Full Text Available Normal aging and exercise exert extensive, often opposing, effects on the dentate gyrus (DG of the hippocampus altering volume, synaptic function, and behaviors. The DG is especially important for behaviors requiring pattern separation—a cognitive process that enables animals to differentiate between highly similar contextual experiences. To determine how age and exercise modulate pattern separation in an aversive setting, young, aged, and aged mice provided with a running wheel were assayed on a fear-based contextual discrimination task. Aged mice showed a profound impairment in contextual discrimination compared to young animals. Voluntary exercise rescued this deficit to such an extent that behavioral pattern separation of aged-run mice was now similar to young animals. Running also resulted in a significant increase in the number of immature neurons with tertiary dendrites in aged mice. Despite this, neurogenesis levels in aged-run mice were still considerably lower than in young animals. Thus, mechanisms other than DG neurogenesis likely play significant roles in improving behavioral pattern separation elicited by exercise in aged animals.

  13. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

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    Li Li

    2016-01-01

    Full Text Available D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apoptosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice.

  14. Spontaneous mutation of Dock7 results in lower trabecular bone mass and impaired periosteal expansion in aged female Misty mice.

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    Le, Phuong T; Bishop, Kathleen A; Maridas, David E; Motyl, Katherine J; Brooks, Daniel J; Nagano, Kenichi; Baron, Roland; Bouxsein, Mary L; Rosen, Clifford J

    2017-12-01

    Misty mice (m/m) have a loss of function mutation in Dock7 gene, a guanine nucleotide exchange factor, resulting in low bone mineral density, uncoupled bone remodeling and reduced bone formation. Dock7 has been identified as a modulator of osteoblast number and in vitro osteogenic differentiation in calvarial osteoblast culture. In addition, m/m exhibit reduced preformed brown adipose tissue innervation and temperature as well as compensatory increase in beige adipocyte markers. While the low bone mineral density phenotype is in part due to higher sympathetic nervous system (SNS) drive in young mice, it is unclear what effect aging would have in mice homozygous for the mutation in the Dock7 gene. We hypothesized that age-related trabecular bone loss and periosteal envelope expansion would be altered in m/m. To test this hypothesis, we comprehensively characterized the skeletal phenotype of m/m at 16, 32, 52, and 78wks of age. When compared to age-matched wild-type control mice (+/+), m/m had lower areal bone mineral density (aBMD) and areal bone mineral content (aBMC). Similarly, both femoral and vertebral BV/TV, Tb.N, and Conn.D were decreased in m/m while there was also an increase in Tb.Sp. As low bone mineral density and decreased trabecular bone were already present at 16wks of age in m/m and persisted throughout life, changes in age-related trabecular bone loss were not observed highlighting the role of Dock7 in controlling trabecular bone acquisition or bone loss prior to 16wks of age. Cortical thickness was also lower in the m/m across all ages. Periosteal and endosteal circumferences were higher in m/m compared to +/+ at 16wks. However, endosteal and periosteal expansion were attenuated in m/m, resulting in m/m having lower periosteal and endosteal circumferences by 78wks of age compared to +/+, highlighting the critical role of Dock7 in appositional bone expansion. Histomorphometry revealed that osteoblasts were nearly undetectable in m/m and marrow

  15. Age-Related Hearing Loss in Mn-SOD Heterozygous Knockout Mice

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    Makoto Kinoshita

    2013-01-01

    Full Text Available Age-related hearing loss (AHL reduces the quality of life for many elderly individuals. Manganese superoxide dismutase (Mn-SOD, one of the antioxidant enzymes acting within the mitochondria, plays a crucial role in scavenging reactive oxygen species (ROS. To determine whether reduction in Mn-SOD accelerates AHL, we evaluated auditory function in Mn-SOD heterozygous knockout (HET mice and their littermate wild-type (WT C57BL/6 mice by means of auditory brainstem response (ABR. Mean ABR thresholds were significantly increased at 16 months when compared to those at 4 months in both WT and HET mice, but they did not significantly differ between them at either age. The extent of hair cell loss, spiral ganglion cell density, and thickness of the stria vascularis also did not differ between WT and HET mice at either age. At 16 months, immunoreactivity of 8-hydroxydeoxyguanosine was significantly greater in the SGC and SV in HET mice compared to WT mice, but that of 4-hydroxynonenal did not differ between them. These findings suggest that, although decrease of Mn-SOD by half may increase oxidative stress in the cochlea to some extent, it may not be sufficient to accelerate age-related cochlear damage under physiological aging process.

  16. Skeletal muscles of aged male mice fail to adapt following contractile activity.

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    Vasilaki, A; Iwanejko, L M; McArdle, F; Broome, C S; Jackson, M J; McArdle, A

    2003-04-01

    Skeletal muscle adapts rapidly following exercise by the increased production of heat-shock proteins (HSPs). The aim of this study was to examine the ability of muscle from adult and aged mice to produce HSPs following non-damaging exercise. Adult and aged B6XSJL mice were anaesthetized and their hind limbs were subjected to isometric contractions. At different time points, muscles were analysed for HSP production by Western and Northern blotting and by electrophoretic mobility-shift assay. HSP protein and mRNA levels in muscles from adult mice increased significantly following exercise. This was not evident in muscles of aged mice. In contrast, binding of the transcription factor heat-shock factor 1 (HSF1) was not grossly altered in muscles of aged mice compared with adult mice. The data suggest that the inability of muscles of aged mice to produce HSPs appears to be due to alterations during gene transcription.

  17. Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice[S

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    Palmisano, Brian T.; Le, Thao D.; Zhu, Lin; Lee, Yoon Kwang; Stafford, John M.

    2016-01-01

    Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver β-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance β-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance β-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism. PMID:27354419

  18. Aged interleukin-10tm1Cgn chronically inflamed mice have substantially reduced fat mass, metabolic rate, and adipokines.

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    Reyhan M Westbrook

    Full Text Available Interleukin 10tm1Cgn (IL 10tm mice have been utilized as a model of chronic inflammation and declining health span because of their propensity to develop chronic activation in NFkB pathways, skeletal muscle and cardiac changes, and mitochondrial dysfunction. We hypothesized that older IL 10tm frail mice would have alterations similar to frail, older humans in measured parameters of glucose metabolism, oxygen consumption (VO2, respiratory quotient (RQ, spontaneous locomotor activity, body composition and plasma adipokine levels. To test this hypothesis, we investigated these metabolic parameters in cohorts of 3, 10, and 20 month old IL 10tm female mice and age and gender matched C57Bl/6 mice. Insulin sensitivity, glucose homeostasis, locomotor activity and RQ were not significantly altered between the two strains of mice. Interestingly, old IL 10tm mice had significantly decreased VO2 when normalized by lean mass, but not when normalized by fat mass or the lean/fat mass ratio. NMR based body composition analysis and dissection weights show that fat mass is decreased with age in IL 10tm mice compared to controls. Further, plasma adiponectin and leptin were also decreased in IL 10tm.These findings suggest that frailty observed in this mouse model of chronic inflammation may in part be driven by alterations in fat mass, hormone secretion and energy metabolism.

  19. Variable Suppression of Serum Thyroxine in Female Mice of Different Inbred Strains by Triiodothyronine Administered in Drinking Water

    Science.gov (United States)

    Hamidi, Sepehr; Aliesky, Holly; Chen, Chun-Rong; Rapoport, Basil

    2010-01-01

    Background Recombinant-inbred mouse strains differ in their susceptibility to Graves'-like hyperthyroidism induced by immunization with adenovirus expressing the human thyrotropin (TSH) receptor. Because one genetic component contributing to this susceptibility is altered thyroid sensitivity to TSH receptor agonist stimulation, we wished to quantify thyroid responsiveness to TSH. For such studies, it is necessary to suppress endogenous TSH by administering L-3,5,3′-triiodothyronine (L-T3), with the subsequent decrease in serum thyroxine (T4) reflecting endogenous TSH suppression. Our two objectives were to assess in different inbred strains of mice (i) the extent of serum T4 suppression after L-T3 administration and (ii) the magnitude of serum T4 increase induced by TSH. Methods Mice were tail-bled to establish baseline-serum T4 before L-T3 administration. We initially employed a protocol of L-T3-supplemented drinking water for 7 days. In subsequent experiments, we injected L-T3 intraperitoneally (i.p.) daily for 3 days. Mice were then injected i.p. with bovine TSH (10 mU) and euthanized 5 hours later. Serum T4 was assayed before L-T3 administration, and before and after TSH injection. In some experiments, serum T3 and estradiol were measured in pooled sera. Results Oral L-T3 (3 or 5 μg/mL) suppressed serum T4 levels by 26%–64% in female BALB/c mice but >95% in males. T4 suppression in female B6 mice ranged from 0% to 90%. In C3H mice, L-T3 at 3 μg/mL was ineffective but 5 μg/mL achieved >80% serum T4 reduction. Unlike inbred mice, in outbred CF1 mice the same protocol was more effective: 83% in females and 100% suppression in males. The degree of T4 suppression was unrelated to baseline T4, T3, or estradiol, but was related to mouse weight and postmortem T3, with greater suppression in larger mice (outbred CF1 animals and inbred males). Among females with serum T4 suppression >80%, the increase in serum T4 after TSH injection was greater for BALB

  20. Staphylococcus epidermidis is involved in a mechanism for female reproduction in mice

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    Chihiro Ono

    2015-06-01

    Full Text Available Both external and internal surfaces of organs (e.g., skin, mouth, gut, and intestine are covered with bacteria, which often contribute to physiological events in host animals. Despite externally opened organs, the presence of bacteria in the mammalian female reproductive tract is uncertain. Here we assessed this problem using wild-type strains of mice, C57BL/6N and ICR. We first demonstrated that bacterial colonies were formed from the oviductal fluid in the C57BL/6N mice with birth experience (“parous”, but not in the mice without birth experience (“non-parous”. Sequence analysis of 16S ribosomal RNA (rRNA revealed that Staphylococcus epidermidis existed in the oviductal fluid of the parous mice, confirmed by immunohistochemical analysis. Furthermore, extinction of bacterial population with intraperitoneal injection of antibiotics, penicillin G and streptomycin, disturbed the regularly implanted pattern of embryos in ICR mice. Our results indicate that symbiotic S. epidermidis plays a role in interaction between embryo and uterus upon implantation in mice.

  1. Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.

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    Lau, Christine Li Ling; Chan, Sook Tyng; Selvaratanam, Manimegahlai; Khoo, Hui Wen; Lim, Adeline Yi Ling; Modamio, Pilar; Mariño, Eduardo L; Segarra, Ignacio

    2015-08-01

    Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P brain (P male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P brain, liver, and kidney (all P male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P female mice and in kidney (male and female mice) but decreased 55% in brain (P differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  2. The Accessory Olfactory System Facilitates the Recovery of the Attraction to Familiar Volatile Female Odors in Male Mice.

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    Muroi, Yoshikage; Nishimura, Masakazu; Ishii, Toshiaki

    2017-10-31

    Odors in female mice induce sexual arousal in male mice. Repeated exposure to female odors attenuates male attraction, which recovers when the odors are removed. The neuronal mechanisms for the recovery of male attraction have not been clarified. In this study, we examined how olfactory systems are involved in the recovery of male attraction to female odors following habituation in mice. Presentation with volatile female odors for 5 min induced habituation in males. To evaluate male attraction to familiar volatile female odors, we measured the duration for investigating volatile female odors from the same female mouse, which was presented twice for 5 min with 1-, 3-, or 5-min interval. Intranasal irrigation with ZnSO4 solution almost completely suppressed investigating behavior, indicating that the main olfactory system is indispensable for inducing the attraction to volatile female odors. In contrast, removal of the vomeronasal organ, bilateral lesions of the accessory olfactory bulb (AOB), or pharmacological blockage of neurotransmission in the AOB did not affect the investigation time at the first odor presentation. However, each one of the treatments decreased the investigation time in the second presentation, compared to that in the first presentation, at longer intervals than control treatment, indicating that the disturbance of neurotransmission in the accessory olfactory system delayed the recovery of the attraction attenuated by the first presentation. These results suggest that the accessory olfactory system facilitates the recovery of the attraction to familiar volatile female odors in male mice. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Age- and sex-dependence of dopamine release and capacity for recovery identified in the dorsal striatum of C57/Bl6J mice.

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    Emma Arvidsson

    Full Text Available The dorsal striatum is the main input structure of the basal ganglia and the major target area of dopaminergic projections originating in the substantia nigra pars compacta. Heavily involved in the regulation of voluntary movement and habit formation, this structure is of strong importance in Parkinson's disease, obsessive-compulsive disorder, Tourette's syndrome and addiction. The C57/Bl6J mouse strain, the most commonly used strain in preclinical research today, is frequently used as a model organism for analysis of dopaminergic parameters implicated in human pathophysiology. Several components of the dopamine system have been shown to vary with age and sex, however knowledge of the contribution of these factors for dopamine release kinetics in the C57/Bl6J mouse strain is lacking. In the present study, we used an intracranial KCl-stimulation challenge paradigm to provoke release from dopaminergic terminals in the dorsal striatum of anaesthetized C57/Bl6J mice. By high-speed in vivo chronoamperometric recordings, we analyzed DA release parameters in male and female mice of two different ages. Our experiments demonstrate elevated DA amplitudes in adult compared to young mice of both sexes and higher DA amplitudes in females compared to males at both ages. Adult mice exhibited higher recovery capabilities after repeated stimulation than did young mice and also showed a lower variability in the kinetic parameters trise and t80 between stimulations. These results identified age- and sex- dimorphisms in DA release parameters and point to the importance of taking these dimorphisms into account when utilizing the C57/Bl6J mouse strain as model for neurological and neuropsychiatric disorders.

  4. NanoTIO2 (UV-Titan does not induce ESTR mutations in the germline of prenatally exposed female mice

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    Boisen Anne Mette

    2012-06-01

    Full Text Available Abstract Background Particulate air pollution has been linked to an increased risk of cardiovascular disease and cancer. Animal studies have shown that inhalation of air particulates induces mutations in the male germline. Expanded simple tandem repeat (ESTR loci in mice are sensitive markers of mutagenic effects on male germ cells resulting from environmental exposures; however, female germ cells have received little attention. Oocytes may be vulnerable during stages of active cell division (e.g., during fetal development. Accordingly, an increase in germline ESTR mutations in female mice prenatally exposed to radiation has previously been reported. Here we investigate the effects of nanoparticles on the female germline. Since pulmonary exposure to nanosized titanium dioxide (nanoTiO2 produces a long-lasting inflammatory response in mice, it was chosen for the present study. Findings Pregnant C57BL/6 mice were exposed by whole-body inhalation to the nanoTiO2 UV-Titan L181 (~42.4 mg UV-Titan/m3 or filtered clean air on gestation days (GD 8–18. Female C57BL/6 F1 offspring were raised to maturity and mated with unexposed CBA males. The F2 descendents were collected and ESTR germline mutation rates in this generation were estimated from full pedigrees (mother, father, offspring of F1 female mice (192 UV-Titan-exposed F2 offspring and 164 F2 controls. ESTR mutation rates of 0.029 (maternal allele and 0.047 (paternal allele in UV-Titan-exposed F2 offspring were not statistically different from those of F2 controls: 0.037 (maternal allele and 0.061 (paternal allele. Conclusions We found no evidence for increased ESTR mutation rates in F1 females exposed in utero to UV-Titan nanoparticles from GD8-18 relative to control females.

  5. Isolation and characterization of string-forming female germline stem cells from ovaries of neonatal mice.

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    Liu, Jing; Shang, Dantong; Xiao, Yao; Zhong, Pei; Cheng, Hanhua; Zhou, Rongjia

    2017-09-29

    Germline stem cells are essential in the generation of both male and female gametes. In mammals, the male testis produces sperm throughout the entire lifetime, facilitated by testicular germline stem cells. Oocyte renewal ceases in postnatal or adult life in mammalian females, suggesting that germline stem cells are absent from the mammalian ovary. However, studies in mice, rats, and humans have recently provided evidence for ovarian female germline stem cells (FGSCs). A better understanding of the role of FGSCs in ovaries could help improve fertility treatments. Here, we developed a rapid and efficient method for isolating FGSCs from ovaries of neonatal mice. Notably, our FGSC isolation method could efficiently isolate on average 15 cell "strings" per ovary from mice at 1-3 days postpartum. FGSCs isolated from neonatal mice displayed the string-forming cell configuration at mitosis ( i.e. a "stringing" FGSC (sFGSC) phenotype) and a disperse phenotype in postnatal mice. We also found that sFGSCs undergo vigorous mitosis especially at 1-3 days postpartum. After cell division, the sFGSC membranes tended to be connected to form sFGSCs. Moreover, F-actin filaments exhibited a cell-cortex distribution in sFGSCs, and E-cadherin converged in cell-cell connection regions, resulting in the string-forming morphology. Our new method provides a platform for isolating FGSCs from the neonatal ovary, and our findings indicate that FGCSs exhibit string-forming features in neonatal mice. The sFGSCs represent a valuable resource for analysis of ovary function and an in vitro model for future clinical use to address ovarian dysfunction. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Protein restriction does not affect body temperature pattern in female mice.

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    Kato, Goro A; Shichijo, Hiroki; Takahashi, Toshihiro; Shinohara, Akio; Morita, Tetsuo; Koshimoto, Chihiro

    2017-10-30

    Daily torpor is a physiological adaptation in mammals and birds characterized by a controlled reduction of metabolic rate and body temperature during the resting phase of circadian rhythms. In laboratory mice, daily torpor is induced by dietary caloric restriction. However, it is not known which nutrients are related to daily torpor expression. To determine whether dietary protein is a key factor in inducing daily torpor in mice, we fed mice a protein-restricted (PR) diet that included only one-quarter of the amount of protein but the same caloric level as a control (C) diet. We assigned six non-pregnant female ICR mice to each group and recorded their body weights and core body temperatures for 4 weeks. Body weights in the C group increased, but those in the PR group remained steady or decreased. Mice in both groups did not show daily torpor, but most mice in a food-restricted group (n=6) supplied with 80% of the calories given to the C group exhibited decreased body weights and frequently displayed daily torpor. This suggests that protein restriction is not a trigger of daily torpor; torpid animals can conserve their internal energy, but torpor may not play a significant role in conserving internal protein. Thus, opportunistic daily torpor in mice may function in energy conservation rather than protein saving.

  7. Joint dysfunction and functional decline in middle age myostatin null mice.

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    Guo, Wen; Miller, Andrew D; Pencina, Karol; Wong, Siu; Lee, Amanda; Yee, Michael; Toraldo, Gianluca; Jasuja, Ravi; Bhasin, Shalender

    2016-02-01

    Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss. However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated. We report herein that male myostatin null mice (mstn(-/-)), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3-6months) to middle age (12-15months) than age-matched wt mice, measured as gripping strength and treadmill endurance. Mstn(-/-) mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration. Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon-bone insertion in mstn(-/-) mice than wt mice, even at the neonatal age. At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn(-/-) mice than wt controls. These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Effect of cadmium chloride on hepatic lipid peroxidation in mice

    DEFF Research Database (Denmark)

    Andersen, H R; Andersen, O

    1988-01-01

    Intraperitoneal administration of cadmium chloride to 8-12 weeks old CBA-mice enhanced hepatic lipid peroxidation. A positive correlation between cadmium chloride dose and level of peroxidation was observed in both male and female mice. A sex-related difference in mortality was not observed...... but at a dose of 25 mumol CdCl2/kg the level of hepatic lipid peroxidation was higher in male mice than in female mice. The hepatic lipid peroxidation was not increased above the control level in 3 weeks old mice, while 6 weeks old mice responded with increased peroxidation as did 8-12 weeks old mice....... The mortality after an acute toxic dose of cadmium chloride was the same in the three age groups. Pretreatment of mice with several low intraperitoneal doses of cadmium chloride alleviated cadmium induced mortality and lipid peroxidation. The results demonstrate both age dependency and a protective effect...

  9. Reduction in podocyte SIRT1 accelerates kidney injury in aging mice.

    Science.gov (United States)

    Chuang, Peter Y; Cai, Weijing; Li, Xuezhu; Fang, Lu; Xu, Jin; Yacoub, Rabi; He, John Cijiang; Lee, Kyung

    2017-09-01

    Both the incidence and prevalence of chronic kidney disease are increasing in the elderly population. Although aging is known to induce kidney injury, the underlying molecular mechanisms remain unclear. Sirtuin 1 (Sirt1), a longevity gene, is known to protect kidney cell injury from various cellular stresses. In previous studies, we showed that the podocyte-specific loss of Sirt1 aggravates diabetic kidney injury. However, the role of Sirt1 in aging-induced podocyte injury is not known. Therefore, in this study we sought to determine the effects of podocyte-specific reduction of Sirt1 in age-induced kidney injury. We employed the inducible podocyte-specific Sirt1 knockdown mice that express shRNA against Sirt1 (Pod-Sirt1 RNAi ) and control mice that express shRNA for luciferase (Pod-Luci RNAi ). We found that reduction of podocyte Sirt1 led to aggravated aging-induced glomerulosclerosis and albuminuria. In addition, urinary level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, was markedly increased in aged Pod-Sirt1 RNAi mice compared with aged Pod-Luci RNAi mice. Although podocyte-specific markers decreased in aged mice compared with the young controls, the decrease was further exacerbated in aged Pod-Sirt1 RNAi compared with Pod-Luci RNAi mice. Interestingly, expression of cellular senescence markers was significantly higher in the glomeruli of Pod-Sirt1 RNAi mice than Pod-Luci RNAi mice, suggesting that cellular senescence may contribute to podocyte loss in aging kidneys. Finally, we confirmed that Pod-Sirt1 RNAi glomeruli were associated with reduced activation of the transcription factors peroxisome proliferator-activated receptor (PPAR)-α coactivador-1 (PGC1α)/PPARγ, forkhead box O (FOXO)3, FOXO4, and p65 NF-κB, through SIRT1-mediated deacetylation. Together, our data suggest that SIRT1 may be a potential therapeutic target to treat patients with aging-related kidney disease.

  10. Pathology of Serially Sacrificed Female B6C3F1 Mice Continuously Exposed to Very Low-Dose-Rate Gamma Rays.

    Science.gov (United States)

    Tanaka, I B; Komura, J; Tanaka, S

    2017-03-01

    We have previously reported on life span shortening as well as increased incidence rates in several neoplasms in B6C3F1 mice that were continuously exposed to 21 mGy/day of gamma rays for 400 days. To clarify whether the life shortening was due to early appearance of neoplasms (shortened latency) or increased promotion/progression, 8-week-old female specific-pathogen-free B6C3F1 mice were gamma-ray irradiated at a low dose rate of 20 mGy/day for 400 days. At 100 days postirradiation, 60-90 mice were sacrificed, and thereafter every 100 days alongside the age-matched nonirradiated controls, for 700 days. Additional groups were allowed to live out their natural life span. Pathological examination was performed on all mice to identify lesions, non-neoplastic and neoplastic, as well as to determine the cause of death. Body weights were significantly increased in irradiated mice from sacrifice days 200-500. Incidence rates for spontaneously occurring non-neoplastic lesions, such as adrenal subcapsular cell hyperplasia, fatty degeneration of the liver, atrophy and tubulostromal hyperplasia of the ovaries, were significantly increased in irradiated mice. Significantly increased incidence rates with no shortening of latency periods were observed in irradiated mice for malignant lymphomas, hepatocellular adenomas/carcinomas, bronchioloalveolar adenomas, harderian gland adenoma/adenocarcinoma. Shortened latencies with significantly increased incidence rates were observed for adrenal subcapsular cell adenomas and ovarian neoplasms (tubulostromal adenoma, granulosa cell tumors) in irradiated mice. Life span shortening in mice exposed to 20 mGy/day was mostly due to malignant lymphomas. Multiple primary neoplasms were significantly increased in mice exposed to 20 mGy/day from sacrifice days 400-700 and in the life span group. Our results confirm that continuous low-dose-rate gamma-ray irradiation of female B6C3F1 mice causes both cancer induction (shortened latency) and

  11. Resilience in Aging Mice.

    Science.gov (United States)

    Kirkland, James L; Stout, Michael B; Sierra, Felipe

    2016-11-01

    Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context

  12. Entire litters developed from transferred eggs in whole body x-irradiated female mice

    International Nuclear Information System (INIS)

    Lin, T.P.

    1980-01-01

    The sensitivity of mouse eggs to sublethal x-irradiation was determined in vitro and in vivo with regard to the development of donor litters in foster mothers. One thousand seven hundred fifty-eight unfertilized eggs of agouti dark-eyed donor mice were transferred into 293 unirradiated or x-irradiated, mated female pink-eyed mice. Two hundred thirty-nine recipients became pregnant; of these 35 produced litters containing solely dark-eyed fetuses. Sublethal doses of x-radiation administered to donor eggs in vitro before transferring into unirradiated recipients did not influence significantly the number of litters of exclusively dark-eyed fetuses produced. However, recipients irradiated by 250 roentgens (r) produced more solely dark-eyed litters than did those irradiated with 100 r. In 21 pregnant females irradiated by 100 r, only 3 (14%) developed solely dark-eyed fetuses as compared to 22 pregnant females irradiated by 250 r, of which 13 (59%) developed solely dark-eyed fetuses, all from unirradiated, transferred eggs. Of another group of 22 pregnant females which received 250 r body irradiation and subsequently received eggs also irradiated by 250 r, only 7 (32%) produced litters of dark-eyed fetuses. No one female of these three groups carried native fetuses. Such radiation-induced infertility resulting from damage of native eggs rather than loss of mother's ability to carry a pregnancy, is frequently remedied by egg transfer

  13. Alternative reproductive tactics in female striped mice: Solitary breeders have lower corticosterone levels than communal breeders.

    Science.gov (United States)

    Hill, Davina L; Pillay, Neville; Schradin, Carsten

    2015-05-01

    Alternative reproductive tactics (ARTs), where members of the same sex and population show distinct reproductive phenotypes governed by decision-rules, have been well-documented in males of many species, but are less well understood in females. The relative plasticity hypothesis (RPH) predicts that switches between plastic ARTs are mediated by changes in steroid hormones. This has received much support in males, but little is known about the endocrine control of female ARTs. Here, using a free-living population of African striped mice (Rhabdomys pumilio) over five breeding seasons, we tested whether females following different tactics differed in corticosterone and testosterone levels, as reported for male striped mice using ARTs, and in progesterone and oestrogen, which are important in female reproduction. Female striped mice employ three ARTs: communal breeders give birth in a shared nest and provide alloparental care, returners leave the group temporarily to give birth, and solitary breeders leave to give birth and do not return. We expected communal breeders and returners to have higher corticosterone, owing to the social stress of group-living, and lower testosterone than solitary breeders, which must defend territories alone. Solitary breeders had lower corticosterone than returners and communal breeders, as predicted, but testosterone and progesterone did not differ between ARTs. Oestrogen levels were higher in returners (measured before leaving the group) than in communal and solitary breeders, consistent with a modulatory role. Our study demonstrates hormonal differences between females following (or about to follow) different tactics, and provides the first support for the RPH in females. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. The effect of maternal chromium status on lipid metabolism in female elderly mice offspring and involved molecular mechanism.

    Science.gov (United States)

    Zhang, Qian; Sun, Xiaofang; Xiao, Xinhua; Zheng, Jia; Li, Ming; Yu, Miao; Ping, Fan; Wang, Zhixin; Qi, Cuijuan; Wang, Tong; Wang, Xiaojing

    2017-04-30

    Maternal malnutrition leads to the incidence of metabolic diseases in offspring. The purpose of this project was to examine whether maternal low chromium could disturb normal lipid metabolism in offspring, altering adipose cell differentiation and leading to the incidence of lipid metabolism diseases, including metabolic syndrome and obesity. Female C57BL mice were given a control diet (CD) or a low chromium diet (LCD) during the gestational and lactation periods. After weaning, offspring was fed with CD or LCD. The female offspring were assessed at 32 weeks of age. Fresh adipose samples from CD-CD group and LCD-CD group were collected. Genome mRNA were analysed using Affymetrix GeneChip Mouse Gene 2.0 ST Whole Transcript-based array. Differentially expressed genes (DEGs) were analysed based on gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis database. Maternal low chromium irreversibly increased offspring body weight, fat-pad weight, serum triglyceride (TG) and TNF-α. Eighty five genes increased and 109 genes reduced in the offspring adipose of the maternal low chromium group. According to KEGG pathway and String analyses, the PPAR signalling pathway may be the key controlled pathway related to the effect of maternal low chromium on female offspring. Maternal chromium status have long-term effects of lipid metabolism in female mice offspring. Normalizing offspring diet can not reverse these effects. The potential underlying mechanisms are the disturbance of the PPAR signalling pathway in adipose tissue. © 2017 The Author(s).

  15. Motor performance is impaired following vestibular stimulation in ageing mice.

    Directory of Open Access Journals (Sweden)

    Victoria W.K. Tung

    2016-02-01

    Full Text Available Balance and maintaining postural equilibrium are important during stationary and dynamic movements to prevent falls, particularly in older adults. While our sense of balance is influenced by vestibular, proprioceptive, and visual information, this study focuses primarily on the vestibular component and its age-related effects on balance. C57Bl/6J mice of ages 1, 5-6, 8-9 and 27-28 months were tested using a combination of standard (such as grip strength and rotarod and newly-developed behavioural tests (including balance beam and walking trajectory tests with a vestibular stimulus. In the current study, we confirm a decline in fore-limb grip strength and gross motor coordination as age increases. We also show that a vestibular stimulus of low frequency (2-3 Hz and duration can lead to age-dependent changes in balance beam performance, which was evident by increases in latency to begin walking on the beam as well as the number of times hind-feet slip from the beam. Furthermore, aged mice (27-28 months that received continuous access to a running wheel for 4 weeks did not improve when retested. Mice of ages 1, 10, 13, and 27-28 months were also tested for changes in walking trajectory as a result of the vestibular stimulus. While no linear relationship was observed between the changes in trajectory and age, 1-month-old mice were considerably less affected than mice of ages 10, 13, and 27-28 months. Conclusion: This study confirms there are age-related declines in grip strength and gross motor coordination. We also demonstrate age-dependent changes to finer motor abilities as a result of a low frequency and duration vestibular stimulus. These changes showed that while the ability to perform the balance beam task remained intact across all ages tested, behavioural changes in task performance were observed.

  16. Motor Performance is Impaired Following Vestibular Stimulation in Ageing Mice.

    Science.gov (United States)

    Tung, Victoria W K; Burton, Thomas J; Quail, Stephanie L; Mathews, Miranda A; Camp, Aaron J

    2016-01-01

    Balance and maintaining postural equilibrium are important during stationary and dynamic movements to prevent falls, particularly in older adults. While our sense of balance is influenced by vestibular, proprioceptive, and visual information, this study focuses primarily on the vestibular component and its age-related effects on balance. C57Bl/6J mice of ages 1, 5-6, 8-9 and 27-28 months were tested using a combination of standard (such as grip strength and rotarod) and newly-developed behavioral tests (including balance beam and walking trajectory tests with a vestibular stimulus). In the current study, we confirm a decline in fore-limb grip strength and gross motor coordination as age increases. We also show that a vestibular stimulus of low frequency (2-3 Hz) and duration can lead to age-dependent changes in balance beam performance, which was evident by increases in latency to begin walking on the beam as well as the number of times hind-feet slip (FS) from the beam. Furthermore, aged mice (27-28 months) that received continuous access to a running wheel for 4 weeks did not improve when retested. Mice of ages 1, 10, 13 and 27-28 months were also tested for changes in walking trajectory as a result of the vestibular stimulus. While no linear relationship was observed between the changes in trajectory and age, 1-month-old mice were considerably less affected than mice of ages 10, 13 and 27-28 months. this study confirms there are age-related declines in grip strength and gross motor coordination. We also demonstrate age-dependent changes to finer motor abilities as a result of a low frequency and duration vestibular stimulus. These changes showed that while the ability to perform the balance beam task remained intact across all ages tested, behavioral changes in task performance were observed.

  17. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

    NARCIS (Netherlands)

    Jurk, Diana; Wilson, Caroline; Passos, Joao F.; Oakley, Fiona; Correia-Melo, Clara; Greaves, Laura; Saretzki, Gabriele; Fox, Chris; Lawless, Conor; Anderson, Rhys; Hewitt, Graeme; Pender, Sylvia L. F.; Fullard, Nicola; Nelson, Glyn; Mann, Jelena; van de Sluis, Bart; Mann, Derek A.; von Zglinicki, Thomas

    Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-kappa B induces premature ageing in mice. We also show that these mice have reduced

  18. Aging and cellular defense mechanisms: age-related changes in resistance of mice to Listeria monocytogenes.

    OpenAIRE

    Patel, P J

    1981-01-01

    Age-related changes in resistance of mice to infection with Listeria monocytogenes were investigated. One-month-old mice exhibited the least resistance, and the resistance level increased over the first few months to reach a maximum by 8 months. Increase in age thereafter was accompanied by a slow but progressive decrease in resistance. Thus, 50% lethal doses for 1-, 8-, and 24-month-old mice were 10(4.2), 10(6.6), and 10(5.2), respectively. In spite of differences in resistance, the growth o...

  19. Genetic and hormonal control of hepatic steatosis in female and male mice.

    Science.gov (United States)

    Norheim, Frode; Hui, Simon T; Kulahcioglu, Emre; Mehrabian, Margarete; Cantor, Rita M; Pan, Calvin; Parks, Brian W; Lusis, Aldons J

    2017-01-01

    The etiology of nonalcoholic fatty liver disease is complex and influenced by factors such as obesity, insulin resistance, hyperlipidemia, and sex. We now report a study on sex difference in hepatic steatosis in the context of genetic variation using a population of inbred strains of mice. While male mice generally exhibited higher concentration of hepatic TG levels on a high-fat high-sucrose diet, sex differences showed extensive interaction with genetic variation. Differences in percentage body fat were the best predictor of hepatic steatosis among the strains and explained about 30% of the variation in both sexes. The difference in percent gonadal fat and HDL explained 9.6% and 6.7% of the difference in hepatic TGs between the sexes, respectively. Genome-wide association mapping of hepatic TG revealed some striking differences in genetic control of hepatic steatosis between females and males. Gonadectomy increased the hepatic TG to body fat percentage ratio among male, but not female, mice. Our data suggest that the difference between the sexes in hepatic TG can be partly explained by differences in body fat distribution, plasma HDL, and genetic regulation. Future studies are required to understand the molecular interactions between sex, genetics, and the environment. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  20. Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period.

    Science.gov (United States)

    Philippot, Gaëtan; Gordh, Torsten; Fredriksson, Anders; Viberg, Henrik

    2017-10-01

    Paracetamol (acetaminophen) is a widely used non-prescription drug with analgesic and antipyretic properties. Among pregnant women and young children, paracetamol is one of the most frequently used drugs and is considered the first-choice treatment for pain and/or fever. Recent findings in both human and animal studies have shown associations between paracetamol intake during brain development and adverse behavioral outcomes later in life. The present study was undertaken to investigate if the induction of these effects depend on when the exposure occurs during a critical period of brain development and if male and female mice are equally affected. Mice of both sexes were exposed to two doses of paracetamol (30 + 30 mg kg -1 , 4 h apart) on postnatal days (PND) 3, 10 or 19. Spontaneous behavior, when introduced to a new home environment, was observed at the age of 2 months. We show that adverse effects on adult behavior and cognitive function occurred in both male and female mice exposed to paracetamol on PND 3 and 10, but not when exposed on PND 19. These neurodevelopmental time points in mice correspond to the beginning of the third trimester of pregnancy and the time around birth in humans, supporting existing human data. Considering that paracetamol is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for future research and, ultimately, for clinical practice. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  1. Focal lesions within the ventral striato-pallidum abolish attraction for male chemosignals in female mice.

    Science.gov (United States)

    Agustín-Pavón, Carmen; Martínez-García, Fernando; Lanuza, Enrique

    2014-02-01

    In rodents, socio-sexual behaviour is largely mediated by chemosensory cues, some of which are rewarding stimuli. Female mice display an innate attraction towards male chemosignals, dependent on the vomeronasal system. This behaviour likely reflects the hedonic value of sexual chemosignals. The anteromedial aspect of the olfactory tubercle, along with its associated islands of Calleja, receives vomeronasal inputs and sexually-dimorphic vasopressinergic innervation. Thus, we hypothesised that this portion of the ventral striato-pallidum, known to be involved in reward processing, might be important for sexual odorant-guided behaviours. In this study, we demonstrate that lesions of this region, but not of regions in the posterolateral striato-pallidum, abolish the attraction of female mice for male chemosignals, without affecting significantly their preference for a different natural reward (a sucrose solution). These results show that, at least in female mice, the integrity of the anterior aspect of the medioventral striato-pallidum, comprising a portion of the olfactory tubercle and associated islands of Calleja, is necessary for the attraction for male chemosignals. We suggest that this region contributes to the processing of the hedonic properties of biologically significant odorants. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Age-related deterioration of rod vision in mice.

    Science.gov (United States)

    Kolesnikov, Alexander V; Fan, Jie; Crouch, Rosalie K; Kefalov, Vladimir J

    2010-08-18

    Even in healthy individuals, aging leads to deterioration in visual acuity, contrast sensitivity, visual field, and dark adaptation. Little is known about the neural mechanisms that drive the age-related changes of the retina and, more specifically, photoreceptors. According to one hypothesis, the age-related deterioration in rod function is due to the limited availability of 11-cis-retinal for rod pigment formation. To determine how aging affects rod photoreceptors and to test the retinoid-deficiency hypothesis, we compared the morphological and functional properties of rods of adult and aged B6D2F1/J mice. We found that the number of rods and the length of their outer segments were significantly reduced in 2.5-year-old mice compared with 4-month-old animals. Aging also resulted in a twofold reduction in the total level of opsin in the retina. Behavioral tests revealed that scotopic visual acuity and contrast sensitivity were decreased by twofold in aged mice, and rod ERG recordings demonstrated reduced amplitudes of both a- and b-waves. Sensitivity of aged rods determined from single-cell recordings was also decreased by 1.5-fold, corresponding to not more than 1% free opsin in these photoreceptors, and kinetic parameters of dim flash response were not altered. Notably, the rate of rod dark adaptation was unaffected by age. Thus, our results argue against age-related deficiency of 11-cis-retinal in the B6D2F1/J mouse rod visual cycle. Surprisingly, the level of cellular dark noise was increased in aged rods, providing an alternative mechanism for their desensitization.

  3. Are age and sex differences in brain oxytocin receptors related to maternal and infanticidal behavior in naïve mice?

    Science.gov (United States)

    Olazábal, Daniel E; Alsina-Llanes, Marcela

    2016-01-01

    This article is part of a Special Issue "Parental Care". There is significant variability in the behavioral responses displayed by naïve young and adult mice when first exposed to pups. This variability has been associated with differences in the expression of oxytocin receptors (OXTRs) in the brain in several species. Experiment I investigated the behavioral responses of juvenile, adolescent, and adult CB57BL/6 males and females when first exposed to pups. We found an age increase in maternal females (11% of juveniles, 20% of adolescents, and 50% of young adults), and infanticidal males (0% of juveniles, 30% of adolescents, 44.5% of young adults, and 100% of older adults). Experiment II investigated OXTR density in the brain of juvenile and adult mice. Our results revealed an age decline in the density of OXTR in several brain regions, including the lateral septum, cingulated and posterior paraventricular thalamic nucleus in both males and females. Adult females had higher OXTR density in the ventromedial nucleus/postero-ventral hypothalamus (VMH) and the accessory olfactory bulb (AOB), but lower density in the ventral region of the lateral septum (LSv) than juveniles. Males had lower OXTR density in the anterior olfactory area (AOA) compared to juveniles. No age or sex differences were found in the medial preoptic area, and amygdaloid nuclei, among other brain regions. This study suggests that 1) maturation of parental and infanticidal behavioral responses is not reached until adulthood; 2) the pattern of development of OXTR in the mouse brain is unique, region specific, and differs from that observed in other rodents; 3) either up or down regulation of OXTR in a few brain regions (VMH/AOB/LSv/AOA) might contribute to age or sex differences in parental or infanticidal behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. No evidence for female discrimination against male house mice carrying a selfish genetic element.

    Science.gov (United States)

    Sutter, Andreas; Lindholm, Anna K

    2016-12-01

    Meiotic drivers distort transmission to the next generation in their favor, with detrimental effects on the fitness of their homologues and the rest of the genome. Male carriers of meiotic drivers commonly inflict costs on their mates through genetic incompatibility, reduced fecundity, or biased brood sex ratios. Given these costs, evidence for female discrimination against male carriers is surprisingly rare. One of few examples is the t haplotype in house mice, a meiotic driver that shows strong transmission distortion in males and is typically homozygote lethal. As a consequence, mating between 2 t heterozygous (+/ t ) mice leads to high embryo mortality. Previous experiments showing that +/ t females avoid this incompatibility cost by preferring +/+ versus +/ t males have inferred preference based on olfactory cues or brief social interactions. Evidence from mating contexts in laboratory settings and semi-natural populations has been inconclusive. Here, we investigated female choice from a large number of no-choice mating trials. We found no evidence for discrimination against +/ t males based on mating, remating, and copulatory behavior. Further, we found no evidence for avoidance of incompatibility through selective interactions between gametes. The likelihood of mating showed significant effects of female weight and genotype, suggesting that our test paradigm enabled females to exhibit mate choice. We discuss the strengths and limitations of our approach. By explicitly considering selection at both the individual and gene level, we argue why precopulatory female discrimination by +/ t females may be less evolutionarily stable than discrimination by all females based on postcopulatory mechanisms.

  5. Gender- and age-dependent gamma-secretase activity in mouse brain and its implication in sporadic Alzheimer disease.

    Directory of Open Access Journals (Sweden)

    Lisa Placanica

    Full Text Available Alzheimer disease (AD is an age-related disorder. Aging and female gender are two important risk factors associated with sporadic AD. However, the mechanism by which aging and gender contribute to the pathogenesis of sporadic AD is unclear. It is well known that genetic mutations in gamma-secretase result in rare forms of early onset AD due to the aberrant production of Abeta42 peptides, which are the major constituents of senile plaques. However, the effect of age and gender on gamma-secretase has not been fully investigated. Here, using normal wild-type mice, we show mouse brain gamma-secretase exhibits gender- and age-dependent activity. Both male and female mice exhibit increased Abeta42ratioAbeta40 ratios in aged brain, which mimics the effect of familial mutations of Presenilin-1, Presenlin-2, and the amyloid precursor protein on Abeta production. Additionally, female mice exhibit much higher gamma-secretase activity in aged brain compared to male mice. Furthermore, both male and female mice exhibit a steady decline in Notch1 gamma-secretase activity with aging. Using a small molecule affinity probe we demonstrate that male mice have less active gamma-secretase complexes than female mice, which may account for the gender-associated differences in activity in aged brain. These findings demonstrate that aging can affect gamma-secretase activity and specificity, suggesting a role for gamma-secretase in sporadic AD. Furthermore, the increased APP gamma-secretase activity seen in aged females may contribute to the increased incidence of sporadic AD in women and the aggressive Abeta plaque pathology seen in female mouse models of AD. In addition, deceased Notch gamma-secretase activity may also contribute to neurodegeneration. Therefore, this study implicates altered gamma-secretase activity and specificity as a possible mechanism of sporadic AD during aging.

  6. Aging-associated oxidative stress inhibits liver progenitor cell activation in mice.

    Science.gov (United States)

    Cheng, Yiji; Wang, Xue; Wang, Bei; Zhou, Hong; Dang, Shipeng; Shi, Yufang; Hao, Li; Luo, Qingquan; Jin, Min; Zhou, Qianjun; Zhang, Yanyun

    2017-04-29

    Recent studies have discovered aging-associated changes of adult stem cells in various tissues and organs, which potentially contribute to the organismal aging. However, aging-associated changes of liver progenitor cells (LPCs) remain elusive. Employing young (2-month-old) and old (24-month-old) mice, we found diverse novel alterations in LPC activation during aging. LPCs in young mice could be activated and proliferate upon liver injury, whereas the counterparts in old mice failed to respond and proliferate, leading to the impaired liver regeneration. Surprisingly, isolated LPCs from young and old mice did not exhibit significant difference in their clonogenic and proliferative capacity. Later, we uncovered that the decreased activation and proliferation of LPCs were due to excessive reactive oxygen species produced by neutrophils infiltrated into niche, which was resulted from chemokine production from activated hepatic stellate cells during aging. This study demonstrates aging-associated changes in LPC activation and reveals critical roles for the stem cell niche, including neutrophils and hepatic stellate cells, in the negative regulation of LPCs during aging.

  7. AβPP/PS1 Transgenic Mice Show Sex Differences in the Cerebellum Associated with Aging.

    Science.gov (United States)

    Ordoñez-Gutierrez, Lara; Fernandez-Perez, Ivan; Herrera, Jose Luis; Anton, Marta; Benito-Cuesta, Irene; Wandosell, Francisco

    2016-09-06

    Cerebellar pathology has been related to presenilin 1 mutations in certain pedigrees of familial Alzheimer's disease. However, cerebellum tissue has not been intensively analyzed in transgenic models of mutant presenilins. Furthermore, the effect of the sex of the mice was not systematically analyzed, despite the fact that important gender differences in the evolution of the disease in the human population have been described. We analyzed whether the progression of amyloidosis in a double transgenic mouse, AβPP/PS1, is susceptible to aging and differentially affects males and females. The accumulation of amyloid in the cerebellum differentially affects males and females of the AβPP/PS1 transgenic line, which was found to be ten-fold higher in 15-month-old females. Amyloid-β accumulation was more evident in the molecular layer of the cerebellum, but glia reaction was only observed in the granular layer of the older mice. The sex divergence was also observed in other neuronal, survival, and autophagic markers. The cerebellum plays an important role in the evolution of the pathology in this transgenic mouse model. Sex differences could be crucial for a complete understanding of this disease. We propose that the human population could be studied in this way. Sex-specific treatment strategies in human populations could show a differential response to the therapeutic approach.

  8. A novel radial water tread maze tracks age-related cognitive decline in mice

    Directory of Open Access Journals (Sweden)

    Christina Pettan-Brewer

    2013-10-01

    Full Text Available There is currently no treatment and cure for age-related dementia and cognitive impairment in humans. Mice suffer from age-related cognitive decline just as people do, but assessment is challenging because of cumbersome and at times stressful performance tasks. We developed a novel radial water tread (RWT maze and tested male C57BL/6 (B6 and C57BL/6 x Balb/c F1 (CB6F1 mice at ages 4, 12, 20, and 28 months. B6 mice showed a consistent learning experience and memory retention that gradually decreased with age. CB6F1 mice showed a moderate learning experience in the 4 and 12 month groups, which was not evident in the 20 and 28 month groups. In conclusion, CB6F1 mice showed more severe age-related cognitive impairment compared to B6 mice and might be a suitable model for intervention studies. In addition, the RWT maze has a number of operational advantages compared to currently accepted tasks and can be used to assess age-related cognition impairment in B6 and CB6F1 mice as early as 12 months of age.

  9. Neuronal erythropoietin overexpression protects mice against age-related hearing loss (presbycusis).

    Science.gov (United States)

    Monge Naldi, Arianne; Belfrage, Celina; Jain, Neha; Wei, Eric T; Canto Martorell, Belén; Gassmann, Max; Vogel, Johannes

    2015-12-01

    So far, typical causes of presbycusis such as degeneration of hair cells and/or primary auditory (spiral ganglion) neurons cannot be treated. Because erythropoietin's (Epo) neuroprotective potential has been shown previously, we determined hearing thresholds of juvenile and aged mice overexpressing Epo in neuronal tissues. Behavioral audiometry revealed in contrast to 5 months of age, that 11-month-old Epo-transgenic mice had up to 35 dB lower hearing thresholds between 1.4 and 32 kHz, and at the highest frequencies (50-80 kHz), thresholds could be obtained in aged Epo-transgenic only but not anymore in old C57BL6 control mice. Click-evoked auditory brainstem response showed similar results. Numbers of spiral ganglion neurons in aged C57BL6 but not Epo-transgenic mice were dramatically reduced mainly in the basal turn, the location of high frequencies. In addition, there was a tendency to better preservation of inner and outer hair cells in Epo-transgenic mice. Hence, Epo's known neuroprotective action effectively suppresses the loss of spiral ganglion cells and probably also hair cells and, thus, development of presbycusis in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Effect of Vomeronasal Organ Removal From Male Mice on Their Preference for and Neural Fos Responses to Female Urinary Odors

    OpenAIRE

    Pankevich, Diana E.; Cherry, James A.; Baum, Michael J.

    2006-01-01

    Four experiments were conducted to determine whether vomeronasal organ (VNO) inputs in male mice mediate the rewarding properties of estrous female urinary odors. Sexually naive male mice with either an intact (VNOi) or lesioned (VNOx) VNO preferred to investigate female urine over water in Y-maze tests. Subsequently, VNOi males ran significantly more quickly and remained in nasal contact longer with estrous female urine than with male urine, whereas VNOx males investigated these odors equall...

  11. Aging-associated renal disease in mice is fructokinase dependent.

    Science.gov (United States)

    Roncal-Jimenez, Carlos A; Ishimoto, Takuji; Lanaspa, Miguel A; Milagres, Tamara; Hernando, Ana Andres; Jensen, Thomas; Miyazaki, Makoto; Doke, Tomohito; Hayasaki, Takahiro; Nakagawa, Takahiko; Marumaya, Shoichi; Long, David A; Garcia, Gabriela E; Kuwabara, Masanari; Sánchez-Lozada, Laura G; Kang, Duk-Hee; Johnson, Richard J

    2016-10-01

    Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.

  12. Rate of lens lesion development and the age of mice at time of irradiation

    International Nuclear Information System (INIS)

    Gajewski, A.K.; Majewska, K.; Slowikowska, M.G.

    1976-01-01

    The rate of lens lesion development has been studied in mice irradiated at different age ranging from one day up to one year old mice. The time needed for the first appearance of lens lesion was shortest in groups of mice irradiated at the age of one, two and three days of life, and longest in groups of mice irradiated at the age of 5 days, 1 week and 2 weeks of life. The time needed for the first appearance of lens lesion for mice irradiated between the third week and one year of life was constant. It was longer than for mice irradiated during the first three days of life and shorter than for mice irradiated at 5 up to 14 days of life. In all but one irradiated groups the age at which the first lens lesion occurred differed significantly from the age at which the first senile changes occurred in the lens of control mice. The one exception was the group of mice irradiated at the age of one year. (author)

  13. Different effects of bisphenol-A on memory behavior and synaptic modification in intact and estrogen-deprived female mice.

    Science.gov (United States)

    Xu, Xiaohong; Gu, Ting; Shen, Qiaoqiao

    2015-03-01

    Bisphenol-A (BPA) has the capability of interfering with the effects of estrogens on modulating brain function. The purpose of this study was to investigate the effects of BPA on memory and synaptic modification in the hippocampus of female mice under different levels of cycling estrogen. BPA exposure (40, 400 μg/kg/day) for 8 weeks did not affect spatial memory and passive avoidance task of gonadally intact mice but improved ovariectomy (Ovx)-induced memory impairment, whereas co-exposure of BPA with estradiol benzoate (EB) diminished the rescue effect of EB on memory behavior of Ovx mice. The results of morphometric measurement showed that BPA positively modified the synaptic interface structure and increased the synaptic density of CA1 pyramidal cell in the hippocampus of Ovx females, but inhibited the enhancement of EB on synaptic modification and synaptogenesis of Ovx mice. Furthermore, BPA up-regulated synaptic proteins synapsin I and PSD-95 and NMDA receptor NR2B but inhibited EB-induced increase in PSD-95 and NR2B in the hippocampus of Ovx mice. These results suggest that BPA interfered with normal hormonal regulation in synaptic plasticity and memory of female mice as a potent estrogen mimetic and as a disruptor of estrogen under various concentrations of cycling estrogen. © 2014 International Society for Neurochemistry.

  14. Determinants of Aged Female Sexuality.

    Science.gov (United States)

    Hoyt, Les Leanne

    Older women (N=50) were asked a series of questions about reference groups, sex roles, sexuality, sexual desire at different stages in the life cycle, appropriateness of certain types of sexual behavior, adjustment to aging, life satisfaction, organizational activities, and male/female interaction. Quantitative and qualitative data provided the…

  15. A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice1

    Science.gov (United States)

    Kauffman, Alexander S.; Thackray, Varykina G.; Ryan, Genevieve E.; Tolson, Kristen P.; Glidewell-Kenney, Christine A.; Semaan, Sheila J.; Poling, Matthew C.; Iwata, Nahoko; Breen, Kellie M.; Duleba, Antoni J.; Stener-Victorin, Elisabet; Shimasaki, Shunichi; Webster, Nicholas J.; Mellon, Pamela L.

    2015-01-01

    Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice. Pubertal female C57BL/6N mice were treated for 5 wk with LET, which resulted in increased serum testosterone and normal diestrus levels of estradiol, similar to the hyperandrogenemia and follicular phase estrogen levels of PCOS women. As in PCOS, ovaries from LET mice were larger, polycystic, and lacked corpora lutea versus controls. Most LET females were acyclic, and all were infertile. LET females displayed elevated serum LH levels and higher Lhb mRNA in the pituitary. In contrast, serum FSH and Fshb were significantly reduced in LET females, demonstrating differential effects on gonadotropins, as in PCOS. Within the ovary, LET females had higher Cyp17, Cyp19, and Fsh receptor mRNA expression. In the hypothalamus, LET females had higher kisspeptin receptor mRNA expression but lower progesterone receptor mRNA levels. LET females also gained more weight than controls, had increased abdominal adiposity and adipocyte size, elevated adipose inflammatory mRNA levels, and impaired glucose tolerance, mirroring the metabolic phenotype in PCOS women. This is the first report of a LET paradigm in mice that recapitulates both reproductive and metabolic PCOS phenotypes and will be useful to genetically probe the PCOS condition. PMID:26203175

  16. Preferences of group-housed female mice regarding structure of softwood bedding.

    Science.gov (United States)

    Kirchner, J; Hackbarth, H; Stelzer, H D; Tsai, P-P

    2012-04-01

    Bedding influences various parameters in the housing of laboratory mice, such as health, physiology and behaviour (often considered as being integral parts of welfare). Notwithstanding existent studies about bedding preferences of individually tested mice, data about group-housed mice are still lacking. The aim of this study was to find out the structure preference for softwood bedding of group-housed mice. One hundred and eight 8-week-old female mice (C57BL6/JOlaHsd and BALB/cOlaHsd) were housed in groups of three and were given one-week free access to two different bedding structures at a time. In three test combinations, softwood shaving bedding was tested versus softwood chip bedding products of three different particle sizes (fine/medium/coarse-grained). The preference test was performed in a DoubleCage system composed of two Makrolon type IIL cages, connected by a perspex tunnel. This validated system was able to detect the crossings of each individual animal with correct crossing time and direction. On the basis of these data, dwelling times on the particular bedding structures were statistically analysed as a parameter for bedding preferences. In all three test combinations, a highly significant shaving preference was detected. On average, mice spent 70% of their dwelling time on the shavings. This preference was more explicit during the light period and in C57BL/6J mice. The relative ranking of the bedding structures was: shavings > coarse-grained chips > medium chips = fine chips. By means of these results, a shaving structure as bedding can be recommended for laboratory mice, whereas fine chip structures should be avoided.

  17. [Effects of aquaporin-4 gene knockout on behavior changes and cerebral morphology during aging in mice].

    Science.gov (United States)

    Su, Shengan; Lu, Yunbi; Zhang, Weiping

    2013-05-01

    To investigate the effects of aquaporin-4 (AQP4) gene knockout on the behavior changes and cerebral morphology during aging in mice,and to compare that of young and aged mice between AQP4 knockout mice (AQP4(-/-)) and wild type mice (AQP4(+/+)). Fifty-eight CD-1 mice were divided into four groups: young (2-3 months old) AQP4(-/-), aged (17-19 months old) AQP4(-/-), young AQP4(+/+) and aged AQP4(+/+). The activity levels and exploring behavior of mice were tested in open field. The neurons were stained with toluidine blue and NeuN, the astrocytes and microglia were stained with GFAP and Iba-1, respectively. The morphological changes of neuron, astrocyte and microglia were then analyzed. Compared with young mice, the total walking distance in open field of aged AQP4(+/+) mice and aged AQP4(-/-) mice decreased 41.2% and 44.1%, respectively (Ptime in the central area of open field. The density of neuron in cortex of aged AQP4(+/+) mice and aged AQP4(-/-) mice decreased 19.6% and 15.8%, respectively (P<0.05), while there was no difference in the thickness of neuron cell body in hippocampus CA1 region. The density of astrocyte in hippocampus CA3 region of aged AQP4(+/+) mice and aged AQP4(-/-) mice increased 57.7% and 64.3%, respectively (P<0.001), while there was no difference in the area of astrocyte. The area of microglia in hippocampus CA3 region of aged AQP4(+/+) mice and aged AQP4(-/-) mice increased 46.9% and 52.0%, respectively (P<0.01), while there was no difference in the density of microglia. Compared with AQP4(+/+) mice, the young and aged AQP4(-/-) mice showed smaller area of astrocyte in hippocampus CA3 region, reduced 18.0% in young mice and 23.6% in aged mice. There was no difference between AQP4(+/+) mice and AQP4(-/-) mice for other observed indexes. AQP4 may be involved in change of astrocyte and astrocyte-related behaviors during aging. AQP4 gene knockout may have limited effects on the change of neuron, microglia and most neuronal behaviors in aging

  18. Cardiac and vascular changes in elderly atherosclerotic mice: the influence of gender

    Directory of Open Access Journals (Sweden)

    Pereira Thiago MC

    2010-08-01

    Full Text Available Abstract Background Although advanced age is considered a risk factor for several diseases, the impact of gender on age-associated cardiovascular diseases, such as atherosclerotic processes and valvular diseases, remains not completely clarified. The present study was designed to assess aortic valve morphology and function and vascular damage in elderly using the apolipoprotein E knockout (ApoE KO mouse. Our hypothesis was that advanced age-related cardiovascular changes are aggravated in atherosclerotic male mice. Methods The grade (0 to 4 of aortic regurgitation was evaluated through angiography. In addition, vascular lipid deposition and senescence were evaluated through histochemical analyses in aged male and female ApoE KO mice, and the results were compared to wild-type C57BL/6J (C57 mice. Results Aortic regurgitation was observed in 92% of the male ApoE KO mice and 100% of the male C57 mice. Comparatively, in age-matched female ApoE KO and C57 mice, aortic regurgitation was observed in a proportion of 58% and 53%, respectively. Histological analysis of the aorta showed an outward (positive remodeling in ApoE KO mice (female: 1.86 ± 0.15; male: 1.89 ± 0.68 using C57 groups as reference values. Histochemical evaluation of the aorta showed lipid deposition and vascular senescence only in the ApoE KO group, which were more pronounced in male mice. Conclusion The data show that male gender contributes to the progression of aortic regurgitation and that hypercholesterolemia and male gender additively contribute to the occurrence of lipid deposition and vascular senescence in elderly mice.

  19. Genetic deletion of P-glycoprotein alters stress responsivity and increases depression-like behavior, social withdrawal and microglial activation in the hippocampus of female mice.

    Science.gov (United States)

    Brzozowska, Natalia I; Smith, Kristie L; Zhou, Cilla; Waters, Peter M; Cavalcante, Ligia Menezes; Abelev, Sarah V; Kuligowski, Michael; Clarke, David J; Todd, Stephanie M; Arnold, Jonathon C

    2017-10-01

    P-glycoprotein (P-gp) is an ABC transporter expressed at the blood brain barrier and regulates the brain uptake of various xenobiotics and endogenous mediators including glucocorticoid hormones which are critically important to the stress response. Moreover, P-gp is expressed on microglia, the brain's immune cells, which are activated by stressors and have an emerging role in psychiatric disorders. We therefore hypothesised that germline P-gp deletion in mice might alter the behavioral and microglial response to stressors. Female P-gp knockout mice displayed an unusual, frantic anxiety response to intraperitoneal injection stress in the light-dark test. They also tended to display reduced conditioned fear responses compared to wild-type (WT) mice in a paradigm where a single electric foot-shock stressor was paired to a context. Foot-shock stress reduced social interaction and decreased microglia cell density in the amygdala which was not varied by P-gp genotype. Independently of stressor exposure, female P-gp deficient mice displayed increased depression-like behavior, idiosyncratic darting behavior, age-related social withdrawal and hyperactivity, facilitated sensorimotor gating and altered startle reactivity. In addition, P-gp deletion increased microglia cell density in the CA3 region of the hippocampus, and the microglial cells exhibited a reactive, hypo-ramified morphology. Further, female P-gp KO mice displayed increased glucocorticoid receptor (GR) expression in the hippocampus. In conclusion, this research shows that germline P-gp deletion affected various behaviors of relevance to psychiatric conditions, and that altered microglial cell activity and enhanced GR expression in the hippocampus may play a role in mediating these behaviors. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Effects of environmental enrichment on anxiety-like behavior, sociability, sensory gating, and spatial learning in male and female C57BL/6J mice.

    Science.gov (United States)

    Hendershott, Taylor R; Cronin, Marie E; Langella, Stephanie; McGuinness, Patrick S; Basu, Alo C

    2016-11-01

    The influence of housing on cognition and emotional regulation in mice presents a problem for the study of genetic and environmental risk factors for neuropsychiatric disorders: standard laboratory housing may result in low levels of cognitive function or altered levels of anxiety that leave little room for assessment of deleterious effects of experimental manipulations. The use of enriched environment (EE) may allow for the measurement of a wider range of performance in cognitive domains. Cognitive and behavioral effects of EE in male mice have not been widely reproduced, perhaps due to variability in the application of enrichment protocols, and the effects of EE in female mice have not been widely studied. We have developed an EE protocol using common laboratory equipment that, without a running wheel for exercise, results in significant cognitive and behavioral effects relative to standard laboratory housing conditions. We compared male and female wild-type C57BL/6J mice reared from weaning age in an EE to those reared in a standard environment (SE), using common measures of anxiety-like behavior, sensory gating, sociability, and spatial learning and memory. Sex was a significant factor in relevant elevated plus maze (EPM) measures, and bordered on significance in a social interaction (SI) assay. Effects of EE on anxiety-like behavior and sociability were indicative of a general increase in exploratory activity. In male and female mice, EE resulted in reduced prepulse inhibition (PPI) of the acoustic startle response, and enhanced spatial learning and use of spatially precise strategies in a Morris water maze task. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Motor Performance is Impaired Following Vestibular Stimulation in Ageing Mice

    Science.gov (United States)

    Tung, Victoria W. K.; Burton, Thomas J.; Quail, Stephanie L.; Mathews, Miranda A.; Camp, Aaron J.

    2016-01-01

    Balance and maintaining postural equilibrium are important during stationary and dynamic movements to prevent falls, particularly in older adults. While our sense of balance is influenced by vestibular, proprioceptive, and visual information, this study focuses primarily on the vestibular component and its age-related effects on balance. C57Bl/6J mice of ages 1, 5–6, 8–9 and 27–28 months were tested using a combination of standard (such as grip strength and rotarod) and newly-developed behavioral tests (including balance beam and walking trajectory tests with a vestibular stimulus). In the current study, we confirm a decline in fore-limb grip strength and gross motor coordination as age increases. We also show that a vestibular stimulus of low frequency (2–3 Hz) and duration can lead to age-dependent changes in balance beam performance, which was evident by increases in latency to begin walking on the beam as well as the number of times hind-feet slip (FS) from the beam. Furthermore, aged mice (27–28 months) that received continuous access to a running wheel for 4 weeks did not improve when retested. Mice of ages 1, 10, 13 and 27–28 months were also tested for changes in walking trajectory as a result of the vestibular stimulus. While no linear relationship was observed between the changes in trajectory and age, 1-month-old mice were considerably less affected than mice of ages 10, 13 and 27–28 months. Conclusion: this study confirms there are age-related declines in grip strength and gross motor coordination. We also demonstrate age-dependent changes to finer motor abilities as a result of a low frequency and duration vestibular stimulus. These changes showed that while the ability to perform the balance beam task remained intact across all ages tested, behavioral changes in task performance were observed. PMID:26869921

  2. Effects of social isolation, re-socialization and age on cognitive and aggressive behaviors of Kunming mice and BALB/c mice.

    Science.gov (United States)

    An, Dong; Chen, Wei; Yu, De-Qin; Wang, Shi-Wei; Yu, Wei-Zhi; Xu, Hong; Wang, Dong-Mei; Zhao, Dan; Sun, Yi-Ping; Wu, Jun-Cheng; Tang, Yi-Yuan; Yin, Sheng-Ming

    2017-05-01

    Both Kunming (KM) mice and BALB/c mice have been widely used as rodent models to investigate stress-associated mental diseases. However, little is known about the different behaviors of KM mice and BALB/c mice after social isolation, particularly cognitive and aggressive behaviors. In this study, the behaviors of KM and BALB/c mice isolated for 2, 4 and 8 weeks and age-matched controls were evaluated using object recognition, object location and resident-intruder tests. The recovery of behavioral deficits by re-socialization was also examined for the isolated mice in adolescence. Our study showed that isolation for 2, 4 and 8 weeks led to cognitive deficits and increased aggressiveness for both KM and BALB/c mice. An important finding is that re-socialization could completely recover spatial/non-spatial cognitive deficits resulted from social isolation for both KM and BALB/c mice. In addition, age only impacted aggressiveness of KM mice. Moreover, isolation duration showed different impacts on cognitive and aggressive behaviors for both KM and BALB/c mice. Furthermore, BALB/c mice showed weak spatial/non-spatial memory and low aggressiveness when they were at the same age and isolation duration, compared to KM mice. In conclusion, KM mice and BALB/c mice behaved characteristically under physiology and isolation conditions. © 2016 Japanese Society of Animal Science.

  3. EAAC1 Gene Deletion Increases Neuronal Death and Blood Brain Barrier Disruption after Transient Cerebral Ischemia in Female Mice

    Directory of Open Access Journals (Sweden)

    Bo Young Choi

    2014-10-01

    Full Text Available EAAC1 is important in modulating brain ischemic tolerance. Mice lacking EAAC1 exhibit increased susceptibility to neuronal oxidative stress in mice after transient cerebral ischemia. EAAC1 was first described as a glutamate transporter but later recognized to also function as a cysteine transporter in neurons. EAAC1-mediated transport of cysteine into neurons contributes to neuronal antioxidant function by providing cysteine substrates for glutathione synthesis. Here we evaluated the effects of EAAC1 gene deletion on hippocampal blood vessel disorganization after transient cerebral ischemia. EAAC1−/− female mice subjected to transient cerebral ischemia by common carotid artery occlusion for 30 min exhibited twice as much hippocampal neuronal death compared to wild-type female mice as well as increased reduction of neuronal glutathione, blood–brain barrier (BBB disruption and vessel disorganization. Pre-treatment of N-acetyl cysteine, a membrane-permeant cysteine prodrug, increased basal glutathione levels in the EAAC1−/− female mice and reduced ischemic neuronal death, BBB disruption and vessel disorganization. These findings suggest that cysteine uptake by EAAC1 is important for neuronal antioxidant function under ischemic conditions.

  4. Similar reliability and equivalent performance of female and male mice in the open field and water‐maze place navigation task

    Science.gov (United States)

    Fritz, Ann‐Kristina; Amrein, Irmgard

    2017-01-01

    Although most nervous system diseases affect women and men differentially, most behavioral studies using mouse models do not include subjects of both sexes. Many researchers worry that data of female mice may be unreliable due to the estrous cycle. Here, we retrospectively evaluated sex effects on coefficient of variation (CV) in 5,311 mice which had performed the same place navigation protocol in the water‐maze and in 4,554 mice tested in the same open field arena. Confidence intervals for Cohen's d as measure of effect size were computed and tested for equivalence with 0.2 as equivalence margin. Despite the large sample size, only few behavioral parameters showed a significant sex effect on CV. Confidence intervals of effect size indicated that CV was either equivalent or showed a small sex difference at most, accounting for less than 2% of total group to group variation of CV. While female mice were potentially slightly more variable in water‐maze acquisition and in the open field, males tended to perform less reliably in the water‐maze probe trial. In addition to evaluating variability, we also directly compared mean performance of female and male mice and found them to be equivalent in both water‐maze place navigation and open field exploration. Our data confirm and extend other large scale studies in demonstrating that including female mice in experiments does not cause a relevant increase of data variability. Our results make a strong case for including mice of both sexes whenever open field or water‐maze are used in preclinical research. PMID:28654717

  5. Circadian rhythm resynchronization improved isoflurane-induced cognitive dysfunction in aged mice.

    Science.gov (United States)

    Song, Jia; Chu, Shuaishuai; Cui, Yin; Qian, Yue; Li, Xiuxiu; Xu, Fangxia; Shao, Xueming; Ma, Zhengliang; Xia, Tianjiao; Gu, Xiaoping

    2018-04-13

    Postoperative cognitive dysfunction (POCD) is a common clinical phenomenon characterized by cognitive deficits in patients after anesthesia and surgery. Advanced age is a significant independent risk factor for POCD. We previously reported that in young mice, sleep-wake rhythm is involved in the isoflurane-induced memory impairment. In present study, we sought to determine whether advanced age increased the risk of POCD through aggravated and prolonged post-anesthetic circadian disruption in the elderly. We constructed POCD model by submitting the mice to 5-h 1.3% isoflurane anesthesia from Zeitgeber Time (ZT) 14 to ZT19. Under novel object recognition assay (NOR) and Morris water maze (MWM) test, We found 5-h isoflurane anesthesia impaired the cognition of young mice for early 3 days after anesthesia but damaged the aged for at least 1 week. With Mini-Mitter continuously monitoring, a 3.22 ± 0.75 h gross motor activity acrophase delay was manifested in young mice on D1, while in the aged mice, the gross motor activity phase shift lasted for 3 days, consistent with the body temperature rhythm trends of change. Melatonin has been considered as an effective remedy for circadian rhythm shift. In aged mice, melatonin was pretreated intragastrically at the dose of 10 mg/kg daily for 7 consecutive days before anesthesia. We found that melatonin prevented isoflurane-induced cognitive impairments by restoring the locomotor activity and temperature circadian rhythm via clock gene resynchronization. Overall, these results indicated that Long-term isoflurane anesthesia induced more aggravated and prolonged memory deficits and circadian rhythms disruption in aged mice. Melatonin could prevent isoflurane-induced cognitive impairments by circadian rhythm resynchronization. Copyright © 2018. Published by Elsevier Inc.

  6. Effects of Aging and Oxidative Stress on Spermatozoa of Superoxide-Dismutase 1- and Catalase-Null Mice.

    Science.gov (United States)

    Selvaratnam, Johanna S; Robaire, Bernard

    2016-09-01

    Advanced paternal age is linked to complications in pregnancy and genetic diseases in offspring. Aging results in excess reactive oxygen species (ROS) and DNA damage in spermatozoa; this damage can be transmitted to progeny with detrimental consequences. Although there is a loss of antioxidants with aging, the impact on aging male germ cells of the complete absence of either catalase (CAT) or superoxide dismutase 1 (SOD1) has not been investigated. We used CAT-null (Cat(-/-)) and SOD1-null (Sod(-/-)) mice to determine whether loss of these antioxidants increases germ cell susceptibility to redox dysfunction with aging. Aging reduced fertility and the numbers of Sertoli and germ cells in all mice. Aged Sod(-/-) mice displayed an increased loss of fertility compared to aged wild-type mice. Treatment with the pro-oxidant SIN-10 increased ROS in spermatocytes of aged wild-type and Sod(-/-) mice, while aged Cat(-/-) mice were able to neutralize this ROS. The antioxidant peroxiredoxin 1 (PRDX1) increased with age in wild-type and Cat(-/-) mice but was consistently low in young and aged Sod(-/-) mice. DNA damage and repair markers (γ-H2AX and 53BP1) were reduced with aging and lower in young Sod(-/-) and Cat(-/-) mice. Colocalization of γ-H2AX and 53BP1 suggested active repair in young wild-type mice but reduced in young Cat(-/-) and in Sod(-/-) mice and with age. Oxidative DNA damage (8-oxodG) increased in young Sod(-/-) mice and with age in all mice. These studies show that aged Sod(-/-) mice display severe redox dysfunction, while wild-type and Cat(-/-) mice have compensatory mechanisms to partially alleviate oxidative stress and reduce age-related DNA damage in spermatozoa. Thus, SOD1 but not CAT is critical to the maintenance of germ cell quality with aging. © 2016 by the Society for the Study of Reproduction, Inc.

  7. Neuropsychiatric Symptom Modeling in Male and Female C57BL/6J Mice after Experimental Traumatic Brain Injury

    Science.gov (United States)

    Tucker, Laura B.; Burke, John F.; Fu, Amanda H.

    2017-01-01

    Abstract Psychiatric symptoms such as anxiety and depression are frequent and persistent complaints following traumatic brain injury (TBI). Modeling these symptoms in animal models of TBI affords the opportunity to determine mechanisms underlying behavioral pathologies and to test potential therapeutic agents. However, testing these symptoms in animal models of TBI has yielded inconsistent results. The goal of the current study was to employ a battery of tests to measure multiple anxiety- and depressive-like symptoms following TBI in C57BL/6J mice, and to determine if male and female mice are differentially affected by the injury. Following controlled cortical impact (CCI) at a parietal location, neither male nor female mice showed depressive-like symptoms as measured by the Porsolt forced-swim test and sucrose preference test. Conclusions regarding anxiety-like behaviors were dependent upon the assay employed; CCI-induced thigmotaxis in the open field suggested an anxiogenic effect of the injury; however, results from the elevated zero maze, light-dark box, and marble-burying tests indicated that CCI reduced anxiety-like behaviors. Fewer anxiety-like behaviors were also associated with the female sex. Increased levels of activity were also measured in female mice and injured mice in these tests, and conclusions regarding anxiety should be taken with caution when experimental manipulations induce changes in baseline activity. These results underscore the irreconcilability of results from studies attempting to model TBI-induced neuropsychiatric symptoms. Changes in injury models or better attempts to replicate the clinical syndrome may improve the translational applicability of rodent models of TBI-induced anxiety and depression. PMID:27149139

  8. No Overt Deficits in Aged Tau-Deficient C57Bl/6.Mapttm1(EGFPKit GFP Knockin Mice.

    Directory of Open Access Journals (Sweden)

    Annika van Hummel

    Full Text Available Several mouse lines with knockout of the tau-encoding MAPT gene have been reported in the past; they received recent attention due to reports that tau reduction prevented Aβ-induced deficits in mouse models of Alzheimer's disease. However, the effects of long-term depletion of tau in vivo remained controversial. Here, we used the tau-deficient GFP knockin line Mapttm1(EGFPkit on a pure C57Bl/6 background and subjected a large cohort of males and females to a range of motor, memory and behavior tests and imaging analysis, at the advanced age of over 16 months. Neither heterozygous nor homozygous Mapttm1(EGFPkit mice presented with deficits or abnormalities compared to wild-type littermates. Differences to reports using other tau knockout models may be due to different genetic backgrounds, respective gene targeting strategies or other confounding factors, such as nutrition. To this end, we report no functional or morphological deficits upon tau reduction or depletion in aged mice.

  9. Female mice lacking cholecystokinin 1 receptors have compromised neurogenesis, and fewer dopaminergic cells in the olfactory bulb

    Directory of Open Access Journals (Sweden)

    Yi eSui

    2013-03-01

    Full Text Available Neurogenesis in the adult rodent brain is largely restricted to the subependymal zone (SVZ of the lateral ventricle and subgranular zone (SGZ of the dentate gyrus (DG. We examined whether cholecystokinin (CCK through actions mediated by CCK1 receptors (CCK1R is involved in regulating neurogenesis. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU injected 2 hours prior to death or by immunoreactivity against Ki67, were reduced by 37% and 42%, respectively, in female (but not male mice lacking CCK1Rs (CCK1R-/- compared to wild-type (WT. Generation of neuroblasts in the SVZ and rostral migratory stream was also affected, since the number of doublecortin (DCX-immunoreactive (ir neuroblasts in these regions decreased by 29%. In the SGZ of female CCK1R-/- mice, BrdU-positive (+ and Ki67-ir cells were reduced by 38% and 56%, respectively, while DCX-ir neuroblasts were down 80%. Subsequently, the effect of reduced SVZ/SGZ proliferation on the generation and survival of mature adult-born cells in female CCK1R-/- mice was examined. In the OB granule cell layer (GCL, the number of neuronal nuclei (NeuN-ir and calretinin-ir cells was stable compared to WT, and 42 days after BrdU injections, the number of BrdU+ cells co-expressing GABA- or NeuN-like immunoreactivity (LI was similar. Compared to WT, the granule cell layer of the DG in female CCK1R-/- mice had a similar number of calbindin-ir cells and BrdU+ cells co-expressing calbindin-LI 42 days after BrdU injections. However, the OB glomerular layer (GL of CCK1R-/- female mice had 11% fewer NeuN-ir cells, 23% less TH-ir cells, and a 38% and 29% reduction in BrdU+ cells that co-expressed TH-LI or GABA-LI, respectively. We conclude that CCK, via CCK1Rs, is involved in regulating the generation of proliferating cells and neuroblasts in the adult female mouse brain, and mechanisms are in place to maintain steady neuronal populations in the OB and DG when the rate of proliferation is

  10. Middle-aged human apoE4 targeted-replacement mice show retention deficits on a wide range of spatial memory tasks.

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    Bour, Alexandra; Grootendorst, Jeannette; Vogel, Elise; Kelche, Christian; Dodart, Jean-Cosme; Bales, Kelly; Moreau, Pierre-Henri; Sullivan, Patrick M; Mathis, Chantal

    2008-11-21

    Apolipoprotein (apo) E4, one of three human apoE (h-apoE) isoforms, has been identified as a major genetic risk factor for Alzheimer's disease and for cognitive deficits associated with aging. However, the biological mechanisms involving apoE in learning and memory processes are unclear. A potential isoform-dependent role of apoE in cognitive processes was studied in human apoE targeted-replacement (TR) mice. These mice express either the human apoE3 or apoE4 gene under the control of endogenous murine apoE regulatory sequences, resulting in physiological expression of h-apoE in both a temporal and spatial pattern similar to humans. Male and female apoE3-TR, apoE4-TR, apoE-knockout and C57BL/6J mice (15-18 months) were tested with spatial memory and avoidance conditioning tasks. Compared to apoE3-TR mice, spatial memory in female apoE4-TR mice was impaired based on their poor performances in; (i) the probe test of the water-maze reference memory task, (ii) the water-maze working memory task and (iii) an active avoidance Y-maze task. Retention performance on a passive avoidance task was also impaired in apoE4-TR mice, but not in other genotypes. These deficits in both spatial and avoidance memory tasks may be related to the anatomical and functional abnormalities previously reported in the hippocampus and the amygdala of apoE4-TR mice. We conclude that the apoE4-TR mice provide an excellent model for understanding the mechanisms underlying apoE4-dependent susceptibility to cognitive decline.

  11. The effect of aging on efferent nerve fibers regeneration in mice.

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    Verdú, E; Butí, M; Navarro, X

    1995-10-23

    This study evaluates the influence of aging on nerve regeneration and reinnervation of target organs in mice aged 2, 6, 9, 12, 18 and 24 months. In animals of each age group the sciatic nerve was subjected to crush, section or section and suture. Reinnervation of plantar muscles and sweat glands (SG) was evaluated over three months after operation by functional methods. Reappearance of SG secretion and motor responses occurred slightly earlier in young than older mice. The degree of motor and sudomotor reinnervation, with respect to preoperative control values, was also significantly higher in young than old animals. The differences were more pronounced after 12 months of age. The degree of recovery progressively decreased with the severity of the lesion, differences being more marked in older mice. Neurorraphy improved recovery, comparatively more in older than in young mice. These results indicate that, after injuries of peripheral nerves, axonal regeneration and reinnervation are maintained throughout life, but tend to be more delayed and slightly less effective with aging.

  12. Treadmill Exercise Attenuates Retinal Oxidative Stress in Naturally-Aged Mice: An Immunohistochemical Study

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    Chan-Sik Kim

    2015-09-01

    Full Text Available In the retina, a number of degenerative diseases, including glaucoma, diabetic retinopathy, and age-related macular degeneration, may occur as a result of aging. Oxidative damage is believed to contribute to the pathogenesis of aging as well as to age-related retinal disease. Although physiological exercise has been shown to reduce oxidative stress in rats and mice, it is not known whether it has a similar effect in retinal tissues. The aim of this study was to evaluate retinal oxidative stress in naturally-aged mice. In addition, we evaluated the effects of aerobic training on retinal oxidative stress by immunohistochemically evaluating oxidative stress markers. A group of twelve-week-old male mice were not exercised (young control. Two groups of twenty-two-month-old male mice were created: an old control group and a treadmill exercise group. The old control group mice were not exercised. The treadmill exercise group mice ran on a treadmill (5 to 12 m/min, 30 to 60 min/day, 3 days/week for 12 weeks. The retinal thickness and number of cells in the ganglion cell layer of the naturally-aged mice were reduced compared to those in the young control mice. However, treadmill exercise reversed these morphological changes in the retinas. We evaluated retinal expression of carboxymethyllysine (CML, 8-hydroxy-2′-deoxyguanosine (8-OHdG and nitrotyrosine. The retinas from the aged mice showed increased CML, 8-OHdG, and nitrotyrosine immunostaining intensities compared to young control mice. The exercise group exhibited significantly lower CML levels and nitro-oxidative stress than the old control group. These results suggest that regular exercise can reduce retinal oxidative stress and that physiological exercise may be distinctly advantageous in reducing retinal oxidative stress.

  13. TWEAK Receptor Deficiency Has Opposite Effects on Female and Male Mice Subjected to Neonatal Hypoxia–Ischemia

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    Anton Kichev

    2018-04-01

    Full Text Available Tumor necrosis factor (TNF-like weak inducer of apoptosis (TWEAK is a multifunctional cytokine member of the TNF family. TWEAK binds to its only known receptor, Fn14, enabling it to activate downstream signaling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signaling in neonatal hypoxia–ischemia (HI. We found that after neonatal HI, both TWEAK and Fn14 expression were increased to a greater extent in male compared with female mice. To assess the role of TWEAK signaling after HI, the size of the injury was measured in neonatal mice genetically deficient in Fn14 and compared with their wild-type and heterozygote littermates. A significant sex difference in the Fn14 knockout (KO animals was observed. Fn14 gene KO was beneficial in females; conversely, reducing Fn14 expression exacerbated the brain injury in male mice. Our findings indicate that the TWEAK/Fn14 pathway is critical for development of hypoxic–ischemic brain injury in immature animals. However, as the responses are different in males and females, clinical implementation depends on development of sex-specific therapies.

  14. Types and rate of cataract development in mice irradiated at different ages

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    Gajewski, A.K.; Majewska, K.; Slowikowska, M.G.; Chomiczewski, K.; Kulig, A.

    1977-01-01

    The effect of age on the development of radiation cataract has been investigated in an inbred A strain of mice and, as a result, the patterns of age dependence and senile mice cataract development were obtained. In general, the lenses of mice 1 to 3 days old were the most sensitive to radiation; the maximum resistance was noted in 5-day-old mice, and from this age up to 3 to 7 weeks of life there was a period of increasing sensitivity. In older animals the lens sensitivity tends to level off. The early stages of cataract occurred in all irradiated groups at a younger age than in the control group, but the late stages occurred in irradiated groups at the same age as the senile cataract occurred in the control group. Two types of cataract were observed. One was typical for young irradiated mice 1 to 5 days of age and the other was typical for all remaining irradiated groups and for a control group. Also, an attempt was made to correlate the obtained results with the cell kinetics in normal lens epithelium

  15. Polysaccharide Extracted from Laminaria japonica Delays Intrinsic Skin Aging in Mice

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    Longyuan Hu

    2016-01-01

    Full Text Available This study aimed to determine the effect of topically applied Laminaria polysaccharide (LP on skin aging. We applied ointment containing LP (10, 25, and 50 μg/g or vitamin E (10 μg/g to the dorsal skin of aging mice for 12 months and young control mice for 4 weeks. Electron microscopy analysis of skin samples revealed that LP increased dermal thickness and skin collagen content. Tissue inhibitor of metalloprotease- (TIMP- 1 expression was upregulated while that of matrix metalloproteinase- (MMP- 1 was downregulated in skin tissue of LP-treated as compared to untreated aging mice. Additionally, phosphorylation of c-Jun N-terminal kinase (JNK and p38 was higher in aging skin than in young skin, while LP treatment suppressed phospho-JNK expression. LP application also enhanced the expression of antioxidative enzymes in skin tissue, causing a decrease in malondialdehyde levels and increases in superoxide dismutase, catalase, and glutathione peroxidase levels relative to those in untreated aging mice. These results indicate that LP inhibits MMP-1 expression by preventing oxidative stress and JNK phosphorylation, thereby delaying skin collagen breakdown during aging.

  16. Short-term Treatment of Daumone Improves Hepatic Inflammation in Aged Mice.

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    Park, Jong Hee; Ha, Hunjoo

    2015-05-01

    Chronic inflammation has been proposed as one of the main molecular mechanisms of aging and age-related diseases. Although evidence in humans is limited, short-term calorie restriction (CR) has been shown to have anti-inflammatory effects in aged experimental animals. We reported on the long-term treatment of daumone, a synthetic pheromone secreted by Caenorhabditis elegans in an energy deficient environment, extends the life-span and attenuates liver injury in aged mice. The present study examined whether late onset short-term treatment of daumone exerts anti-inflammatory effects in the livers of aged mice. Daumone was administered orally at doses of 2 or 20 mg/kg/day for 5 weeks to 24-month-old male C57BL/6J mice. Increased liver macrophage infiltration and gene expression of proinflammatory cytokines in aged mice were significantly attenuated by daumone treatment, suggesting that short-term oral administration of daumone may have hepatoprotective effects. Daumone also dose-dependently suppressed tumor necrosis factor-α (TNF-α)-induced nuclear factor-κB (NF-κB) phosphorylation in HepG2 cells. The present data demonstrated that short-term treatment of daumone has anti-inflammatory effects in aged mouse livers possibly through suppression of NF-κB signaling and suggest that daumone may become a lead compound targeting aging and age-associated diseases.

  17. Biosystems Study of the Molecular Networks Underlying Hippocampal Aging Progression and Anti-aging Treatment in Mice

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    Jiao Wang

    2017-12-01

    Full Text Available Aging progression is a process that an individual encounters as they become older, and usually results from a series of normal physiological changes over time. The hippocampus, which contributes to the loss of spatial and episodic memory and learning in older people, is closely related to the detrimental effects of aging at the morphological and molecular levels. However, age-related genetic changes in hippocampal molecular mechanisms are not yet well-established. To provide additional insight into the aging process, differentially-expressed genes of 3- versus 24- and 29-month old mice were re-analyzed. The results revealed that a large number of immune and inflammatory response-related genes were up-regulated in the aged hippocampus, and membrane receptor-associated genes were down-regulated. The down-regulation of transmembrane receptors may indicate the weaker perception of environmental exposure in older people, since many transmembrane proteins participate in signal transduction. In addition, molecular interaction analysis of the up-regulated immune genes indicated that the hub gene, Ywhae, may play essential roles in immune and inflammatory responses during aging progression, as well as during hippocampal development. Our biological experiments confirmed the conserved roles of Ywhae and its partners between human and mouse. Furthermore, comparison of microarray data between advanced-age mice treated with human umbilical cord blood plasma protein and the phosphate-buffered saline control showed that the genes that contribute to the revitalization of advanced-age mice are different from the genes induced by aging. These results implied that the revitalization of advanced-age mice is not a simple reverse process of normal aging progression. Our data assigned novel roles of genes during aging progression and provided further theoretic evidence for future studies exploring the underlying mechanisms of aging and anti-aging-related disease

  18. Tuning the brain for motherhood: prolactin-like central signalling in virgin, pregnant, and lactating female mice.

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    Salais-López, Hugo; Lanuza, Enrique; Agustín-Pavón, Carmen; Martínez-García, Fernando

    2017-03-01

    Prolactin is fundamental for the expression of maternal behaviour. In virgin female rats, prolactin administered upon steroid hormone priming accelerates the onset of maternal care. By contrast, the role of prolactin in mice maternal behaviour remains unclear. This study aims at characterizing central prolactin activity patterns in female mice and their variation through pregnancy and lactation. This was revealed by immunoreactivity of phosphorylated (active) signal transducer and activator of transcription 5 (pSTAT5-ir), a key molecule in the signalling cascade of prolactin receptors. We also evaluated non-hypophyseal lactogenic activity during pregnancy by administering bromocriptine, which suppresses hypophyseal prolactin release. Late-pregnant and lactating females showed significantly increased pSTAT5-ir resulting in a widespread pattern of immunostaining with minor variations between pregnant and lactating animals, which comprises nuclei of the sociosexual and maternal brain, including telencephalic (septum, nucleus of the stria terminalis, and amygdala), hypothalamic (preoptic, paraventricular, supraoptic, and ventromedial), and midbrain (periaqueductal grey) regions. During late pregnancy, this pattern was not affected by the administration of bromocriptine, suggesting it to be elicited mostly by non-hypophyseal lactogenic agents, likely placental lactogens. Virgin females displayed, instead, a variable pattern of pSTAT5-ir restricted to a subset of the brain nuclei labelled in pregnant and lactating mice. A hormonal substitution experiment confirmed that estradiol and progesterone contribute to the variability found in virgin females. Our results reflect how the shaping of the maternal brain takes place prior to parturition and suggest that lactogenic agents are important candidates in the development of maternal behaviours already during pregnancy.

  19. Effects of strain and age on ear wound healing and regeneration in mice

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    R.A. Costa

    2009-12-01

    Full Text Available Round holes in the ears of MRL mice tend to close with characteristics of regeneration believed to be absent in other mouse strains (e.g., C57BL/6. We evaluated the kinetics and the histopathology of ear wound closure in young (8 weeks old C57BL/6 and BALB/c mice. We also used middle-aged (40 weeks old C57BL/6 mice to evaluate the influence of aging on this process. A circular through-and-through hole was made in the ear, photographs were taken at different times after injury and wound area was measured with digital analysis software. The percentages of closed area measured on day 100 were: 23.57 ± 8.66% for young BALB/c mice, 56.47 ± 7.39% for young C57BL/6 mice, and 75.31 ± 23.65% for middle-aged C57BL/6 mice. Mice were sacrificed on days 1, 3, 5, 25, 44, and 100 for histological evaluation with hematoxylin and eosin, Gomori’s trichrome, periodic acid-Schiff, or picrosirius red staining. In young mice of both strains, healing included re-epithelialization, chondrogenesis, myogenesis, and collagen deposition. Young C57BL/6 and BALB/c mice differed in the organization of collagen fibers visualized using picrosirius-polarization. Sebaceous glands and hair follicles regenerated and chondrogenesis was greater in young C57BL/6 mice. In middle-aged C57BL/6 mice all aspects of regeneration were depressed. The characteristics of regeneration were present during ear wound healing in both young BALB/c and young C57BL/6 mice although they differed in intensity and pattern. Greater ear wound closure in middle-aged C57BL/6 mice was not correlated with regeneration.

  20. Sex-dependent alterations in motor and anxiety-like behavior of aged bacterial peptidoglycan sensing molecule 2 knockout mice.

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    Arentsen, Tim; Khalid, Roksana; Qian, Yu; Diaz Heijtz, Rochellys

    2018-01-01

    Peptidoglycan recognition proteins (PGRPs) are key sensing-molecules of the innate immune system that specifically detect bacterial peptidoglycan (PGN) and its derivates. PGRPs have recently emerged as potential key regulators of normal brain development and behavior. To test the hypothesis that PGRPs play a role in motor control and anxiety-like behavior in later life, we used 15-month old male and female peptidoglycan recognition protein 2 (Pglyrp2) knockout (KO) mice. Pglyrp2 is an N-acetylmuramyl-l-alanine amidase that hydrolyzes PGN between the sugar backbone and the peptide chain (which is unique among the mammalian PGRPs). Using a battery of behavioral tests, we demonstrate that Pglyrp2 KO male mice display decreased levels of anxiety-like behavior compared with wild type (WT) males. In contrast, Pglyrp2 KO female mice show reduced rearing activity and increased anxiety-like behavior compared to WT females. In the accelerated rotarod test, however, Pglyrp2 KO female mice performed better compared to WT females (i.e., they had longer latency to fall off the rotarod). Further, Pglyrp2 KO male mice exhibited decreased expression levels of synaptophysin, gephyrin, and brain-derived neurotrophic factor in the frontal cortex, but not in the amygdala. Pglyrp2 KO female mice exhibited increased expression levels of spinophilin and alpha-synuclein in the frontal cortex, while exhibiting decreased expression levels of synaptophysin, gephyrin and spinophilin in the amygdala. Our findings suggest a novel role for Pglyrp2asa key regulator of motor and anxiety-like behavior in late life. Copyright © 2017. Published by Elsevier Inc.

  1. SERCA2a gene transfer improves electrocardiographic performance in aged mdx mice

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    Hajjar Roger

    2011-08-01

    Full Text Available Abstract Background Cardiomyocyte calcium overloading has been implicated in the pathogenesis of Duchenne muscular dystrophy (DMD heart disease. The cardiac isoform of sarcoplasmic reticulum calcium ATPase (SERCA2a plays a major role in removing cytosolic calcium during heart muscle relaxation. Here, we tested the hypothesis that SERCA2a over-expression may mitigate electrocardiography (ECG abnormalities in old female mdx mice, a murine model of DMD cardiomyopathy. Methods 1 × 1012 viral genome particles/mouse of adeno-associated virus serotype-9 (AAV-9 SERCA2a vector was delivered to 12-m-old female mdx mice (N = 5 via a single bolus tail vein injection. AAV transduction and the ECG profile were examined eight months later. Results The vector genome was detected in the hearts of all AAV-injected mdx mice. Immunofluorescence staining and western blot confirmed SERCA2a over-expression in the mdx heart. Untreated mdx mice showed characteristic tachycardia, PR interval reduction and QT interval prolongation. AAV-9 SERCA2a treatment corrected these ECG abnormalities. Conclusions Our results suggest that AAV SERCA2a therapy may hold great promise in treating dystrophin-deficient heart disease.

  2. The ERα-PI3K Cascade in Proopiomelanocortin Progenitor Neurons Regulates Feeding and Glucose Balance in Female Mice.

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    Zhu, Liangru; Xu, Pingwen; Cao, Xuehong; Yang, Yongjie; Hinton, Antentor Othrell; Xia, Yan; Saito, Kenji; Yan, Xiaofeng; Zou, Fang; Ding, Hongfang; Wang, Chunmei; Yan, Chunling; Saha, Pradip; Khan, Sohaib A; Zhao, Jean; Fukuda, Makoto; Tong, Qingchun; Clegg, Deborah J; Chan, Lawrence; Xu, Yong

    2015-12-01

    Estrogens act upon estrogen receptor (ER)α to inhibit feeding and improve glucose homeostasis in female animals. However, the intracellular signals that mediate these estrogenic actions remain unknown. Here, we report that anorexigenic effects of estrogens are blunted in female mice that lack ERα specifically in proopiomelanocortin (POMC) progenitor neurons. These mutant mice also develop insulin resistance and are insensitive to the glucose-regulatory effects of estrogens. Moreover, we showed that propyl pyrazole triol (an ERα agonist) stimulates the phosphatidyl inositol 3-kinase (PI3K) pathway specifically in POMC progenitor neurons, and that blockade of PI3K attenuates propyl pyrazole triol-induced activation of POMC neurons. Finally, we show that effects of estrogens to inhibit food intake and to improve insulin sensitivity are significantly attenuated in female mice with PI3K genetically inhibited in POMC progenitor neurons. Together, our results indicate that an ERα-PI3K cascade in POMC progenitor neurons mediates estrogenic actions to suppress food intake and improve insulin sensitivity.

  3. Characterization of the anti-inflammatory Lactobacillus reuteri BM36301 and its probiotic benefits on aged mice.

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    Lee, Joon; Yang, Woo; Hostetler, Andrew; Schultz, Nathan; Suckow, Mark A; Stewart, Kay L; Kim, Daniel D; Kim, Hyung Soo

    2016-04-19

    The gut microbiota is playing more important roles in host immune regulation than was initially expected. Since many benefits of microbes are highly strain-specific and their mechanistic details remain largely elusive, further identification of new probiotic bacteria with immunoregulatory potentials is of great interest. We have screened our collection of probiotic lactic acid bacteria (LAB) for their efficacy in modulating host immune response. Some LAB are characterized by suppression of TNF-α induction when LAB culture supernatants are added to THP-1 cells, demonstrating the LAB's anti-inflammatory potential. These suppressive materials were not inactivated by heat or trypsin. On the other hand, treatment of THP-1 directly with live bacterial cells identified a group of pro-inflammatory LAB, which stimulated significant production of TNF-α. Among those, we chose the Lactobacillus reuteri BM36301 as an anti-inflammatory strain and the L. reuteri BM36304 as a pro-inflammatory strain, and further studied their in vivo effects. We supplied C57BL/6 mice with these bacteria in drinking water while feeding them a standard diet for 20 weeks. Interestingly, these L. reuteri strains evoked different consequences depending on the gender of the mice. That is, males treated with anti-inflammatory BM36301 experienced less weight gain and higher testosterone level; females treated with BM36301 maintained lower serum TNF-α as well as healthy skin with active folliculogenesis and hair growth. Furthermore, while males treated with pro-inflammatory BM36304 developed higher serum levels of TNF-α and insulin, in contrast females did not experience such effects from this bacteria strain. The L. reuteri BM36301 was selected as an anti-inflammatory strain in vitro. It helped mice maintain healthy conditions as they aged. These findings propose the L. reuteri BM36301 as a potential probiotic strain to improve various aspects of aging issues.

  4. Prevalence of vaginitis in different age groups among females in Greece.

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    Sianou, Argiri; Galyfos, George; Moragianni, Dimitra; Baka, Stavroula

    2017-08-01

    Patients with vaginitis were classified into four groups: Group A (prepubertal under-aged females); Group B (pubertal under-aged females); Group C (reproductive age adult females); Group D (postmenopausal adult females). All vaginal specimens underwent microscopy, amine testing, Gram staining and culturing. Overall, 163 patients were included (33, 14, 81 and 35 patients, respectively). The most common infection was bacterial vaginosis (BV), followed by Ureaplasma infection, aerobic vaginitis (AV) and candidiasis. The most common AV-associated organism was Escherichia coli and the most common BV-associated organism was Gardnerella vaginalis. AV was more frequent in Group A, BV in Group C and Ureaplasma infections in Groups C/D. Decreased lactobacilli concentrations were associated with BV in fertile patients (Groups B-C). Although presentation of vaginitis is similar among females of different age in Greece, type and prevalence of pathogens differ. Normal vaginal flora changes are associated with higher risk of vaginitis in specific age groups. Impact Statement The worldwide incidence of reproductive tract infections has been increasing, with specific pathogens being associated with significant risk of morbidity and complications. However, literature data on the distribution of such infections in different age groups is limited. Therefore, the aim of this study was to provide data on the prevalence and causes of vaginitis in adult and non-adult females of all ages. This study has shown that although presentation of vaginitis is similar among females of different age groups and menstrual status in Greece, type and prevalence of responsible pathogens are different among groups. Changes in normal vaginal flora seem to be associated with higher risk of vaginitis in specific age-groups as well. These findings could contribute in adjusting diagnostic and therapeutic strategies for each age group according to the prevailing pathogens. Further research on antibiotic

  5. Psychological stress exposure to aged mice causes abnormal feeding patterns with changes in the bout number.

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    Yamada, Chihiro; Mogami, Sachiko; Hattori, Tomohisa

    2017-11-09

    Stress responses are affected by aging. However, studies on stress-related changes in feeding patterns with aging subject are minimal. We investigated feeding patterns induced by two psychological stress models, revealing characteristics of stress-induced feeding patterns as "meal" and "bout" (defined as the minimum feeding behavior parameters) in aged mice. Feeding behaviors of C57BL/6J mice were monitored for 24 h by an automatic monitoring device. Novelty stress reduced the meal amount over the 24 h in both young and aged mice, but as a result of a time course study it was persistent in aged mice. In addition, the decreased bout number was more pronounced in aged mice than in young mice. The 24-h meal and bout parameters did not change in either the young or aged mice following water avoidance stress (WAS). However, the meal amount and bout number increased in aged mice for 0-6 h after WAS exposure but remained unchanged in young mice. Our findings suggest that changes in bout number may lead to abnormal stress-related feeding patterns and may be one tool for evaluating eating abnormality in aged mice.

  6. Long term low dose rate irradiation causes recovery from type II diabetes and suppression of aging in type II diabetes-prone mice

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    Namura, T.; Oda, T.

    2003-01-01

    The effects of low dose rate gamma irradiation on model C57BL/KsJ-db/db mice with Type II diabetes mellitus was investigated. These mice develop Type II diabetes by 10 weeks of age, due to obesity, and are characterized by hyperinsulinemia. A group of 12 female 10-week old mice were irradiated at 0.65 mGy/hr in the low dose rate irradiation facility in the Low Dose Radiation Research Center. The urine glucose levels of all of the mice were strongly positive at the beginning of the irradiation. In the irradiated group, a decrease in the glucose level was observed in three mice, one in the 35th week, another in the 52nd week and the third in the 80th week. No recovery from the diabetes was observed in the 12 mice of non-irradiated control group. There was no systematic change of body weight or consumption of food and drinking water between the irradiated group and the non-irradiated group or between the recovered mice and the non-recovered mice. Survival was better in the irradiated group. The surviving fraction at the age of 90 weeks was 75 % in the irradiated group but only 40 % in the non-irradiated. A marked difference was also observed in the appearance of the coat hair, skin and tail. The irradiated group was in much better condition. Mortality was delayed and the healthy appearance was prolonged in the irradiated mice by about 20-30 weeks compared with the control mice. These results suggest that the low dose irradiation modified the condition of the diabetic mice, leading not only to recovery from diabetes, but also to suppression of the aging process

  7. Similar reliability and equivalent performance of female and male mice in the open field and water-maze place navigation task.

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    Fritz, Ann-Kristina; Amrein, Irmgard; Wolfer, David P

    2017-09-01

    Although most nervous system diseases affect women and men differentially, most behavioral studies using mouse models do not include subjects of both sexes. Many researchers worry that data of female mice may be unreliable due to the estrous cycle. Here, we retrospectively evaluated sex effects on coefficient of variation (CV) in 5,311 mice which had performed the same place navigation protocol in the water-maze and in 4,554 mice tested in the same open field arena. Confidence intervals for Cohen's d as measure of effect size were computed and tested for equivalence with 0.2 as equivalence margin. Despite the large sample size, only few behavioral parameters showed a significant sex effect on CV. Confidence intervals of effect size indicated that CV was either equivalent or showed a small sex difference at most, accounting for less than 2% of total group to group variation of CV. While female mice were potentially slightly more variable in water-maze acquisition and in the open field, males tended to perform less reliably in the water-maze probe trial. In addition to evaluating variability, we also directly compared mean performance of female and male mice and found them to be equivalent in both water-maze place navigation and open field exploration. Our data confirm and extend other large scale studies in demonstrating that including female mice in experiments does not cause a relevant increase of data variability. Our results make a strong case for including mice of both sexes whenever open field or water-maze are used in preclinical research. © 2017 The Authors. American Journal of Medical Genetics Part C Published by Wiley Periodicals, Inc.

  8. Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice

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    Weber Mitch

    2008-03-01

    Full Text Available Abstract Background Women with polycystic ovary syndrome (PCOS are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD, which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a mice, possessing a mutation (Ay in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction. Methods Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4 or an equal volume of vehicle (DMSO; n = 4 for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression. Results Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM, and actin-related protein 6 homolog (ARP6. For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a non-mutant lean mice. Conclusion TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.

  9. Genistein Stimulates Jejunum Chloride Secretion via an Akt-Mediated Pathway in Intact Female Mice

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    Lana Leung

    2015-02-01

    Full Text Available Background/Aims: We have previously shown that daily subcutaneous injections with the naturally occurring phytoestrogen genistein (600 mg genistein/kg body weight/day, 600G results in a significantly increased basal intestinal chloride, Cl-, secretion (Isc, a measure of transepithelial secretion in intact C57BL/6J female mice after 1-week of treatment, compared to controls (DMSO vehicle injected. Removal of endogenous estrogen via ovariectomy (OVX had no effect on the 600G-mediated increase in basal Isc. Methods: Given the estrogen-like characteristics of genistein, we compared the effects of daily estradiol (E2 injections (10 mg E2/kg body weight/day, 10E2 on basal Isc in intact and OVX mice. In intact mice, 10E2 was without effect on basal Isc, however, in OVX mice, 10E2 significantly increased basal Isc (mimicked 600G. The goal of the current study was to characterize the intracellular signaling pathways responsible for mediating 600G- or 10E2-stimulated increases in basal Isc in intact female or OVX mice. Results: We measured total protein expression in isolated segments of jejunum using western blot from the following six groups of mice; intact or OVX with; 600G, 10E2 or control. The proteins of interest were: Akt, p-Akt, p-PDK1, p-PTEN, p-c-Raf, p-GSK-3β, rap-1 and ERK1/2. All blots were normalized to GAPDH levels (n = 6-18/group. Conclusion: These data suggest that the presence of the endogenous sex steroid, estrogen, modifies the intracellular signaling pathway required to mediate Cl- secretion when the intestine is exposed to exogenous 600G or E2. These studies may have relevance for designing pharmacological tools for women with intestinal chloride secretory dysfunctions.

  10. Changes with age in swimming performance of X-irradiated mice

    International Nuclear Information System (INIS)

    Norimura, T.; Yoshikawa, I.; Okajima, S.

    1980-01-01

    The time required to swim 250 cm was determined once weekly for the entire life of fifteen pairs of male dd/K mice. The irradiated group was exposed to a single 224 rad of X-rays at 20 weeks of age. Median survival time (ST 50 ) for the control was 88.9 weeks and that for the irradiated group was 77.4 weeks, and both regression lines relating to death rate and age were parallel. The swimming ability of control mice began to decrease when the mice were 40 weeks of age, after which there was a gradual reduction with age at 0.00646/day. In the irradiated group, the swimming ability decreased from seven weeks after irradiation. The time of 50% reduction of swimming speed (TRS 50 ) for the control was 78.9 weeks and that for the irradiated group was 66.3 weeks, and the slopes of the regression lines relating reduction rate and age were similar. Differences between ST 50 and TRS 50 were 10 weeks in the control and 11 weeks in the irradiated group, respectively. These results indicate that there is no basic difference in the reduction in swimming ability between control and irradiated mice. The X-irradiation may simply mean that the reduction in the swimming ability is displaced to an earlier time with no alteration in the rate of reduction, and that the earlier appearance in the irradiated group is related to premature aging as induced by irradiation. (author)

  11. Performance of Male and Female C57BL/6J Mice on Motor and Cognitive Tasks Commonly Used in Pre-Clinical Traumatic Brain Injury Research

    Science.gov (United States)

    Tucker, Laura B.; Fu, Amanda H.

    2016-01-01

    Abstract To date, clinical trials have failed to find an effective therapy for victims of traumatic brain injury (TBI) who live with motor, cognitive, and psychiatric complaints. Pre-clinical investigators are now encouraged to include male and female subjects in all translational research, which is of particular interest in the field of neurotrauma given that circulating female hormones (progesterone and estrogen) have been demonstrated to exert neuroprotective effects. To determine whether behavior of male and female C57BL6/J mice is differentially impaired by TBI, male and cycling female mice were injured by controlled cortical impact and tested for several weeks with functional assessments commonly employed in pre-clinical research. We found that cognitive and motor impairments post-TBI, as measured by the Morris water maze (MWM) and rotarod, respectively, were largely equivalent in male and female animals. However, spatial working memory, assessed by the y-maze, was poorer in female mice. Female mice were generally more active, as evidenced by greater distance traveled in the first exposure to the open field, greater distance in the y-maze, and faster swimming speeds in the MWM. Statistical analysis showed that variability in all behavioral data was no greater in cycling female mice than it was in male mice. These data all suggest that with careful selection of tests, procedures, and measurements, both sexes can be included in translational TBI research without concern for effect of hormones on functional impairments or behavioral variability. PMID:25951234

  12. Short-term social memory deficits in adult female mice exposed to tannery effluent and possible mechanism of action.

    Science.gov (United States)

    Estrela, Fernanda Neves; Rabelo, Letícia Martins; Vaz, Boniek Gontijo; de Oliveira Costa, Denys Ribeiro; Pereira, Igor; de Lima Rodrigues, Aline Sueli; Malafaia, Guilherme

    2017-10-01

    The accumulated organic residues in tannery-plant courtyards are an eating attraction to small rodents; however, the contact of these animals with these residues may change their social behavior. Thus, the aim of the present study is to investigate whether the exposure to tannery effluent (TE) can damage the social recognition memory of female Swiss mice, as well as to assess whether vitamin C supplementation could provide information about how TE constituents can damage these animals' memory. We have observed that resident females exposed to TE (without vitamin supplementation) did not explore the anogenital region, their body or chased intruding females for shorter time or with lower frequency during the retest session of the social recognition test, fact that indicates social recognition memory deficit in these animals. Such finding is reinforced by the confirmation that there was no change in the animals' olfactory function during the buried food test, or locomotor changes in females exposed to the pollutant. Since no behavioral change was observed in the females exposed to TE and treated with vitamin C (before or after the exposure), it is possible saying that these social cognitive impairments seem to be directly related to the imbalance between the cellular production of reactive oxygen species and the counteracting antioxidant mechanisms (oxidative stress) in female mice exposed to the pollutant (without vitamin supplementation). Therefore, the present study evidences that the direct contact with tannery effluent, even for a short period-of-time, may cause short-term social memory deficits in adult female Swiss mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. A selfish genetic element influencing longevity correlates with reactive behavioural traits in female house mice (Mus domesticus.

    Directory of Open Access Journals (Sweden)

    Yannick Auclair

    Full Text Available According to theory in life-history and animal personality, individuals with high fitness expectations should be risk-averse, while individuals with low fitness expectations should be more bold. In female house mice, a selfish genetic element, the t haplotype, is associated with increased longevity under natural conditions, representing an appropriate case study to investigate this recent theory empirically. Following theory, females heterozygous for the t haplotype (+/t are hypothesised to express more reactive personality traits and be more shy, less explorative and less active compared to the shorter-lived homozygous wildtype females (+/+. As males of different haplotype do not differ in survival, no similar pattern is expected. We tested these predictions by quantifying boldness, exploration, activity, and energetic intake in both +/t and +/+ mice. +/t females, unlike +/+ ones, expressed some reactive-like personality traits: +/t females were less active, less prone to form an exploratory routine and tended to ingest less food. Taken together these results suggest that differences in animal personality may contribute to the survival advantage observed in +/t females but fail to provide full empirical support for recent theory.

  14. Healthy ageing

    DEFF Research Database (Denmark)

    Harrison, Adrian Paul; Brüggemann, Dagmar Adeline; Bartels, Else Marie

    2009-01-01

    The study employed mechanical stretching in vitro of sections of abdominal aorta of elderly mice to investigate any benefits of oral treatment with alpha-ketoglutarate (AKG) on arterial elasticity. Eighteen female mice (50-weeks-old) were assigned to a control (2% w/v) Na2-AKG or (2% w/v) a Ca-AK...... investigation as a candidate for therapies targeting arterial stiffening with age....

  15. Susceptibility to hippocampal kindling seizures is increased in aging C57 black mice

    Directory of Open Access Journals (Sweden)

    Kurt R. Stover

    2017-12-01

    Full Text Available The incidence of seizures increases with old age. Stroke, dementia and brain tumors are recognized risk factors for new-onset seizures in the aging populations and the incidence of these conditions also increased with age. Whether aging is associated with higher seizure susceptibility in the absence of the above pathologies remains unclear. We used classic kindling to explore this issue as the kindling model is highly reproducible and allows close monitoring of electrographic and motor seizure activities in individual animals. We kindled male young and aging mice (C57BL/6 strain, 2–3 and 18–22 months of age via daily hippocampal CA3 stimulation and monitored seizure activity via video and electroencephalographic recordings. The aging mice needed fewer stimuli to evoke stage-5 motor seizures and exhibited longer hippocampal afterdischarges and more frequent hippocampal spikes relative to the young mice, but afterdischarge thresholds and cumulative afterdischarge durations to stage 5 motor seizures were not different between the two age groups. While hippocampal injury and structural alterations at cellular and micro-circuitry levels remain to be examined in the kindled mice, our present observations suggest that susceptibility to hippocampal CA3 kindling seizures is increased with aging in male C57 black mice.

  16. Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice.

    Science.gov (United States)

    Wang, Jian; Xu, Bo; Tian, Geng G; Sun, Tao; Wu, Ji

    2018-01-01

    Oogenesis is a highly complex process that is intricately regulated by interactions of multiple genes and signaling molecules. However, the underlying molecular mechanisms are poorly understood. There is emerging evidence that microRNAs contribute to oogenesis. Here, we aimed to investigate the role of miR-17-92 cluster in regulating oogenesis. The miR-17-92 cluster was genetically ablated in germ cells of female mice by applying the Cre-loxp system for conditional gene knockout. Mating experiment, superovulation and histological analysis were used to assess the fertility of the model female mice. TUNEL assay was used to identify apoptotic cells in ovaries. The expression level of apoptosis- and follicular atresia- related genes was evaluated by qRT-PCR. Western blotting was performed to detect protein expression. Bioinformatics software and dual luciferase reporter assay were applied to predict and verify the target of miR-17-92 cluster. Deletion of miR-17-92 cluster in germ cells of female mice caused increased oocyte degradation and follicular atresia, perturbed oogenesis, and ultimately led to subfertility. Genes involved in follicular atresia and the mitochondrial apoptotic pathway were obviously up-regulated. Furthermore, we verified that miR-19a regulated oogenesis at the post-transcriptional level by targeting Bmf in the ovaries of miR-17-92 cluster conditional knockout female mice. The miR-17-92 cluster is an important regulator of oogenesis. These findings will assist in better understanding the etiology of disorders in oogenesis and in developing new therapeutic targets for female infertility. © 2018 The Author(s). Published by S. Karger AG, Basel.

  17. Infertility as a consequence of spermagglutinating Staphylococcus aureus colonization in genital tract of female mice.

    Directory of Open Access Journals (Sweden)

    Siftjit Kaur

    Full Text Available Various studies have shown Staphylococcus aureus to be one of the most prevalent organism in male and female genital tract but most practitioners dismiss it as mere contamination which is assumed to be of no significance. However, it is now suggested that the presence of this organism should not be ignored, as incubation of spermatozoa with S. aureus results in reduced sperm motility. Although S. aureus has been reported to cause immobilization of spermatozoa, however, its role in infertility has yet to be elucidated. The present study was designed to establish a spermagglutinating strain of S. aureus isolated from the cervix of a woman with unexplained infertility, in mouse and evaluate its effect on fertility outcome. Female Balb/c mice were inoculated intravaginally with different doses of S. aureus (10(4, 10(6 or 10(8cfu/20 µl for 10 consecutive days. Microbial colonization monitored every 3(rd day by vaginal cultures, revealed that strain could efficiently colonize mouse vagina. Mating on day 12, with proven breeder males led to 100% decrease in fertility as compared to control. Even a single dose of 10(6 or 10(8cfu could lead to vaginal colonization which persisted for 10 days followed by gradual clearing till 21 days, vaginal cultures were negative thereafter. Female mice mated on day 7 (culture positive, were rendered infertile, however, the mice mated on day 22 (culture negative, retained fertility and delivered pups indicating its role in provoking infertility. Further, except infertility, no other clinical manifestation could be seen apparently or histologically. However, when a non-spermagglutinating/immobilizing standard strain of S. aureus MTCC6625 was inoculated intravaginally at 10(8cfu for 10 days followed by mating on day 12, fertility was observed in all the female mice. This supports the hypothesis that infertility observed in the former groups was as a result of colonization with spermagglutinating strain of S. aureus.

  18. Distribution and time course of corticosterone excretion in faeces and urine of female mice with varying systemic concentrations

    DEFF Research Database (Denmark)

    Kalliokoski, Otto; Hau, Jann; Jacobsen, Kirsten R

    2010-01-01

    distribution and time course of corticosterone excretion, after intravenous injection of varying corticosterone concentrations, was investigated in female mice. Female BALB/c mice excreted 60% of all corticosterone in the urine with an approximate delay of 5h from tail vein administration. The remaining 40......% were excreted in faeces, with an approximate delay of 9h from administration. The faecal/urinary excretion ratio, as well as time course of excretion, remained unaltered by administration of various doses of corticosterone covering the entire physiological range of serum corticosterone. Although...

  19. How age influences phonotaxis in virgin female Jamaican field crickets (Gryllus assimilis

    Directory of Open Access Journals (Sweden)

    Karen Pacheco

    2013-08-01

    Full Text Available Female mating preference can be a dominant force shaping the evolution of sexual signals. However, females rarely have consistent mating preferences throughout their lives. Preference flexibility results from complex interactions of predation risk, social and sexual experience, and age. Because residual reproductive value should theoretically decline with age, older females should not be as choosy as younger females. We explored how age influences phonotaxis towards a standard mate attraction signal using a spherical treadmill (trackball and a no-choice experimental protocol. Female Jamaican field crickets, Gryllus assimilis, were highly variable in their phonotaxis; age explained up to 64% of this variation. Females 10 days post imaginal eclosion and older oriented toward the mate attraction signal, with 10- and 13-day females exhibiting the greatest movement in the direction of the signal. Our study suggests 10- and 13-day old females would be most responsive when quantifying the preference landscape for G. assimilis sexual signals.

  20. Age impact on autoimmune thyroid disease in females

    Science.gov (United States)

    Stoian, Dana; Craciunescu, Mihalea; Timar, Romulus; Schiller, Adalbert; Pater, Liana; Craina, Marius

    2013-10-01

    Thyroid autoimmune disease, a widespread phenomenon in female population, impairs thyroid function during pregnancy. Identifying cases, which will develop hypothyroidism during pregnancy, is crucial in the follow-up process. The study group comprised 108 females, with ages between 20-40 years; with known inactive autoimmune thyroid disease, before pregnancy that became pregnant in the study follow-up period. They were monitored by means of clinical, hormonal and immunological assays. Supplemental therapy with thyroid hormones was used, where needed. Maternal age and level of anti-thyroid antibodies were used to predict thyroid functional impairment.

  1. Ageing influence for the evaluation of DXA precision in female subjects

    International Nuclear Information System (INIS)

    Lin Qiang; Yu Wei; Qin Mingwei; Shang Wei; Tian Junping; Han Shaomei

    2006-01-01

    Objective: To investigate whether aging factor influence the precision of DXA measurement at the lumbar spine in females. Methods: A total of 90 female subjects were recruited and divided into three age groups, i.e. 45-55 years, 56-65 years and 66-75 years. There were 30 female subjects for each age group. Each subject was scanned twice at the same day. Mean BMD values from L2 to L4 were collected and grouped by calculating the root mean square (RMS). Precision errors were expressed as root mean square (RMS). P 2 , (0.992±0.010) g/cm 2 , (0.910±0.010) g/cm 2 , respectively. Mean BMD values from L2 to L4 decreased with increasing age group. Root mean square was lower in the 45 -55 age group, and was same between 56-65 and 66-75 age group. There were significant difference of BMD standard deviation between both there groups (F=5.213, P<0.05) any age group (q value I vs II 0.035; II vs III 0.500; I vs III 0.035, P<0.05). Conclusion: Age could influence the precision of DXA measurement at the site of lumbar spine in females. Therefore, caution should be paid to the age of female subjects recruited for the evaluation of precision for DXA measurement in the clinical trials. (authors)

  2. Stress and estrous cycle affect strategy but not performance of female C57BL/6J mice

    NARCIS (Netherlands)

    ter Horst, J.P.; Kentrop, J.; de Kloet, E.R.; Oitzl, M.S.

    2013-01-01

    Stress induces a switch in learning strategies of male C57BL/6J mice from predominantly spatial to more stimulus-response learning. To study generalization of these findings over sex, we investigated female C57BL/6J mice at three phases of the estrous cycle under non stress and acute (10 min)

  3. Two-year body composition analyses of long-lived GHR null mice.

    Science.gov (United States)

    Berryman, Darlene E; List, Edward O; Palmer, Amanda J; Chung, Min-Yu; Wright-Piekarski, Jacob; Lubbers, Ellen; O'Connor, Patrick; Okada, Shigeru; Kopchick, John J

    2010-01-01

    Growth hormone receptor gene-disrupted (GHR-/-) mice exhibit increased life span and adipose tissue mass. Although this obese phenotype has been reported extensively for young adult male GHR-/- mice, data for females and for other ages in either gender are lacking. Thus, the purpose of this study was to evaluate body composition longitudinally in both male and female GHR-/- mice. Results show that GHR-/- mice have a greater percent fat mass with no significant difference in absolute fat mass throughout life. Lean mass shows an opposite trend with percent lean mass not significantly different between genotypes but absolute mass reduced in GHR-/- mice. Differences in body composition are more pronounced in male than in female mice, and both genders of GHR-/- mice show specific enlargement of the subcutaneous adipose depot. Along with previously published data, these results suggest a consistent and intriguing protective effect of excess fat mass in the subcutaneous region.

  4. Spatial learning of female mice: a role of the mineralocorticoid receptor during stress and the estrous cycle

    Directory of Open Access Journals (Sweden)

    Judith P Ter Horst

    2013-05-01

    Full Text Available Corticosterone facilitates behavioral adaptation to a novel experience in a coordinate manner via mineralocorticoid (MR and glucocorticoid receptors (GR. Initially, MR mediates corticosterone action on appraisal processes, risk assessment and behavioral flexibility and then, GR activation promotes consolidation of the new information into memory. Here, we studied on the circular holeboard (CHB the spatial performance of female mice with genetic deletion of MR from the forebrain (MRCaMKCre and their wild type littermates (MRflox/flox mice over the estrous cycle and in response to an acute stressor. The estrous cycle had no effect on the spatial performance of MRflox/flox mice and neither did the acute stressor. However, the MRCaMKCre mutants needed significantly more time to find the exit and made more hole visit errors than the MRflox/flox mice, especially when in proestrus and estrus. In addition, stressed MRCaMKCre mice in estrus had a shorter exit latency than the control estrus MRCaMKCre mice. About 70% of the female MRCaMKCre and MRflox/flox mice used a hippocampal (spatial, extra maze cues rather than the caudate nucleus (stimulate-response, S-R, intra-maze cue strategy and this preference did neither change over the estrous cycle nor after stress. However, stressed MRCaMKCre mice using the S-R strategy needed significantly more time to find the exit hole as compared to the spatial strategy using mice suggesting that the MR could be needed for the stress-induced strategy switch towards a spatial strategy. In conclusion, the results suggest that loss of MR interferes with performance of a spatial task especially when estrogen levels are high suggesting a strong interaction between stress and sex hormones.

  5. Relative Age Affects Marathon Performance in Male and Female Athletes

    OpenAIRE

    Connick, Mark J.; Beckman, Emma M.; Tweedy, Sean M.

    2015-01-01

    Marathon runners are ranked in 5-year age groups. However the extent to which 5-year groupings facilitates equitable competition has not been evaluated. The aim of this study was to evaluate the effect of relative age in male and female marathon running. Marathon finishing times for the top ten male (aged 20-69 years) and female athletes (aged 20-64 years) were obtained from the 2013 New York and Chicago marathons. Intra-class and inter-class validity were evaluated by comparing performances ...

  6. Male chimpanzees' grooming rates vary by female age, parity, and fertility status

    DEFF Research Database (Denmark)

    Proctor, Darby P; Lambeth, Susan P; Schapiro, Steve

    2011-01-01

    , should show little or no preference when choosing mating partners (e.g. should mate indiscriminately). To determine if the preferences indicated by copulations appear in other contexts as well as how they interact, we examined how male chimpanzees' grooming patterns varied amongst females. We found...... that males' preferences were based on interactions among females' fertility status, age, and parity. First, grooming increased with increasing female parity. We further found an effect of the estrous cycle on grooming; when females were at the lowest point of their cycle, males preferentially groomed parous...... females at peak reproductive age, but during maximal tumescence, males preferred the oldest multiparous females. Nulliparous females received relatively little grooming regardless of age or fertility. Thus, male chimpanzees apparently chose grooming partners based on both female's experience and fertility...

  7. Influence of female sex and fertile age on neuromyelitis optica spectrum disorders.

    Science.gov (United States)

    Borisow, Nadja; Kleiter, Ingo; Gahlen, Anna; Fischer, Katrin; Wernecke, Klaus-Dieter; Pache, Florence; Ruprecht, Klemens; Havla, Joachim; Krumbholz, Markus; Kümpfel, Tania; Aktas, Orhan; Ringelstein, Marius; Geis, Christian; Kleinschnitz, Christoph; Berthele, Achim; Hemmer, Bernhard; Angstwurm, Klemens; Weissert, Robert; Stellmann, Jan-Patrick; Schuster, Simon; Stangel, Martin; Lauda, Florian; Tumani, Hayrettin; Mayer, Christoph; Zeltner, Lena; Ziemann, Ulf; Linker, Ralf A; Schwab, Matthias; Marziniak, Martin; Then Bergh, Florian; Hofstadt-van Oy, Ulrich; Neuhaus, Oliver; Winkelmann, Alexander; Marouf, Wael; Rückriem, Lioba; Faiss, Jürgen; Wildemann, Brigitte; Paul, Friedemann; Jarius, Sven; Trebst, Corinna; Hellwig, Kerstin

    2017-07-01

    Gender and age at onset are important epidemiological factors influencing prevalence, clinical presentation, and treatment response in autoimmune diseases. To evaluate the impact of female sex and fertile age on aquaporin-4-antibody (AQP4-ab) status, attack localization, and response to attack treatment in patients with neuromyelitis optica (NMO) and its spectrum disorders (neuromyelitis optica spectrum disorder (NMOSD)). Female-to-male ratios, diagnosis at last visit (NMO vs NMOSD), attack localization, attack treatment, and outcome were compared according to sex and age at disease or attack onset. A total of 186 NMO/SD patients (82% female) were included. In AQP4-ab-positive patients, female predominance was most pronounced during fertile age (female-to-male ratio 23:1). Female patients were more likely to be positive for AQP4-abs (92% vs 55%; p 40 years. Our data suggest an influence of sex and age on susceptibility to AQP4-ab-positive NMO/SD. Genetic and hormonal factors might contribute to pathophysiology of NMO/SD.

  8. Differential metabolism of acrylonitrile to cyanide is responsible for the greater sensitivity of male vs female mice: role of CYP2E1 and epoxide hydrolases

    International Nuclear Information System (INIS)

    Chanas, Brian; Wang, Hongbing; Ghanayem, Burhan I.

    2003-01-01

    Acrylonitrile (AN) is a potent toxicant and a known rodent carcinogen. AN epoxidation to cyanoethylene oxide (CEO) via CYP2E1 and its subsequent metabolism via epoxide hydrolases (EH) to yield cyanide is thought to be responsible for the acute toxicity and mortality of AN. Recent reports showed that male mice are more sensitive than females to the acute toxicity/mortality of AN. The present work was undertaken to assess the metabolic and enzymatic basis for the greater sensitivity of male vs female mice to AN toxicity. Male and female wild-type and CYP2E1-null mice received AN at 0, 2.5, 10, 20, or 40 mg/kg by gavage. Cyanide concentrations were measured at 1 or 3 h after dosing. Current data demonstrated that cyanide levels in blood and tissues of AN-treated wild-type mice of both sexes were significantly greater than in vehicle-treated controls and increased in a dose-dependent manner. In contrast, cyanide levels in AN-treated CYP2E1-null mice were not statistically different from those measured in vehicle-treated controls. Furthermore, higher levels of cyanide were detected in male wild-type mice vs females in association with greater sensitivity of males to the acute toxicity/mortality of this chemical. Using Western blot analysis, negligible difference in CYP2E1 expression with higher levels of soluble and microsomal EH (sEH and mEH) was detected in the liver of male vs female mice. In kidneys, male mice exhibited higher expression of both renal CYP2E1 and sEH than did female mice. In conclusion, higher blood and tissue cyanide levels are responsible for the greater sensitivity of male vs female mice to AN. Further, higher expression of CYP2E1 and EH in male mice may contribute to greater formation of CEO and its subsequent metabolism to yield cyanide, respectively

  9. Altered left ventricular performance in aging physically active mice with an ankle sprain injury.

    Science.gov (United States)

    Turner, Michael J; Guderian, Sophie; Wikstrom, Erik A; Huot, Joshua R; Peck, Bailey D; Arthur, Susan T; Marino, Joseph S; Hubbard-Turner, Tricia

    2016-02-01

    We assessed the impact of differing physical activity levels throughout the lifespan, using a musculoskeletal injury model, on the age-related changes in left ventricular (LV) parameters in active mice. Forty male mice (CBA/J) were randomly placed into one of three running wheel groups (transected CFL group, transected ATFL/CFL group, SHAM group) or a SHAM Sedentary group (SHAMSED). Before surgery and every 6 weeks after surgery, LV parameters were measured under 2.5 % isoflurane inhalation. Group effects for daily distance run was significantly greater for the SHAM and lesser for the ATLF/CFL mice (p = 0.013) with distance run decreasing with age for all mice (p age, interaction (group × age) was noted with LV posterior wall thickness-to-radius ratios (h/r) where h/r increased with age in the ATFL/CFL and SHAMSED mice while the SHAM and CFL mice exhibited decreased h/r with age (p = 0.0002). Passive filling velocity (E wave) was significantly greater in the SHAM mice and lowest for the ATFL/CFL and SHAMSED mice (p age. Active filling velocity (A wave) was not different between groups (p = 0.10). Passive-to-active filling velocity ratio (E/A ratio) was different between groups (p activity beginning at 9 months of age. Passive-to-active filling velocity ratio decreased with age (p activity throughout the lifespan improved LV structure, passive filling velocity, and E/A ratio by 6 to 9 months of age and attenuated any negative alterations throughout the second half of life. The diastolic filling differences were found to be significantly related to the amount of activity performed by 9 months and at the end of the lifespan.

  10. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment.

    Science.gov (United States)

    Wang, Tina; Tsui, Brian; Kreisberg, Jason F; Robertson, Neil A; Gross, Andrew M; Yu, Michael Ku; Carter, Hannah; Brown-Borg, Holly M; Adams, Peter D; Ideker, Trey

    2017-03-28

    Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1 df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.

  11. Idh2 deficiency accelerates renal dysfunction in aged mice.

    Science.gov (United States)

    Lee, Su Jeong; Cha, Hanvit; Lee, Seoyoon; Kim, Hyunjin; Ku, Hyeong Jun; Kim, Sung Hwan; Park, Jung Hyun; Lee, Jin Hyup; Park, Kwon Moo; Park, Jeen-Woo

    2017-11-04

    The free radical or oxidative stress theory of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species (ROS) that are produced as by-products of normal metabolic processes in mitochondria. The oxidative stress may arise as a result of either increased ROS production or decreased ability to detoxify ROS. The availability of the mitochondrial NADPH pool is critical for the maintenance of the mitochondrial antioxidant system. The major enzyme responsible for generating mitochondrial NADPH is mitochondrial NADP + -dependent isocitrate dehydrogenase (IDH2). Depletion of IDH2 in mice (idh2 -/- ) shortens life span and accelerates the degeneration of multiple age-sensitive traits, such as hair grayness, skin pathology, and eye pathology. Among the various internal organs tested in this study, IDH2 depletion-induced acceleration of senescence was uniquely observed in the kidney. Renal function and structure were greatly deteriorated in 24-month-old idh2 -/- mice compared with wild-type. In addition, disruption of redox status, which promotes oxidative damage and apoptosis, was more pronounced in idh2 -/- mice. These data support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice, and thus support the oxidative stress theory of aging. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. Extracellular signal-regulated kinase 1 and 2 are not required for GnRH neuron development and normal female reproductive axis function in mice.

    Science.gov (United States)

    Wierman, Margaret E; Xu, Mei; Pierce, A; Bliesner, B; Bliss, S P; Roberson, M S

    2012-01-01

    Selective deletion of extracellular signal-regulated kinase (ERK) 1 and ERK2 in the pituitary gonadotrope and ovarian granulosa cells disrupts female reproductive axis function. Thus, we asked if ERK1 and ERK2 are critical for GnRH neuron ontogeny or the central control of female reproductive function. GnRH-Cre-recombinase (Cre+) expressing mice were crossed with mice with a global deletion of ERK1 and a floxed ERK2 allele (Erk1-/Erk2fl/fl) to selectively delete ERK2 in GnRH neurons. Cre-recombinase mRNA was selectively expressed in the brain of Cre+ mice. GnRH neuron number and location were determined during embryogenesis and in the adult. GnRH neuron counts at E15 did not differ between experimental and control groups (1,198 ± 65 and 1,160 ± 80 respectively, p = NS). In adults, numbers of GnRH neurons in the GnRHCre+Erk1-/Erk2- mice (741 ± 157) were similar to those in controls (756 ± 7), without alteration in their distribution across the forebrain. ERK1 and 2 deficiency did not alter the timing of vaginal opening, age at first estrus, or estrous cyclicity. Although ERK1 and 2 are components of a dominant signaling pathway in GnRH neuronal cells that modulates survival and control of GnRH gene expression, other signaling pathways compensate for their deletion in vivo to allow GnRH neuron survival and targeting and normal onset of female sexual maturation and reproductive function. In contrast to effects at the pituitary and the ovary, ERK1 and ERK2 are dispensable at the level of the GnRH neuron. Copyright © 2011 S. Karger AG, Basel.

  13. Age at first reproduction in philopatric female muriquis ( Brachyteles arachnoides hypoxanthus).

    Science.gov (United States)

    Martins, Waldney P; Strier, Karen B

    2004-01-01

    Female northern muriquis ( Brachyteles arachnoides hypoxanthus or B. hypoxanthus) at the Estação Biológica de Caratinga/RPPN-FMA, Minas Gerais, Brazil typically disperse from their natal groups at an average age of 6.1+/-0.6 years (median =6.0 years, range =5.3-7.8 years, n =22), prior to the onset of puberty and sexual activity. Immigrants do not conceive until at least their second mating season, and the minimum interval from immigration to first reproduction has been 2.0 years. Age at first reproduction in dispersing females, previously estimated at 8.9 years, has now been documented at 9.0 and 9.25 years for two females whose birth dates are known. This is older than the 7.5 years at which the only female previously known to have reproduced in her natal group gave birth. Here, we present new data from a second female that reproduced in her natal group. This female (BA) was first observed to copulate at 5.5 years, and gave birth to her first infant at 7.25 years of age. Her 1.75-year cycling-to-first conception delay was only slightly shorter than the minimum recorded for immigrant females, and thus was not responsible for her young age at first reproduction compared to dispersing females. Although our sample size is small, our findings suggest that early puberty may permit females to reproduce in their natal group, implying a possible link between life history trade-offs and dispersal patterns. Because the only two females that have reproduced in their natal group were maternal sisters, it is also possible that maternal effects on age at puberty can impact dispersal patterns, particularly in small populations of primates.

  14. Age-Associated Changes in Estrogen Receptor Ratios Correlate with Increased Female Susceptibility to Coxsackievirus B3-Induced Myocarditis

    Directory of Open Access Journals (Sweden)

    Andreas Koenig

    2017-11-01

    Full Text Available Sexual bias is a hallmark in various diseases. This review evaluates sexual dimorphism in clinical and experimental coxsackievirus B3 (CVB3 myocarditis, and how sex bias in the experimental disease changes with increased age. Coxsackieviruses are major causes of viral myocarditis, an inflammation of the heart muscle, which is more frequent and severe in men than women. Young male mice infected with CVB3 develop heart-specific autoimmunity and severe myocarditis. Females infected during estrus (high estradiol develop T-regulatory cells and when infected during diestrus (low estradiol develop autoimmunity similar to males. During estrus, protection depends on estrogen receptor alpha (ERα, which promotes type I interferon, activation of natural killer/natural killer T cells and suppressor cell responses. Estrogen receptor beta has opposing effects to ERα and supports pro-inflammatory immunity. However, the sexual dimorphism of the disease is significantly ameliorated in aged animals when old females become as susceptible as males. This correlates to a selective loss of the ERα that is required for immunosuppression. Therefore, sex-associated hormones control susceptibility in the virus-mediated disease, but their impact can alter with the age and physiological stage of the individual.

  15. Effects of Sleep Deprivation and Aging on Long-Term and Remote Memory in Mice

    Science.gov (United States)

    Vecsey, Christopher G.; Park, Alan J.; Khatib, Nora; Abel, Ted

    2015-01-01

    Sleep deprivation (SD) following hippocampus-dependent learning in young mice impairs memory when tested the following day. Here, we examined the effects of SD on remote memory in both young and aged mice. In young mice, we found that memory is still impaired 1 mo after training. SD also impaired memory in aged mice 1 d after training, but, by a…

  16. Radiation-induced nondisjunction of oocytes of aged mice

    International Nuclear Information System (INIS)

    Uchida, I.A.; Freeman, C.P.V.

    1977-01-01

    It is stated that some human epidemiological studies suggest that there may be an association between chromosomal nondisjunction and pre-conception abdominal exposure to X-rays in women, and that this appears to increase with age. In order to test this, some experimental evidence was sought by studying second metaphase chromosomes of cultured oocytes of mice. It had previously been found that abnormal segregation was induced in young mice by exposing them to a low dose of whole body 137 Cs γ-radiation. The new studies confirmed that this radiosensitivity increases with age. The radiation dose was kept low to minimise chromosome breakage. The results indicated that abnormal segregation may be induced during first meiotic division by in vivo exposure of mouse ovaries to low radiation doses, and that this radiosensitivity appears to increase markedly with age. This supports a suggestion that the risk of producing trisomic off-spring in humans is increased with exposure of the abdomen to diagnostic X-rays, and that this increases with age. (U.K.)

  17. Hormonal and molecular effects of restraint stress on formalin-induced pain-like behavior in male and female mice.

    Science.gov (United States)

    Long, Caela C; Sadler, Katelyn E; Kolber, Benedict J

    2016-10-15

    The evolutionary advantages to the suppression of pain during a stressful event (stress-induced analgesia (SIA)) are obvious, yet the reasoning behind sex-differences in the expression of this pain reduction are not. The different ways in which males and females integrate physiological stress responses and descending pain inhibition are unclear. A potential supraspinal modulator of stress-induced analgesia is the central nucleus of the amygdala (CeA). This limbic brain region is involved in both the processing of stress and pain; the CeA is anatomically and molecularly linked to regions of the hypothalamic pituitary adrenal (HPA) axis and descending pain network. The CeA exhibits sex-based differences in response to stress and pain that may differentially induce SIA in males and females. Here, sex-based differences in behavioral and molecular indices of SIA were examined following noxious stimulation. Acute restraint stress in male and female mice was performed prior to intraplantar injections of formalin, a noxious inflammatory agent. Spontaneous pain-like behaviors were measured for 60min following formalin injection and mechanical hypersensitivity was evaluated 120 and 180min post-injection. Restraint stress altered formalin-induced spontaneous behaviors in male and female mice and formalin-induced mechanical hypersensitivity in male mice. To assess molecular indices of SIA, tissue samples from the CeA and blood samples were collected at the 180min time point. Restraint stress prevented formalin-induced increases in extracellular signal regulated kinase 2 (ERK2) phosphorylation in the male CeA, but no changes associated with pERK2 were seen with formalin or restraint in females. Sex differences were also seen in plasma corticosterone concentrations 180min post injection. These results demonstrate sex-based differences in behavioral, molecular, and hormonal indices of acute stress in mice that extend for 180min after stress and noxious stimulation. Copyright

  18. Bioactive silica nanoparticles reverse age-associated bone loss in mice.

    Science.gov (United States)

    Weitzmann, M Neale; Ha, Shin-Woo; Vikulina, Tatyana; Roser-Page, Susanne; Lee, Jin-Kyu; Beck, George R

    2015-05-01

    We recently reported that in vitro, engineered 50nm spherical silica nanoparticles promote the differentiation and activity of bone building osteoblasts but suppress bone-resorbing osteoclasts. Furthermore, these nanoparticles promote bone accretion in young mice in vivo. We have now investigated the capacity of these nanoparticles to reverse bone loss in aged mice, a model of human senile osteoporosis. Aged mice received nanoparticles weekly and bone mineral density (BMD), bone structure, and bone turnover were quantified. Our data revealed a significant increase in BMD, bone volume, and biochemical markers of bone formation. Biochemical and histological examinations failed to identify any abnormalities caused by nanoparticle administration. Our studies demonstrate that silica nanoparticles effectively blunt and reverse age-associated bone loss in mice by a mechanism involving promotion of bone formation. The data suggest that osteogenic silica nanoparticles may be a safe and effective therapeutic for counteracting age-associated bone loss. Osteoporosis poses a significant problem in the society. Based on their previous in-vitro findings, the authors' group investigated the effects of spherical silica nanoparticles in reversing bone loss in a mouse model of osteoporosis. The results showed that intra-peritoneal injections of silica nanoparticles could increase bone mineral density, with little observed toxic side effects. This novel method may prove important in future therapy for combating osteoporosis. Published by Elsevier Inc.

  19. The ERa-PI3K cascade in proopiomelanocortin progenitor neurons regulates feeding and glucose balance in female mice

    Science.gov (United States)

    Estrogens act upon estrogen receptor (ER)a to inhibit feeding and improve glucose homeostasis in female animals. However, the intracellular signals that mediate these estrogenic actions remain unknown. Here, we report that anorexigenic effects of estrogens are blunted in female mice that lack ERa sp...

  20. Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice.

    Science.gov (United States)

    Antoch, Marina P; Wrobel, Michelle; Kuropatwinski, Karen K; Gitlin, Ilya; Leonova, Katerina I; Toshkov, Ilia; Gleiberman, Anatoli S; Hutson, Alan D; Chernova, Olga B; Gudkov, Andrei V

    2017-03-19

    The development of healthspan-extending pharmaceuticals requires quantitative estimation of age-related progressive physiological decline. In humans, individual health status can be quantitatively assessed by means of a frailty index (FI), a parameter which reflects the scale of accumulation of age-related deficits. However, adaptation of this methodology to animal models is a challenging task since it includes multiple subjective parameters. Here we report a development of a quantitative non-invasive procedure to estimate biological age of an individual animal by creating physiological frailty index (PFI). We demonstrated the dynamics of PFI increase during chronological aging of male and female NIH Swiss mice. We also demonstrated acceleration of growth of PFI in animals placed on a high fat diet, reflecting aging acceleration by obesity and provide a tool for its quantitative assessment. Additionally, we showed that PFI could reveal anti-aging effect of mTOR inhibitor rapatar (bioavailable formulation of rapamycin) prior to registration of its effects on longevity. PFI revealed substantial sex-related differences in normal chronological aging and in the efficacy of detrimental (high fat diet) or beneficial (rapatar) aging modulatory factors. Together, these data introduce PFI as a reliable, non-invasive, quantitative tool suitable for testing potential anti-aging pharmaceuticals in pre-clinical studies.

  1. Learning and memory in mice with neuropathic pain: impact of old age and progranulin deficiency

    Directory of Open Access Journals (Sweden)

    Boris eAlbuquerque

    2013-11-01

    Full Text Available Persistent neuropathic pain is a frequent consequence of peripheral nerve injuries, particularly in the elderly. Using the IntelliCage we studied if a sciatic nerve injury obstructed learning and memory in young and aged mice, each in wild type and progranulin deficient mice, which develop premature signs of brain aging and are more susceptible to nerve injury evoked nociceptive hypersensitivity and hence allow to assess a potential mutual aggravation of pain and old age. Both young and aged mice developed long-term nerve injury-evoked hyperalgesia and allodynia but, in both genotypes, only aged mice with neuropathic pain showed high error rates in place avoidance acquisition tasks. Once learnt however, aged mice with neuropathic pain maintained the aversive memory longer, i.e. the extinction was significantly slowed. In addition, nerve injury in progranulin deficient mice impaired the learning of spatial sequences of awarded places, particularly in aged mice, whereas easy place preference learning was not affected by nerve injury or progranulin deficiency. The sequencing task required a discrimination of clockwise and anti-clockwise sequences and spatial flexibility to re-learn a novel sequence. The loss of spatial flexibility did not occur in sham operated mice, i.e. was a consequence of nerve injury and suggests that neuropathic pain accelerates manifestations of old age and progranulin deficiency. Neuropathic pain at old age, irrespective of the genotype, resulted in a long maintenance of aversive memory suggesting a negative alliance and possibly mutual aggravation of chronic neuropathic pain and aversive memory at old age.

  2. Involvement of oxidative stress in SAMP10 mice with age-related neurodegeneration.

    Science.gov (United States)

    Wang, Jun; Lei, Hongtao; Hou, Jincai; Liu, Jianxun

    2015-05-01

    Age-related changes in the brain tissue are reflected in many aspects. We sought to determine the morphology, Nissl bodies, behavioral appearance and oxidative stress in the brain using SAMP10 mice, a substrain of the senescence-accelerated mouse. SAMP10 mice groups divided by different ages (3, 5, 8 and 14 months) were compared with those of control groups with the above corresponding ages. Cortical thickness, Nissl bodies, behavioral appearance and oxidative stress were evaluated through image software, thionine staining, step-down test and colorimetry, respectively. The weight and cortical thickness of the brain in SAMP10 mice significantly reduced from 8 months of age. The results showed that the number of Nissl bodies decreased or Nissl bodies shrank with dark staining in histology. The same result appeared in a step-down test. As the SAMP10 mice grew older, the oxidative stress-related markers superoxide dismutase decreased and malondialdehyde increased after 8 months. Glutathione peroxidase activities showed no age-related changes. The changes of brain morphology and productions of oxidative stress in the brain tissue might contribute to the behavioral abnormality. Deceleration of age-related production of oxidative stress might be expected to be a potent strategy for anti-aging interventions.

  3. Defining Subpopulations of Arcuate Nucleus GABA Neurons in Male, Female, and Prenatally Androgenized Female Mice.

    Science.gov (United States)

    Marshall, Christopher J; Desroziers, Elodie; McLennan, Timothy; Campbell, Rebecca E

    2017-01-01

    Arcuate nucleus (ARN) γ-aminobutyric acid (GABA) neurons are implicated in many critical homeostatic mechanisms, from food intake to fertility. To determine the functional relevance of ARN GABA neurons, it is essential to define the neurotransmitters co-expressed with and potentially co-released from ARN GABA neurons. The present study investigated the expression of markers of specific signaling molecules by ARN GABA neurons in brain sections from male, female, and, in some cases, prenatally androgen-treated (PNA) female, vesicular GABA transporter (VGaT)-ires-Cre/tdTomato reporter mice. Immunofluorescence for kisspeptin, β-endorphin, neuropeptide Y (NPY), tyrosine hydroxylase (TH) and neuronal nitric oxide synthase (nNOS) was detected by confocal microscopy, and co-localization with tdTomato VGaT reporter expression throughout the ARN was quantified. GABA neurons rarely co-localized with kisspeptin (95%) co-localized with VGaT across groups. Both TH and nNOS labeling was co-localized with ∼10% of ARN GABA neurons. The proportion of TH neurons co-localized with VGaT was significantly greater in males than either control or PNA females, and the proportion of nNOS neurons co-localizing VGaT was higher in control and PNA females compared with males. These data highlight NPY as a significant subpopulation of ARN GABA neurons, demonstrate no significant impact of PNA on signal co-expression, and, for the first time, show sexually dimorphic co-expression patterns of TH and nNOS with ARN GABA neurons. © 2016 S. Karger AG, Basel.

  4. Effect of aging and Alzheimer's disease-like pathology on brain monoamines in mice

    DEFF Research Database (Denmark)

    Von Linstow, C. U.; Severino, Maurizio; Metaxas, Athanasios

    2017-01-01

    , but these can both be age- and/or disease-related. We examined whether brain monoamine levels change as part of physiological aging and/or AD-like disease in APPSWE/PS1δE9 (APP/PS1) transgenic mice. The neocortex, hippocampus, striatum, brainstem and cerebellum of 6-, 12-, 18- and 24-month-old B6C3 wild......-type (WT) mice and of 18-month old APP/PS1 and WT mice were analysed for 5-HT, DA and NA contents by high pressure liquid chromatography (HPLC), along with neocortex from 14-month-old APP/PS1 and WT mice. While, we observed no aging effect in WT mice, we detected region-specific changes in the levels...... of all monoamines in 18-month-old transgenic compared with WT mice. This included reductions in 5-HT (-30%), DA (-47%) and NA (-32%) levels in the neocortex and increases of 5-HT in the brainstem (+18%). No changes were observed in any of the monoamines in the neocortex from 14-month-old APP/PS1 mice...

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

    Science.gov (United States)

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

    2014-04-03

    Food restriction (FR) seems to be the unique experimental manipulation that leads to a remarkable increase in lifespan in rodents. Evidences have suggested that FR can enhance memory in distinct animal models mainly during aging. However, only few studies systemically evaluated the effects FR on memory formation in both adult (3-month-old) and aged (18-24-month-old) mice. Thus, the aim of the present study was to investigate the effects of acute (12h) or repeated (12h/day for 2days) FR protocols on learning and memory of adult and aged mice evaluated in the plus-maze discriminative avoidance task (PM-DAT), an animal model that concurrently (but independently) evaluates learning and memory, anxiety and locomotion. We also investigated the possible role of FR-induced stress by the corticosterone concentration in adult mice. Male mice were kept at home cage with food ad libitum (CTRL-control condition) or subjected to FR during the dark phase of the cycle for 12h/day or 12h/2days. The FR protocols were applied before training, immediately after it or before testing. Our results demonstrated that only FR for 2days enhanced memory persistence when applied before training in adults and before testing in aged mice. Conversely, FR for 2days impaired consolidation and exerted no effects on retrieval irrespective of age. These effects do not seem to be related to corticosterone concentration. Collectively, these results indicate that FR for 2days can promote promnestic effects not only in aged mice but also in adults. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Ornamentation, age, and survival of female striped plateau lizards, Sceloporus virgatus

    Science.gov (United States)

    Weiss, Stacey L.

    2016-04-01

    Individuals with greater expression of secondary sexual traits are often older and have higher survivorship than individuals with lower expression; if so, assessment of such indicator traits may provide genetic and/or direct benefits to potential mates. I examined the relationship between ornament expression, age, and survival in the striped plateau lizard, Sceloporus virgatus, a species with female-specific ornamentation that honestly signals reproductive quality. I followed a group of females from 2008 to 2013, examined ornament color and size as females aged, and compared ornamentation of survivors versus non-survivors. In addition, I explored whether other (non-ornamental) phenotypic characters predicted survival. I found that peak ornament expression (both color and size) of individual females changed year to year but appeared to be a weak signal of age due to high among-female variation in ornament expression that occurred independent of age and a non-linear pattern of change for ornament color. However, both absolute and relative ornament size did increase significantly as an individual aged and therefore may provide some age-related information such as reproductive investment, which is expected to increase as residual reproductive value declines with age. Individual survival was unrelated to peak ornament expression and to other phenotypic variables measured, providing no support for the ornament as a viability indicator and suggesting that individual survival prospects are affected by stochastic and environmental factors.

  7. Metabolic and adaptive immune responses induced in mice infected ...

    African Journals Online (AJOL)

    This study investigated metabolic and immuno-inflammatory responses of mice infected with tissue-dwelling larvae of Trichinella zimbabwensis and explored the relationship between infection, metabolic parameters and Th1/Th17 immune responses. Sixty (60) female BALB/c mice aged between 6 to 8 weeks old were ...

  8. Overexpression of catalase in mice reduces age-related oxidative stress and maintains sperm production.

    Science.gov (United States)

    Selvaratnam, Johanna; Robaire, Bernard

    2016-11-01

    Advanced paternal age is associated with increased complications in pregnancy and genetic diseases in offspring. Oxidative stress is a major contributor to the damage accumulated in sperm during aging. Complex networks of antioxidants regulate reactive oxygen species (ROS) in the testis. While mounting evident shows that redox dysfunction compromises the quality of developing male germ cells, the mechanisms by which aging causes this remain unclear. Furthermore, therapies to successfully alleviate aging-associated loss in germ cell quality are limited. The antioxidant catalase (CAT) has been used in aging-associated pathologies to alleviate oxidative stress. We used mice overexpressing CAT (MCAT) to determine whether CAT overexpression alleviates the redox dysfunction observed with aging. We found that MCAT mice did not exhibit the age-dependent loss of spermatozoa, nor did they show aging associated loss in testicular germ and Sertoli cells seen in wild type (WT). Low overall ROS and reduced peroxynitrite levels were detected in spermatocytes from aged MCAT mice, following exposure to the pro-oxidant tert-butyl hydroperoxide. Germ cells from young MCATs showed elevated levels of DNA-damage repair markers, γ-H2AX and 53BP1, but this response was lost with aging. Finally, we found oxidative stress induced 8-oxodG lesions to increase in sperm with aging; these lesions were significantly reduced in aged MCAT and these mice showed no decrease in the age-dependent number of pups per litter. Thus we conclude that aged MCAT mice generate sperm at the same rate as young mice; these sperm are protected from oxidative stress associated damage. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Chronic exposure to trichloroethene causes early onset of SLE-like disease in female MRL +/+ mice

    International Nuclear Information System (INIS)

    Cai Ping; Koenig, Rolf; Boor, Paul J.; Kondraganti, Shakuntala; Kaphalia, Bhupendra S.; Khan, M. Firoze; Ansari, G.A.S.

    2008-01-01

    Trichloroethene (TCE) exacerbates the development of autoimmune responses in autoimmune-prone MRL +/+ mice. Although TCE-mediated autoimmune responses are associated with an increase in serum immunoglobulins and autoantibodies, the underlying mechanism of autoimmunity is not known. To determine the progression of TCE-mediated immunotoxicity, female MRL +/+ mice were chronically exposed to TCE through the drinking water (0.5 mg/ml of TCE) for various periods of time. Serum concentrations of antinuclear antibodies increased after 36 and 48 weeks of TCE exposure. Histopathological analyses showed lymphocyte infiltration in the livers of MRL +/+ mice exposed to TCE for 36 or 48 weeks. Lymphocyte infiltration was also apparent in the pancreas, lungs, and kidneys of mice exposed to TCE for 48 weeks. Immunoglobulin deposits in kidney glomeruli were found after 48 weeks of exposure to TCE. Our results suggest that chronic exposure to TCE promotes inflammation in the liver, pancreas, lungs, and kidneys, which may lead to SLE-like disease in MRL +/+ mice

  10. Novel object recognition ability in female mice following exposure to nanoparticle-rich diesel exhaust

    Energy Technology Data Exchange (ETDEWEB)

    Win-Shwe, Tin-Tin, E-mail: tin.tin.win.shwe@nies.go.jp [Center for Environmental Health Sciences, National Institute for Environmental Studies, 16‐2 Onogawa, Tsukuba, Ibaraki 305‐8506 (Japan); Fujimaki, Hidekazu; Fujitani, Yuji; Hirano, Seishiro [Center for Environmental Risk Research, National Institute for Environmental Studies, 16‐2 Onogawa, Tsukuba, Ibaraki 305‐8506 (Japan)

    2012-08-01

    Recently, our laboratory reported that exposure to nanoparticle-rich diesel exhaust (NRDE) for 3 months impaired hippocampus-dependent spatial learning ability and up-regulated the expressions of memory function-related genes in the hippocampus of female mice. However, whether NRDE affects the hippocampus-dependent non-spatial learning ability and the mechanism of NRDE-induced neurotoxicity was unknown. Female BALB/c mice were exposed to clean air, middle-dose NRDE (M-NRDE, 47 μg/m{sup 3}), high-dose NRDE (H-NRDE, 129 μg/m{sup 3}), or filtered H-NRDE (F-DE) for 3 months. We then investigated the effect of NRDE exposure on non-spatial learning ability and the expression of genes related to glutamate neurotransmission using a novel object recognition test and a real-time RT-PCR analysis, respectively. We also examined microglia marker Iba1 immunoreactivity in the hippocampus using immunohistochemical analyses. Mice exposed to H-NRDE or F-DE could not discriminate between familiar and novel objects. The control and M-NRDE-exposed groups showed a significantly increased discrimination index, compared to the H-NRDE-exposed group. Although no significant changes in the expression levels of the NMDA receptor subunits were observed, the expression of glutamate transporter EAAT4 was decreased and that of glutamic acid decarboxylase GAD65 was increased in the hippocampus of H-NRDE-exposed mice, compared with the expression levels in control mice. We also found that microglia activation was prominent in the hippocampal area of the H-NRDE-exposed mice, compared with the other groups. These results indicated that exposure to NRDE for 3 months impaired the novel object recognition ability. The present study suggests that genes related to glutamate metabolism may be involved in the NRDE-induced neurotoxicity observed in the present mouse model. -- Highlights: ► The effects of nanoparticle-induced neurotoxicity remain unclear. ► We investigated the effect of exposure to

  11. Novel object recognition ability in female mice following exposure to nanoparticle-rich diesel exhaust

    International Nuclear Information System (INIS)

    Win-Shwe, Tin-Tin; Fujimaki, Hidekazu; Fujitani, Yuji; Hirano, Seishiro

    2012-01-01

    Recently, our laboratory reported that exposure to nanoparticle-rich diesel exhaust (NRDE) for 3 months impaired hippocampus-dependent spatial learning ability and up-regulated the expressions of memory function-related genes in the hippocampus of female mice. However, whether NRDE affects the hippocampus-dependent non-spatial learning ability and the mechanism of NRDE-induced neurotoxicity was unknown. Female BALB/c mice were exposed to clean air, middle-dose NRDE (M-NRDE, 47 μg/m 3 ), high-dose NRDE (H-NRDE, 129 μg/m 3 ), or filtered H-NRDE (F-DE) for 3 months. We then investigated the effect of NRDE exposure on non-spatial learning ability and the expression of genes related to glutamate neurotransmission using a novel object recognition test and a real-time RT-PCR analysis, respectively. We also examined microglia marker Iba1 immunoreactivity in the hippocampus using immunohistochemical analyses. Mice exposed to H-NRDE or F-DE could not discriminate between familiar and novel objects. The control and M-NRDE-exposed groups showed a significantly increased discrimination index, compared to the H-NRDE-exposed group. Although no significant changes in the expression levels of the NMDA receptor subunits were observed, the expression of glutamate transporter EAAT4 was decreased and that of glutamic acid decarboxylase GAD65 was increased in the hippocampus of H-NRDE-exposed mice, compared with the expression levels in control mice. We also found that microglia activation was prominent in the hippocampal area of the H-NRDE-exposed mice, compared with the other groups. These results indicated that exposure to NRDE for 3 months impaired the novel object recognition ability. The present study suggests that genes related to glutamate metabolism may be involved in the NRDE-induced neurotoxicity observed in the present mouse model. -- Highlights: ► The effects of nanoparticle-induced neurotoxicity remain unclear. ► We investigated the effect of exposure to

  12. Mid-aged and aged wild-type and progestin receptor knockout (PRKO) mice demonstrate rapid progesterone and 3alpha,5alpha-THP-facilitated lordosis.

    Science.gov (United States)

    Frye, C A; Sumida, K; Lydon, J P; O'Malley, B W; Pfaff, D W

    2006-05-01

    Progesterone (P) and its 5alpha-reduced metabolite, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP), facilitate sexual behavior of rodents via agonist-like actions at intracellular progestin receptors (PRs) and membrane GABA(A)/benzodiazepine receptor complexes (GBRs), respectively. Given that ovarian secretion of progestins declines with aging, whether or not senescent mice are responsive to progestins was of interest. Homozygous PR knockout (PRKO) or wild-type mice that were between 10-12 (mid-aged) or 20-24 (aged) months of age were administered P or 3alpha,5alpha-THP, and the effect on lordosis were examined. Effects of a progestin-priming regimen that enhances PR-mediated (experiment 1) or more rapid, PR-independent effects of progestins (experiments 2 and 3) on sexual behavior were examined. Levels of P, 3alpha,5alpha-THP, and muscimol binding were examined in tissues from aged mice (experiment 4). Wild-type, but not PRKO, mice were responsive when primed with 17beta-estradiol (E(2); 0.5 microg) and administered P (500 microg, subcutaneously). Mid-aged wild-type mice demonstrated greater increases in lordosis 6 h later compared to their pre-P, baseline test than did aged wild-type mice (experiment 1). Lordosis of younger and older wild-type, but not PRKO, mice was significantly increased within 5 min of intravenous (IV) administration of P (100 ng), compared with E(2)-priming alone (experiment 2). However, wild-type and PRKO mice demonstrated significant increases in lordosis 5 min after IV administration of 3alpha,5alpha-THP, an effect which was more pronounced in mid-aged than in aged animals (100 ng-experiment 3). In tissues from aged wild-type and PRKO mice, levels of P, 3alpha,5alpha-THP, and muscimol binding were increased by P administration (experiment 4). PR binding was lower in the cortex of PRKO than that of wild-type mice. Mid-aged and aged PRKO and wild-type mice demonstrated rapid P or 3alpha,5alpha-THP-facilitated lordosis that may be

  13. Effect of voluntary physical activity initiated at age 7 months on skeletal hindlimb and cardiac muscle function in mdx mice of both genders.

    Science.gov (United States)

    Ferry, Arnaud; Benchaouir, Rachid; Joanne, Pierre; Peat, Rachel A; Mougenot, Nathalie; Agbulut, Onnik; Butler-Browne, Gillian

    2015-11-01

    The effects of voluntary activity initiated in adult mdx (C57BL/10ScSc-DMD(mdx) /J) mice on skeletal and cardiac muscle function have not been studied extensively. We studied the effects of 3 months of voluntary wheel running initiated at age 7 months on hindlimb muscle weakness, increased susceptibility to muscle contraction-induced injury, and left ventricular function in mdx mice. We found that voluntary wheel running did not worsen the deficit in force-generating capacity and the force drop after lengthening contractions in either mdx mouse gender. It increased the absolute maximal force of skeletal muscle in female mdx mice. Moreover, it did not affect left ventricular function, structural heart dimensions, cardiac gene expression of inflammation, fibrosis, or remodeling markers. These results indicate that voluntary activity initiated at age 7 months had no detrimental effects on skeletal or cardiac muscles in either mdx mouse gender. © 2015 Wiley Periodicals, Inc.

  14. Cdc20 is critical for meiosis I and fertility of female mice.

    Directory of Open Access Journals (Sweden)

    Fang Jin

    2010-09-01

    Full Text Available Chromosome missegregation in germ cells is an important cause of unexplained infertility, miscarriages, and congenital birth defects in humans. However, the molecular defects that lead to production of aneuploid gametes are largely unknown. Cdc20, the activating subunit of the anaphase-promoting complex/cyclosome (APC/C, initiates sister-chromatid separation by ordering the destruction of two key anaphase inhibitors, cyclin B1 and securin, at the transition from metaphase to anaphase. The physiological significance and full repertoire of functions of mammalian Cdc20 are unclear at present, mainly because of the essential nature of this protein in cell cycle progression. To bypass this problem we generated hypomorphic mice that express low amounts of Cdc20. These mice are healthy and have a normal lifespan, but females produce either no or very few offspring, despite normal folliculogenesis and fertilization rates. When mated with wild-type males, hypomorphic females yield nearly normal numbers of fertilized eggs, but as these embryos develop, they become malformed and rarely reach the blastocyst stage. In exploring the underlying mechanism, we uncover that the vast majority of these embryos have abnormal chromosome numbers, primarily due to chromosome lagging and chromosome misalignment during meiosis I in the oocyte. Furthermore, cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I; and anaphase I onset is markedly delayed. These results demonstrate that the physiologically effective threshold level of Cdc20 is high for female meiosis I and identify Cdc20 hypomorphism as a mechanism for chromosome missegregation and formation of aneuploid gametes.

  15. Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice.

    Science.gov (United States)

    Chew, Chii Chii; Ng, Salby; Chee, Yun Lee; Koo, Teng Wai; Liew, Ming Hui; Chee, Evelyn Li-Ching; Modamio, Pilar; Fernández, Cecilia; Mariño, Eduardo L; Segarra, Ignacio

    2017-08-01

    Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC 0→∞ 38% in plasma (p diclofenac increased the liver uptake efficiency in male (27%, p diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.

  16. Trends in Female Breast Cancer by Age Group in the Chiang

    Science.gov (United States)

    Sripan, Patumrat; Sriplung, Hutcha; Pongnikorn, Donsuk; Virani, Shama; Bilheem, Surichai; Chaisaengkhaum, Udomlak; Maneesai, Puttachart; Waisri, Narate; Hanpragopsuk, Chirapong; Tansiri, Panrada; Khamsan, Varunee; Poungsombat, Malisa; Mawoot, Aumnart; Chitapanarux, Imjai

    2017-05-01

    Objectives: This study was conducted to determine incidence trends of female breast cancer according to age groups and to predict future change in Chiang Mai women through 2028. Method: Data were collected from all hospitals in Chiang Mai in northern Thailand, from 1989 through 2013, and used to investigate effects of age, year of diagnosis (period) and year of birth (cohort) on female breast cancer incidences using an age-period-cohort model. This model features geometric cut trends to predict change by young (<40 years), middle-aged (40-59) and elderly (≥60) age groups. Result: Of 5, 417 female breast cancer patients with a median age of 50 years (interquartile range: 43 to 59 years), 15%, 61% and 24% were young, middle-aged and elderly, respectively. Seventy nine percent of cancer cases in this study were detected at advanced stage. The trend in stage classification showed an increase in percentage of early stage and a decrease in metastatic cancers. Linear trends for cohort and period were not found in young females but were observed in middle-aged and elderly groups. Age-standardized rates (ASR) can be expected to remain stable around 6.8 per 100,000 women-years in young females. In the other age groups, the ASR trends were calculated to increase and reach peaks in 2024 of 120.2 and 138.2 per 100,000 women-years, respectively. Conclusion: Cohort effects or generation-specific effects, such as life style factors and the year of diagnosis (period) might have impacted on increased incidence in women aged over 40 years but not those under 40 years. A budget should be provided for treatment facilities and strategies to detect early stage cancers. The cost effectiveness of screening measures i.e. mammographic screening may need to be reconsidered for women age over 40 years. Creative Commons Attribution License

  17. Generation of ERα-floxed and knockout mice using the Cre/LoxP system

    International Nuclear Information System (INIS)

    Antonson, P.; Omoto, Y.; Humire, P.; Gustafsson, J.-Å.

    2012-01-01

    Highlights: ► ERα floxed and knockout mice were generated. ► Disruption of the ERα gene results in sterility in both male and female mice. ► ERα −/− mice have ovaries with hemorrhagic follicles and hypoplastic uterus. ► Female ERα −/− mice develop obesity. -- Abstract: Estrogen receptor alpha (ERα) is a nuclear receptor that regulates a range of physiological processes in response to estrogens. In order to study its biological role, we generated a floxed ERα mouse line that can be used to knock out ERα in selected tissues by using the Cre/LoxP system. In this study, we established a new ERα knockout mouse line by crossing the floxed ERα mice with Cre deleter mice. Here we show that genetic disruption of the ERα gene in all tissues results in sterility in both male and female mice. Histological examination of uterus and ovaries revealed a dramatically atrophic uterus and hemorrhagic cysts in the ovary. These results suggest that infertility in female mice is the result of functional defects of the reproductive tract. Moreover, female knockout mice are hyperglycemic, develop obesity and at the age of 4 months the body weight of these mice was more than 20% higher compared to wild type littermates and this difference increased over time. Our results demonstrate that ERα is necessary for reproductive tract development and has important functions as a regulator of metabolism in females.

  18. Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice.

    Science.gov (United States)

    Nohara, Kazunari; Waraich, Rizwana S; Liu, Suhuan; Ferron, Mathieu; Waget, Aurélie; Meyers, Matthew S; Karsenty, Gérard; Burcelin, Rémy; Mauvais-Jarvis, Franck

    2013-06-15

    Among women, the polycystic ovarian syndrome (PCOS) is considered a form of metabolic syndrome with reproductive abnormalities. Women with PCOS show increased sympathetic tone, visceral adiposity with enlarged adipocytes, hypoadiponectinemia, insulin resistance, glucose intolerance, increased inactive osteocalcin, and hypertension. Excess fetal exposure to androgens has been hypothesized to play a role in the pathogenesis of PCOS. Previously, we showed that neonatal exposure to the androgen testosterone (NT) programs leptin resistance in adult female mice. Here, we studied the impact of NT on lean and adipose tissues, sympathetic tone in cardiometabolic tissues, and the development of metabolic dysfunction in mice. Neonatally androgenized adult female mice (NTF) displayed masculinization of lean tissues with increased cardiac and skeletal muscle as well as kidney masses. NTF mice showed increased and dysfunctional white adipose tissue with increased sympathetic tone in both visceral and subcutaneous fat as well as increased number of enlarged and insulin-resistant adipocytes that displayed altered expression of developmental genes and hypoadiponectinemia. NTF exhibited dysfunctional brown adipose tissue with increased mass and decreased energy expenditure. They also displayed decreased undercarboxylated and active osteocalcin and were predisposed to obesity during chronic androgen excess. NTF showed increased renal sympathetic tone associated with increased blood pressure, and they developed glucose intolerance and insulin resistance. Thus, developmental exposure to testosterone in female mice programs features of cardiometabolic dysfunction, as can be observed in women with PCOS, including increased sympathetic tone, visceral adiposity, insulin resistance, prediabetes, and hypertension.

  19. Asic3(-/- female mice with hearing deficit affects social development of pups.

    Directory of Open Access Journals (Sweden)

    Wei-Li Wu

    Full Text Available BACKGROUND: Infant crying is an important cue for mothers to respond adequately. Inappropriate response to infant crying can hinder social development in infants. In rodents, the pup-mother interaction largely depends on pup's calls. Mouse pups emit high frequency to ultrasonic vocalization (2-90 kHz to communicate with their dam for maternal care. However, little is known about how the maternal response to infant crying or pup calls affects social development over the long term. METHODOLOGY/PRINCIPAL FINDINGS: Here we used mice lacking acid-sensing ion channel 3 (Asic3(-/- to create a hearing deficit to probe the effect of caregiver hearing on maternal care and adolescent social development. Female Asic3(-/- mice showed elevated hearing thresholds for low to ultrasonic frequency (4-32 kHz on auditory brain stem response, which thus hindered their response to their pups' wriggling calls and ultrasonic vocalization, as well as their retrieval of pups. In adolescence, pups reared by Asic3(-/- mice showed a social deficit in juvenile social behaviors as compared with those reared by wild-type or heterozygous dams. The social-deficit phenotype in juvenile mice reared by Asic3(-/- mice was associated with the reduced serotonin transmission of the brain. However, Asic3(-/- pups cross-fostered to wild-type dams showed rescued social deficit. CONCLUSIONS/SIGNIFICANCE: Inadequate response to pups' calls as a result of ASIC3-dependent hearing loss confers maternal deficits in caregivers and social development deficits in their young.

  20. Ginseng Berry Extract Supplementation Improves Age-Related Decline of Insulin Signaling in Mice

    Directory of Open Access Journals (Sweden)

    Eunhui Seo

    2015-04-01

    Full Text Available The aim of this study was to evaluate the effects of ginseng berry extract on insulin sensitivity and associated molecular mechanisms in aged mice. C57BL/6 mice (15 months old were maintained on a regular diet (CON or a regular diet supplemented with 0.05% ginseng berry extract (GBD for 24 or 32 weeks. GBD-fed mice showed significantly lower serum insulin levels (p = 0.016 and insulin resistance scores (HOMA-IR (p = 0.012, suggesting that GBD improved insulin sensitivity. Pancreatic islet hypertrophy was also ameliorated in GBD-fed mice (p = 0.007. Protein levels of tyrosine phosphorylated insulin receptor substrate (IRS-1 (p = 0.047, and protein kinase B (AKT (p = 0.037, were up-regulated in the muscle of insulin-injected GBD-fed mice compared with CON-fed mice. The expressions of forkhead box protein O1 (FOXO1 (p = 0.036 and peroxisome proliferator-activated receptor gamma (PPARγ (p = 0.032, which are known as aging- and insulin resistance-related genes, were also increased in the muscle of GBD-fed mice. We conclude that ginseng berry extract consumption might increase activation of IRS-1 and AKT, contributing to the improvement of insulin sensitivity in aged mice.

  1. Analyses of Selenotranscriptomes and Selenium Concentrations in Response to Dietary Selenium Deficiency and Age Reveal Common and Distinct Patterns by Tissue and Sex in Telomere-Dysfunctional Mice.

    Science.gov (United States)

    Cao, Lei; Zhang, Li; Zeng, Huawei; Wu, Ryan Ty; Wu, Tung-Lung; Cheng, Wen-Hsing

    2017-10-01

    Background: The hierarchies of tissue selenium distribution and selenotranscriptomes are thought to critically affect healthspan and longevity. Objective: We determined selenium status and selenotranscriptomes in response to long-term dietary selenium deficiency and age in tissues of male and female mice. Methods: Weanling telomerase RNA component knockout C57BL/6 mice were fed a selenium-deficient (0.03 mg Se/kg) Torula yeast-based AIN-93G diet or a diet supplemented with sodium selenate (0.15 mg Se/kg) until age 18 or 24 mo. Plasma, hearts, kidneys, livers, and testes were collected to assay for selenotranscriptomes, selected selenoproteins, and tissue selenium concentrations. Data were analyzed with the use of 2-factor ANOVA (diet × age) in both sexes. Results: Dietary selenium deficiency decreased ( P ≤ 0.05) selenium concentrations (65-72%) and glutathione peroxidase (GPX) 3 (82-94%) and selenoprotein P (SELENOP) (17-41%) levels in the plasma of both sexes of mice and mRNA levels (9-68%) of 4, 4, and 12 selenoproteins in the heart, kidney, and liver of males, respectively, and 5, 16, and 14 selenoproteins, respectively, in females. Age increased selenium concentrations and SELENOP levels (27% and 30%, respectively; P ≤ 0.05) in the plasma of males only but decreased (12-46%; P selenium deficiency and age in ≥1 tissue or sex, or both. Dietary selenium deficiency upregulated (40-160%; P ≤ 0.05) iodothyronine deiodinase 2 ( Dio2 ) and selenoprotein N ( Selenon ) in the kidneys of males. Age upregulated (11-44%; P selenium status and selenotranscriptomes because of dietary selenium deficiency and age. © 2017 American Society for Nutrition.

  2. Effect of aging and Alzheimer's disease-like pathology on brain monoamines in mice.

    Science.gov (United States)

    Von Linstow, C U; Severino, M; Metaxas, A; Waider, J; Babcock, A A; Lesch, K P; Gramsbergen, J B; Finsen, B

    2017-09-01

    Aging is the greatest single risk factor of the neurodegenerative disorder Alzheimer's disease (AD). The monoaminergic system, including serotonin (5-HT), dopamine (DA) and noradrenaline (NA) modulates cognition, which is affected in AD. Changes in monoamine levels have been observed in AD, but these can both be age- and/or disease-related. We examined whether brain monoamine levels change as part of physiological aging and/or AD-like disease in APP SWE /PS1 ΔE9 (APP/PS1) transgenic mice. The neocortex, hippocampus, striatum, brainstem and cerebellum of 6-, 12-, 18- and 24-month-old B6C3 wild-type (WT) mice and of 18-month old APP/PS1 and WT mice were analysed for 5-HT, DA and NA contents by high pressure liquid chromatography (HPLC), along with neocortex from 14-month-old APP/PS1 and WT mice. While, we observed no aging effect in WT mice, we detected region-specific changes in the levels of all monoamines in 18-month-old transgenic compared with WT mice. This included reductions in 5-HT (-30%), DA (-47%) and NA (-32%) levels in the neocortex and increases of 5-HT in the brainstem (+18%). No changes were observed in any of the monoamines in the neocortex from 14-month-old APP/PS1 mice. In combination, these findings indicate that aging alone is not sufficient to affect brain monoamine levels, unlike the APP SWE /PS1 ΔE9 genotype. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Effect of aged garlic extract on immune responses to experimental fibrosarcoma tumor in BALB/c mice.

    Science.gov (United States)

    Tabari, M Abouhosseini; Ebrahimpour, S

    2014-01-01

    Aged garlic extract (AGE) has many biological activities including radical scavenging, antioxidative and immunomodulative effects. In this research work, the antitumor and immunomodulatory effects of AGE against fibrosarcoma implanted tumor were studied. WEHI-164 fibrosarcoma cells were implanted subcutaneously on day 0 into the right flank of 40 BALB/c mice at age of 8 weeks. Mice were randomly categorized in two separate groups: First received AGE (100 mg/kg, IP), second group as the control group received phosphate buffered saline. Treatments were carried out 3 times/week. Tumor growth was measured and morbidity was recorded. Subpopulations of CD4+/CD8+ T cells were determined using flow cytometry. WEHI-164 cell specific cytotoxicity of splenocytes and in vitro production of interferon gamma (IFN-γ) and interleukin-4 cytokines were measured. The mice received AGE had significantly longer survival time compared with the control mice. The inhibitory effect on tumor growth was seen in AGE treated mice. The CD4+/CD8+ ratio and in vitro IFN-γ production of splenocytes were significantly increased in AGE group. WEHI-164 specific cytotoxicity of splenocytes from AGE mice was also significantly increased at 25:1 E: T ratio. Administration of AGE resulted in improved immune responses against experimentally implanted fibrosarcoma tumors in BALB/c mice. AGE showed significant effects on inhibition of tumor growth and longevity of survival times.

  4. Effect of Cistanche deserticola Ma extract on memory of aged mice ...

    African Journals Online (AJOL)

    Orobanchaceae) extract (CDME) on normal aged mice. Methods: An open-field test was used to study the effects of various doses of CDME on mouse locomotive activity. The mice were sacrificed following the locomotor test and the brain ...

  5. Protective effect of metformin on D-galactose-induced aging model in mice.

    Science.gov (United States)

    Fatemi, Iman; Khaluoi, Amin; Kaeidi, Ayat; Shamsizadeh, Ali; Heydari, Sara; Allahtavakoli, Mohammad Aa

    2018-01-01

    Metformin (Met), an antidiabetic biguanide, reduces hyperglycemia via improving glucose utilization and reducing the gluconeogenesis. Met has been shown to exert neuroprotective, antioxidant and anti-inflammatory properties. The present study investigated the possible effect of Met on the D-galactose (D-gal)-induced aging in mice. Met (1 and 10 mg/kg/p.o.), was administrated daily in D-gal-received (500 mg/kg/p.o.) mice model of aging for six weeks. Anxiety-like behavior, cognitive function, and physical power were evaluated by the elevated plus-maze, novel object recognition task (NORT), and forced swimming capacity test, respectively. The brains were analyzed for the level of superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF). Met decreased the anxiety-like behavior in D-gal-treated mice. Also, Met treated mice showed significantly improved learning and memory ability in NORT compared to the D-gal-treated mice. Furthermore, Met increased the physical power as well as the activity of SOD and BDNF level in D-gal-treated mice. Our results suggest that the use of Met can be an effective strategy for prevention and treatment of D-gal-induced aging in animal models. This effect seems to be mediated by attenuation of oxidative stress and enhancement of the neurotrophic factors.

  6. Impact of Triclosan on Female Reproduction through Reducing Thyroid Hormones to Suppress Hypothalamic Kisspeptin Neurons in Mice

    Directory of Open Access Journals (Sweden)

    Xin-Yuan Cao

    2018-01-01

    Full Text Available Triclosan (TCS, a broad-spectrum antimicrobial agent, is widely used in clinical settings and various personal care products. The aim of this study was to evaluate the influence of TCS on reproductive endocrine and function. Here, we show that the exposure of adult female mice to 10 or 100 mg/kg/day TCS caused prolongation of diestrus, and decreases in antral follicles and corpora lutea within 2 weeks. TCS mice showed decreases in the levels of serum luteinizing hormone (LH, follicle-stimulating hormone (FSH and progesterone, and gonadotrophin-releasing hormone (GnRH mRNA with the lack of LH surge and elevation of prolactin (PRL. TCS mice had lower kisspeptin immunoreactivity and kiss1 mRNA in anteroventral periventricular nucleus (AVPV and arcuate nucleus (ARC. Moreover, the estrogen (E2-enhanced AVPV-kisspeptin expression was reduced in TCS mice. In addition, the serum thyroid hormones (triiodothyronine (T3 and thyroxine (T4 in TCS mice were reduced with increases in levels of thyroid stimulating hormone (TSH and thyroid releasing hormone (TRH. In TCS mice, the treatment with Levothyroxine (L-T4 corrected the increases in PRL, TSH and TRH; the administration of L-T4 or type-2 dopamine receptors agonist quinpirole inhibiting PRL release could rescue the decline of kisspeptin expression in AVPV and ARC; the treatment with L-T4, quinpirole or the GPR45 agonist kisspeptin-10 recovered the levels of serum LH and FSH and progesterone, and GnRH mRNA. Furthermore, TCS mice treated with L-T4 or quinpirole resumed regular estrous cycling, follicular development and ovulation. Together, these results indicate that exposing adult female mice to TCS (≥10 mg/kg reduces thyroid hormones causing hyperprolactinemia that then suppresses hypothalamic kisspeptin expression, leading to deficits in reproductive endocrine and function.

  7. Effects of low dose rate irradiation on life span prolongation of human premature-aging syndrome model mice

    International Nuclear Information System (INIS)

    Nomura, Takaharu

    2006-01-01

    We previously showed that Type II diabetes model mice prolonged of their life span by life long low dose rate irradiation. We also found that antioxidant function in variety tissues of some strain of mice were enhancement after low dose/low dose rate irradiation. The prolongation of life span might depend on certain damaged level of reactive oxygen species. We thought the effect of the prolongation was due to the enhancement of the antioxidant activities after irradiation. We investigated whether the enhancement of antioxidant activities after low dose rate irradiation had an effect on life span prolongation. Four-week-old female human premature-aging syndrome model mice, kl/kl (klotho) mice, which the life span of this model mouse is about 65 days, were irradiated with gamma rays at 0.35, 0.70 or 1.2 mGy/hr. The 0.70 mGy/hr-irradiated group remarkably effected on the prolongation of their life span. Some mice of the group were extremely survived for about and more 100 days. Antioxidant activities in the irradiated groups were enhancement by low dose rate irradiation, however the dependence of the dose rates were not clearly difference. These results suggest that the antioxidant activities in this model mouse were enhanced by the low dose rate irradiation, and may make it possible to prolong the life span of this mouse. (author)

  8. Immune Alterations in Male and Female Mice after 2-Deoxy-D-Glucose Administration

    Science.gov (United States)

    Dreau, Didier; Morton, Darla S.; Foster, Mareva; Swiggett, Jeanene P.; Sonnenfeld, Gerald

    1995-01-01

    Administration of 2-deoxy-D-glucose (2-DG), an analog of glucose which inhibits glycolysis by competitive antagonism for phosphohexose isomerase, results in acute periods of intracellular glucoprivation and hyperglycemia resulting in hyperphagia. In addition to these changes in the carbohydrate metabolism, injection of 2-DG results in alterations of both the endocrine and neurological systems as suggested by modifications in oxytocin and glucocorticoid levels and norepinephrine production. Moreover, alterations of the immune response, such as a decrease in the in vitro proliferation of splenocytes after mitogen-stimulation, were observed in mice injected with 2-DG. Sex, genotype and environment are among the factors that may modulate effects of catecholamines and hypothalamo-pituitary-adrenal axis on these immune changes. Sexual dimorphism in immune function resulting from the effects of sex hormones on immune effector cells has been shown in both animals and humans. These observations have important implications, especially with regard to higher incidence of many autoimmune diseases in females. Evidence exists that reproductive hormones influence the immune system and increase the risk of immunologically related disorders in both animals and humans. Indeed, immunological responses in stressful situations may also be confounded by fluctuations of sex hormones especially in females. Lymphocyte distribution, cytoldne production, and the ability of lymphocyte to proliferate in vitro were analyzed in male and female mice to determine if sex influenced 2-DG immunomodulation. In addition, the influence of hormones, especially sex hormones, on these changes were evaluated.

  9. Increased susceptibility to collagen-induced arthritis in female mice carrying congenic Cia40/Pregq2 fragments

    DEFF Research Database (Denmark)

    Liljander, Maria; Andersson, Åsa Inga Maria; Holmdahl, Rikard

    2008-01-01

    ABSTRACT: INTRODUCTION: Collagen-induced arthritis (CIA) in mice is a commonly used experimental model for rheumatoid arthritis (RA). We have previously identified a significant quantitative trait locus denoted Cia40 on chromosome 11 that affects CIA in older female mice. This locus colocalizes...... with another locus, denoted Pregq2, known to affect reproductive success. The present study was performed to evaluate the role of the Cia40 locus in congenic B10.Q mice and to identify possible polymorphic candidate genes, which may also be relevant in the context of RA. METHODS: Congenic B10.Q mice carrying...... an NFR/N fragment surrounding the Cia40/Pregq2 loci were created by 10 generations of backcrossing (N10). The congenic mice were investigated in the CIA model, and the incidence and severity of arthritis as well as the serum levels of anti-collagen II (CII) antibodies were recorded. RESULTS: Significant...

  10. Cold hypersensitivity increases with age in mice with sickle cell disease

    Science.gov (United States)

    Zappia, Katherine J.; Garrison, Sheldon R.; Hillery, Cheryl A.; Stucky, Cheryl L.

    2014-01-01

    Sickle cell disease (SCD) is associated with acute vaso-occlusive crises that trigger painful episodes and frequently involves ongoing, chronic pain. Additionally, both humans and mice with SCD experience heighted cold sensitivity. However, studies have not addressed the mechanism(s) underlying the cold sensitization, nor its progression with age. Here we measured thermotaxis behavior in young and aged mice with severe SCD. Sickle mice had a marked increase in cold sensitivity measured by a cold preference test. Further, cold hypersensitivity worsened with advanced age. We assessed whether enhanced peripheral input contributes to the chronic cold pain behavior by recording from C fibers, many of which are cold-sensitive, in skin-nerve preparations. We observed that C fibers from sickle mice displayed a shift to warmer (more sensitive) cold-detection thresholds. To address mechanisms underlying the cold sensitization in primary afferent neurons, we quantified mRNA expression levels for ion channels thought to be involved in cold detection. These included the Transient Receptor Potential Melastatin 8 (Trpm8) and TRP Ankyrin 1 (Trpa1) channels, as well as the two-pore domain potassium channels, TREK-1 (Kcnk2), TREK-2 (Kcnk4), and TRAAK (Kcnk10). Surprisingly, transcript expression levels of all of these channels were comparable between sickle and control mice. We further examined transcript expression of 83 additional pain-related genes and found increased mRNA levels for endothelin 1 and tachykinin receptor 1. These factors may contribute to hypersensitivity in sickle mice at both the afferent and behavioral levels. Sensory neurons from sickle cell disease mice are sensitized to cold, mirroring behavioral observations, and have increased expression of endothelin 1 and tachykinin receptor 1. PMID:24953902

  11. Neurokinin B is critical for normal timing of sexual maturation but dispensable for adult reproductive function in female mice.

    Science.gov (United States)

    True, Cadence; Nasrin Alam, Sayeda; Cox, Kimberly; Chan, Yee-Ming; Seminara, Stephanie B

    2015-04-01

    Humans carrying mutations in neurokinin B (NKB) or the NKB receptor fail to undergo puberty due to decreased secretion of GnRH. Despite this pubertal delay, many of these patients go on to achieve activation of their hypothalamic-pituitary-gonadal axis in adulthood, a phenomenon termed reversal, indicating that NKB signaling may play a more critical role for the timing of pubertal development than adult reproductive function. NKB receptor-deficient mice are hypogonadotropic but have no defects in the timing of sexual maturation. The current study has performed the first phenotypic evaluation of mice bearing mutations in Tac2, the gene encoding the NKB ligand, to determine whether they have impaired sexual development similar to their human counterparts. Male Tac2-/- mice showed no difference in the timing of sexual maturation or fertility compared with wild-type littermates and were fertile. In contrast, Tac2-/- females had profound delays in sexual maturation, with time to vaginal opening and first estrus occurring significantly later than controls, and initial abnormalities in estrous cycles. However, cycling recovered in adulthood and Tac2-/- females were fertile, although they produced fewer pups per litter. Thus, female Tac2-/- mice parallel humans harboring NKB pathway mutations, with delayed sexual maturation and activation of the reproductive cascade later in life. Moreover, direct comparison of NKB ligand and receptor-deficient females confirmed that only NKB ligand-deficient animals have delayed sexual maturation, suggesting that in the absence of the NKB receptor, NKB may regulate the timing of sexual maturation through other tachykinin receptors.

  12. Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice.

    Science.gov (United States)

    Montalvo-Ortiz, Janitza L; Fisher, Daniel W; Rodríguez, Guadalupe; Fang, Deyu; Csernansky, John G; Dong, Hongxin

    2017-08-01

    Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. In this study, we treated young (2-3 months old) and aged (22-24 months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14 days to evaluate HAL-induced motor side effects. In addition, we pretreated separate groups of young and aged mice with histone deacetylase (HDAC) inhibitors valproic acid (VPA) or entinostat (MS-275) and then administered HAL. Our results show that the motor side effects of HAL are exaggerated in aged mice as compared to young mice and that HDAC inhibitors are able to reverse the severity of these deficits. HAL-induced motor deficits in aged mice are associated with an age- and drug-dependent decrease in striatal D2R protein levels and functionality. Further, histone acetylation was reduced while histone tri-methylation was increased at specific lysine residues of H3 and H4 within the Drd2 promoter in the striatum of aged mice. HDAC inhibitors, particularly VPA, restored striatal D2R protein levels and functionality and reversed age- and drug-related histone modifications at the Drd2 promoter. These results suggest that epigenetic changes at the striatal Drd2 promoter drive age-related increases in antipsychotic side effect susceptibility, and HDAC inhibitors may be an effective adjunct treatment strategy to reduce side effects in aged populations.

  13. Gait disorder as a predictor of spatial learning and memory impairment in aged mice

    Directory of Open Access Journals (Sweden)

    Xin Wang

    2017-01-01

    Full Text Available Objective To investigate whether gait dysfunction is a predictor of severe spatial learning and memory impairment in aged mice. Methods A total of 100 12-month-old male mice that had no obvious abnormal motor ability and whose Morris water maze performances were not significantly different from those of two-month-old male mice were selected for the study. The selected aged mice were then divided into abnormal or normal gait groups according to the results from the quantitative gait assessment. Gaits of aged mice were defined as abnormal when the values of quantitative gait parameters were two standard deviations (SD lower or higher than those of 2-month-old male mice. Gait parameters included stride length, variability of stride length, base of support, cadence, and average speed. After nine months, mice exhibiting severe spatial learning and memory impairment were separated from mice with mild or no cognitive dysfunction. The rate of severe spatial learning and memory impairment in the abnormal and normal gait groups was tested by a chi-square test and the correlation between gait dysfunction and decline in cognitive function was tested using a diagnostic test. Results The 12-month-old aged mice were divided into a normal gait group (n = 75 and an abnormal gait group (n = 25. Nine months later, three mice in the normal gait group and two mice in the abnormal gait group had died. The remaining mice were subjected to the Morris water maze again, and 17 out of 23 mice in the abnormal gait group had developed severe spatial learning and memory impairment, including six with stride length deficits, 15 with coefficient of variation (CV in stride length, two with base of support (BOS deficits, five with cadence dysfunction, and six with average speed deficits. In contrast, only 15 out of 72 mice in the normal gait group developed severe spatial learning and memory impairment. The rate of severe spatial learning and memory impairment was

  14. Intestinal immunity in hypopituitary dwarf mice: effects of age.

    Science.gov (United States)

    Wang, Xin; Darcy, Justin; Cai, Chuan; Jin, Junfei; Bartke, Andrzej; Cao, Deliang

    2018-03-02

    Hypopituitary dwarf mice demonstrate advantages of longevity, but little is known of their colon development and intestinal immunity. Herein we found that Ames dwarf mice have shorter colon and colonic crypts, but larger ratio of mesenteric lymph nodes (MLNs) over body weight than age-matched wild type (WT) mice. In the colonic lamina propria (cLP) of juvenile Ames mice, more inflammatory neutrophils (Ā: 0.15% vs. 0.03% in WT mice) and monocytes (Ā: 7.97% vs. 5.15%) infiltrated, and antigen presenting cells CD11c+ dendritic cells (Ā: 1.39% vs. 0.87%), CD11b+ macrophages (Ā: 3.22% vs. 0.81%) and gamma delta T (γδ T) cells (Ā: 5.56% vs. 1.35%) were increased. In adult Ames dwarf mice, adaptive immune cells, such as IL-17 producing CD4+ T helper (Th17) cells (Ā: 8.3% vs. 4.7%) were augmented. In the MLNs of Ames dwarf mice, the antigen presenting and adaptive immune cells also altered when compared to WT mice, such as a decrease of T-regulatory (Treg) cells in juvenile Ames mice (Ā: 7.7% vs.10.5%), but an increase of Th17 cells (Ā: 0.627% vs.0.093%). Taken together, these data suggest that somatotropic signaling deficiency influences colon development and intestinal immunity.

  15. Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type

    Science.gov (United States)

    Kane, Alice E.; Mitchell, Sarah J.; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; de Cabo, Rafael; Hilmer, Sarah N.

    2018-01-01

    Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID:26615879

  16. The effects of serotonin1A receptor on female mice body weight and food intake are associated with the differential expression of hypothalamic neuropeptides and the GABAA receptor.

    Science.gov (United States)

    Butt, Isma; Hong, Andrew; Di, Jing; Aracena, Sonia; Banerjee, Probal; Shen, Chang-Hui

    2014-10-01

    Both common eating disorders anorexia nervosa and bulimia nervosa are characteristically diseases of women. To characterize the role of the 5-HT1A receptor (5-HT1A-R) in these eating disorders in females, we investigated the effect of saline or 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) treatment on feeding behavior and body weight in adult WT female mice and in adult 5-HT1A-R knockout (KO) female mice. Our results showed that KO female mice have lower food intake and body weight than WT female mice. Administration of 8-OH-DPAT decreased food intake but not body weight in WT female mice. Furthermore, qRT-PCR was employed to analyze the expression levels of neuropeptides, γ-aminobutyric acid A receptor subunit β (GABAA β subunits) and glutamic acid decarboxylase in the hypothalamic area. The results showed the difference in food intake between WT and KO mice was accompanied by differential expression of POMC, CART and GABAA β2, and the difference in body weight between WT and KO mice was associated with significantly different expression levels of CART and GABAA β2. As such, our data provide new insight into the role of 5-HT1A-R in both feeding behavior and the associated expression of neuropeptides and the GABAA receptor. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms.

    Science.gov (United States)

    Ashpole, Nicole M; Herron, Jacquelyn C; Mitschelen, Matthew C; Farley, Julie A; Logan, Sreemathi; Yan, Han; Ungvari, Zoltan; Hodges, Erik L; Csiszar, Anna; Ikeno, Yuji; Humphrey, Mary Beth; Sonntag, William E

    2016-02-01

    Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, whereas others report that loss of IGF-1 is beneficial because it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igf(f/f) mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan: early in postnatal development (crossing albumin-cyclic recombinase [Cre] mice with Igf(f/f) mice); and in early adulthood and in late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using micro-computed tomography (μCT) and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NF-κB-ligand (RANKL) levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2-fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data

  18. Excessive Vitamin E Intake Does Not Cause Bone Loss in Male or Ovariectomized Female Mice Fed Normal or High-Fat Diets.

    Science.gov (United States)

    Ikegami, Hiroko; Kawawa, Rie; Ichi, Ikuyo; Ishikawa, Tomoko; Koike, Taisuke; Aoki, Yoshinori; Fujiwara, Yoko

    2017-10-01

    Background: Animal studies on the effects of vitamin E on bone health have yielded conflicting and inconclusive results, and to our knowledge, no studies have addressed the effect of vitamin E on bone in animals consuming a high-fat diet (HFD). Objective: This study aimed to evaluate the effect of excessive vitamin E on bone metabolism in normal male mice and ovariectomized female mice fed a normal diet (ND) or HFD. Methods: In the first 2 experiments, 7-wk-old male mice were fed an ND (16% energy from fat) containing 75 (control), 0 (vitamin E-free), or 1000 (high vitamin E) mg vitamin E/kg (experiment 1) or an HFD (46% energy from fat) containing 0, 200, 500, or 1000 mg vitamin E/kg (experiment 2) for 18 wk. In the third experiment, 7-wk-old sham-operated or ovariectomized female mice were fed the ND (75 mg vitamin E/kg) or HFD containing 0 or 1000 mg vitamin E/kg for 8 wk. At the end of the feeding period, blood and femurs were collected to measure bone turnover markers and analyze histology and microcomputed tomography. Results: In experiments 1 and 2, vitamin E intake had no effect on plasma alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) activity, or bone formation, resorption, or volume in femurs in mice fed the ND or HFDs. In experiment 3, bone volume was significantly reduced (85%) in ovariectomized mice compared with that in sham-operated mice ( P vitamin E/kg. Conclusions: The results suggest that excess vitamin E intake does not cause bone loss in normal male mice or in ovariectomized or sham-operated female mice, regardless of dietary fat content. © 2017 American Society for Nutrition.

  19. Collagen VI Null Mice as a Model for Early Onset Muscle Decline in Aging

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    Daniele Capitanio

    2017-10-01

    Full Text Available Collagen VI is an extracellular matrix (ECM protein playing a key role in skeletal muscles and whose deficiency leads to connective tissue diseases in humans and in animal models. However, most studies have been focused on skeletal muscle features. We performed an extensive proteomic profiling in two skeletal muscles (diaphragm and gastrocnemius of wild-type and collagen VI null (Col6a1−/− mice at different ages, from 6- (adult to 12- (aged month-old to 24 (old month-old. While in wild-type animals the number of proteins and the level of modification occurring during aging were comparable in the two analyzed muscles, Col6a1−/− mice displayed a number of muscle-type specific variations. In particular, gastrocnemius displayed a limited number of dysregulated proteins in adult mice, while in aged muscles the modifications were more pronounced in terms of number and level. In diaphragm, the differences displayed by 6-month-old Col6a1−/− mice were more pronounced compared to wild-type mice and persisted at 12 months of age. In adult Col6a1−/− mice, the major variations were found in the enzymes belonging to the glycolytic pathway and the tricarboxylic acid (TCA cycle, as well as in autophagy-related proteins. When compared to wild-type animals Col6a1−/− mice displayed a general metabolic rewiring which was particularly prominent the diaphragm at 6 months of age. Comparison of the proteomic features and the molecular analysis of metabolic and autophagic pathways in adult and aged Col6a1−/− diaphragm indicated that the effects of aging, culminating in lipotoxicity and autophagic impairment, were already present at 6 months of age. Conversely, the effects of aging in Col6a1−/− gastrocnemius were similar but delayed becoming apparent at 12 months of age. A similar metabolic rewiring and autophagic impairment was found in the diaphragm of 24-month-old wild-type mice, confirming that fatty acid synthase (FASN increment and

  20. The mouse as a model for understanding chronic diseases of aging: the histopathologic basis of aging in inbred mice

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    David Harrison

    2011-06-01

    Full Text Available Inbred mice provide a unique tool to study aging populations because of the genetic homogeneity within an inbred strain, their short life span, and the tools for analysis which are available. A large-scale longitudinal and cross-sectional aging study was conducted on 30 inbred strains to determine, using histopathology, the type and diversity of diseases mice develop as they age. These data provide tools that when linked with modern in silico genetic mapping tools, can begin to unravel the complex genetics of many of the common chronic diseases associated with aging in humans and other mammals. In addition, novel disease models were discovered in some strains, such as rhabdomyosarcoma in old A/J mice, to diseases affecting many but not all strains including pseudoxanthoma elasticum, pulmonary adenoma, alopecia areata, and many others. This extensive data set is now available online and provides a useful tool to help better understand strain-specific background diseases that can complicate interpretation of genetically engineered mice and other manipulatable mouse studies that utilize these strains.

  1. Long-Term Exercise Protects against Cellular Stresses in Aged Mice

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    Irina Belaya

    2018-01-01

    Full Text Available The current study examined the effect of aging and long-term wheel-running on the expression of heat shock protein (HSP, redox regulation, and endoplasmic reticulum (ER stress markers in tibialis anterior (T.A. and soleus muscle of mice. Male mice were divided into young (Y, 3-month-old, old-sedentary (OS, 24-month-old, and old-exercise (OE, 24-month-old groups. The OE group started voluntary wheel-running at 3 months and continued until 24 months of age. Aging was associated with a higher thioredoxin-interacting protein (TxNiP level, lower thioredoxin-1 (TRX-1 to TxNiP ratio—a determinant of redox regulation and increased CHOP, an indicator of ER stress-related apoptosis signaling in both muscles. Notably, GRP78, a key indicator of ER stress, was selectively elevated in T.A. Long-term exercise decreased TxNiP in T.A. and soleus muscles and increased the TRX-1/TxNiP ratio in soleus muscle of aged mice. Inducible HSP70 and constituent HSC70 were upregulated, whereas CHOP was reduced after exercise in soleus muscle. Thus, our data demonstrated that aging induced oxidative stress and activated ER stress-related apoptosis signaling in skeletal muscle, whereas long-term wheel-running improved redox regulation, ER stress adaptation and attenuated ER stress-related apoptosis signaling. These findings suggest that life-long exercise can protect against age-related cellular stress.

  2. Test-retest paradigm of the forced swimming test in female mice is not valid for predicting antidepressant-like activity: participation of acetylcholine and sigma-1 receptors.

    Science.gov (United States)

    Su, Jing; Hato-Yamada, Noriko; Araki, Hiroaki; Yoshimura, Hiroyuki

    2013-01-01

    The forced swimming test (FST) in mice is widely used to predict the antidepressant activity of a drug, but information describing the immobility of female mice is limited. We investigated whether a prior swimming experience affects the immobility duration in a second FST in female mice and whether the test-retest paradigm is a valid screening tool for antidepressants. Female ICR mice were exposed to the FST using two experimental paradigms: a single FST and a double FST in which mice had experienced FST once 24 h prior to the second trail. The initial FST experience reliably prolonged immobility duration in the second FST. The antidepressants imipramine and paroxetine significantly reduced immobility duration in the single FST, but not in the double FST. Scopolamine and the sigma-1 (σ1) antagonist NE-100 administered before the second trial significantly prevented the prolongation of immobility. Neither a 5-HT1A nor a 5-HT2A receptor agonist affected immobility duration. We suggest that the test-retest paradigm in female mice is not adequate for predicting antidepressant-like activity of a drug; the prolongation of immobility in the double FST is modulated through acetylcholine and σ1 receptors.

  3. Does foraging performance change with age in female little penguins (Eudyptula minor?

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    Ilka Zimmer

    Full Text Available Age-related changes in breeding performance are likely to be mediated through changes in parental foraging performance. We investigated the relationship of foraging performance with age in female little penguins at Phillip Island, Australia, during the guard phase of the 2005 breeding season. Foraging parameters were recorded with accelerometers for birds grouped into three age-classes: (1 young, (2 middle age and (3 old females. We found the diving behaviour of middle-aged birds differed from young and old birds. The dive duration of middle age females was shorter than that of young and old birds while their dive effort (measure for dive and post-dive duration relation was lower than that of young ones, suggesting middle-aged birds were in better physical condition than other ones. There was no difference in prey pursuit frequency or duration between age classes, but in the hunting tactic. Females pursued more prey around and after reaching the maximum depth of dives the more experienced they were (old > middle age > young, an energy saving hunting tactic by probably taking advantage of up-thrust momentum. We suggest middle age penguins forage better than young or old ones because good physical condition and foraging experience could act simultaneously.

  4. Nature of fatty acids in high fat diets differentially delineates obesity-linked metabolic syndrome components in male and female C57BL/6J mice

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    El Akoum Souhad

    2011-12-01

    Full Text Available Abstract Background Adverse effects of high-fat diets (HFD on metabolic homeostasis are linked to adipose tissue dysfunction. The goal of this study was to examine the effect of the HFD nature on adipose tissue activity, metabolic disturbances and glucose homeostasis alterations in male mice compared with female mice. Methods C57BL/6J mice were fed either a chow diet or HFD including vegetal (VD or animal (AD fat. Body weight, plasmatic parameters and adipose tissue mRNA expression levels of key genes were evaluated after 20 weeks of HFD feeding. Results HFD-fed mice were significantly heavier than control at the end of the protocol. Greater abdominal visceral fat accumulation was observed in mice fed with AD compared to those fed a chow diet or VD. Correlated with weight gain, leptin levels in systemic circulation were increased in HFD-fed mice in both sexes with a significant higher level in AD group compared to VD group. Circulating adiponectin levels as well as adipose tissue mRNA expression levels were significantly decreased in HFD-fed male mice. Although its plasma levels remained unchanged in females, adiponectin mRNA levels were significantly reduced in adipose tissue of both HFD-fed groups with a more marked decrease in AD group compared to VD group. Only HFD-fed male mice were diabetic with increased fasting glycaemia. On the other hand, insulin levels were only increased in AD-fed group in both sexes associated with increased resistin levels. VD did not induce any apparent metabolic alteration in females despite the increased weight gain. Peroxisome Proliferator-Activated Receptors gamma-2 (PPARγ2 and estrogen receptor alpha (ERα mRNA expression levels in adipose tissue were decreased up to 70% in HFD-fed mice but were more markedly reduced in male mice as compared with female mice. Conclusions The nature of dietary fat determines the extent of metabolic alterations reflected in adipocytes through modifications in the pattern of

  5. Fibroblast growth factor 21 has no direct role in regulating fertility in female mice

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    Garima Singhal

    2016-08-01

    Full Text Available Objective: Reproduction is an energetically expensive process. Insufficient calorie reserves, signaled to the brain through peripheral signals such as leptin, suppress fertility. Recently, fibroblast growth factor 21 (FGF21 was implicated as a signal from the liver to the hypothalamus that directly inhibits the hypothalamic–gonadotropin axis during fasting and starvation. However, FGF21 itself increases metabolic rate and can induce weight loss, which suggests that the effects of FGF21 on fertility may not be direct and may reflect changes in energy balance. Methods: To address this important question, we evaluated fertility in several mouse models with elevated FGF21 levels including ketogenic diet fed mice, fasted mice, mice treated with exogenous FGF21 and transgenic mice over-expressing FGF21. Results: We find that ketogenic diet fed mice remain fertile despite significant elevation in serum FGF21 levels. Absence of FGF21 does not alter transient infertility induced by fasting. Centrally infused FGF21 does not suppress fertility despite its efficacy in inducing browning of inguinal white adipose tissue. Furthermore, a high fat diet (HFD can restore fertility of female FGF21-overexpressing mice, a model of growth restriction, even in the presence of supraphysiological serum FGF21 levels. Conclusions: We conclude that FGF21 is not a direct physiological regulator of fertility in mice. The infertility observed in FGF21 overexpressing mice is likely driven by the increased energy expenditure and consequent excess calorie requirements resulting from high FGF21 levels. Keywords: FGF21, Fertility, Leptin, Hypothalamic action

  6. The Female Stroke Survival Advantage: Relation to Age

    DEFF Research Database (Denmark)

    Olsen, Tom Skyhøj; Dehlendorff, Christian; Andersen, Klaus Kaae

    2009-01-01

    Background: Age-related hormonal factors are thought to be related to the gender gap in longevity. Testing the hypothesis that survival is best in young premenopausal women we studied the effect of age on 1-week mortality in stroke patients. Methods: A registry was started in 2001 with the aim...... in women. While mortality increased almost linearly in women over the entire age range, it increased steeply in men from the age of 50 and at the age of 80 years survival was 80% better in women. Conclusion: The female stroke survival advantage applies to all ages. It increases with age due to a steeply...

  7. 2C.07: INVOLVEMENT OF THE RENIN-ANGIOTENSIN SYSTEM IN A PREMATURE AGING MOUSE MODEL.

    Science.gov (United States)

    Van Thiel, B S; Ridwan, Y; Garrelds, I M; Vermeij, M; Groningen, M C Clahsen-Van; Danser, A H J; Essers, J; Van Der Pluijm, I

    2015-06-01

    Changes in the renin-angiotensin system (RAS), known for its critical role in the regulation of blood pressure and sodium homeostasis, may contribute to aging and age-related diseases. Here we characterized the RAS and kidney pathology in mice with genomic instability due to a defective nucleotide excision repair gene (Ercc1d/- mice). These mice display premature features of aging, including vascular dysfunction. Studies were performed in male and female Ercc1d/- mice and their wild type controls (Ercc1+/+) at the age of 12 or 18 weeks before and after treatment with losartan. The renin-activatable near-infrared fluorescent probe ReninSense 680™ was applied in vivo to allow non-invasive imaging of renin activity. Plasma renin concentrations (PRC) were additionally measured ex vivo by quantifying Ang I generation in the presence of excess angiotensinogen. Kidneys were harvested and examined for markers of aging, and albumin was determined in urine. Kidneys of 12-week old Ercc1d/- mice showed signs of aging, including tubular anisokaryosis, cell-senescence and increased apoptosis. This was even more pronounced at the age of 18 weeks. Yet, urinary albumin was normal at 12 weeks. The ReninSense 680™ probe showed increased intrarenal renin activity in Ercc1d/- mice versus Ercc1+/+ mice, both at 12 and 18 weeks of age, while PRC in these mice tended to be lower compared to Ercc1+/+ mice. Renin was higher in male than female mice, both in the kidney and in plasma, and losartan increased kidney and plasma renin in both Ercc1d/- and Ercc1+/+ mice. Rapidly aging Ercc1d/- mice display an activated intrarenal RAS, as evidenced by the increased fluorescence detected with the ReninSense 680™ probe. This increased RAS activity may contribute to the disturbed kidney pathology in these mice. The increased intrarenal activity detected with the ReninSense 680™ probe in male vs. female mice, as well as after losartan treatment, are in full agreement with the literature, and

  8. Disruption of the GH Receptor Gene in Adult Mice Increases Maximal Lifespan in Females

    DEFF Research Database (Denmark)

    Junnila, Riia K.; Duran-Ortiz, Silvana; Suer, Ozan

    2016-01-01

    GH and IGF-1 are important for a variety of physiological processes including growth, development, and aging. Mice with reduced levels of GH and IGF-1 have been shown to live longer than wild-type controls. Our laboratory has previously found that mice with a GH receptor gene knockout (GHRKO) fro...

  9. Toll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging.

    Science.gov (United States)

    Ghosh, Amiya K; O'Brien, Martin; Mau, Theresa; Yung, Raymond

    2017-09-07

    Adipose tissue (AT) inflammation is a central mechanism for metabolic dysfunction in both diet-induced obesity and age-associated obesity. Studies in diet-induced obesity have characterized the role of Fetuin A (Fet A) in Free Fatty Acids (FFA)-mediated TLR4 activation and adipose tissue inflammation. However, the role of Fet A & TLR4 in aging-related adipose tissue inflammation is unknown. In the current study, analysis of epidymymal fat pads of C57/Bl6 male mice, we found that, in contrast to data from diet-induced obesity models, adipose tissue from aged mice have normal Fet A and TLR4 expression. Interestingly, aged TLR4-deficient mice have diminished adipose tissue inflammation compared to normal controls. We further demonstrated that reduced AT inflammation in old TLR4-deficient mice is linked to impaired ER stress, augmented autophagy activity, and diminished senescence phenomenon. Importantly, old TLR4-deficient mice have improved glucose tolerance compared to age-matched wild type mice, suggesting that the observed reduced AT inflammation in aged TLR4-deficient mice has important physiological consequences. Taken together, our present study establishes novel aspect of aging-associated AT inflammation that is distinct from diet-induced AT inflammation. Our results also provide strong evidence that TLR4 plays a significant role in promoting aging adipose tissue inflammation.

  10. Supplementation with α-lipoic acid, CoQ10, and vitamin E augments running performance and mitochondrial function in female mice.

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    Arkan Abadi

    Full Text Available Antioxidant supplements are widely consumed by the general public; however, their effects of on exercise performance are controversial. The aim of this study was to examine the effects of an antioxidant cocktail (α-lipoic acid, vitamin E and coenzyme Q10 on exercise performance, muscle function and training adaptations in mice. C57Bl/J6 mice were placed on antioxidant supplement or placebo-control diets (n = 36/group and divided into trained (8 wks treadmill running (n = 12/group and untrained groups (n = 24/group. Antioxidant supplementation had no effect on the running performance of trained mice nor did it affect training adaptations; however, untrained female mice that received antioxidants performed significantly better than placebo-control mice (p ≤ 0.05. Furthermore, antioxidant-supplemented females (untrained showed elevated respiratory capacity in freshly excised muscle fibers (quadriceps femoris (p ≤ 0.05, reduced oxidative damage to muscle proteins (p ≤ 0.05, and increased expression of mitochondrial proteins (p ≤ 0.05 compared to placebo-controls. These changes were attributed to increased expression of proliferator-activated receptor gamma coactivator 1α (PGC-1α (p ≤ 0.05 via activation of AMP-activated protein kinase (AMPK (p ≤ 0.05 by antioxidant supplementation. Overall, these results indicate that this antioxidant supplement exerts gender specific effects; augmenting performance and mitochondrial function in untrained females, but does not attenuate training adaptations.

  11. Long-lived ames dwarf mice are resistant to chemical stressors.

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    Bokov, Alex F; Lindsey, Merry L; Khodr, Christina; Sabia, Marian R; Richardson, Arlan

    2009-08-01

    To probe the connection between longevity and stress resistance, we compared the sensitivity of Ames long-lived dwarf mice and control littermates with paraquat, diquat, and dobutamine. In young adult animals, 95% of male and 39% of female controls died after paraquat administration, but no dwarf animals died. When the experiment was repeated at an older age or a higher dosage of paraquat, dwarf mice still showed greater resistance. Dwarf mice also were more resistant to diquat; 80% of male and 60% of female controls died compared with 40% and 20% of dwarf mice, despite greater sensitivity of dwarf liver to diquat. Dwarf mice were also less sensitive to dobutamine-induced cardiac stress and had lower levels of liver and lung F(2)-isoprostanes. This is the first direct in vivo evidence that long-lived Ames dwarf mice have enhanced resistance to chemical insult, particularly oxidative stressors.

  12. Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice.

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    Cathy Joanna Jensen

    Full Text Available In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the β2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific β2-adrenergic receptor knock-out mice were generated by crossing homozygous β2-adrenergic receptor floxed mice (Adrb2flox and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2. Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle administration did not reveal any differences in physical health or motor functions between the knock-out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that β2-adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function.

  13. Perioral rejuvenation: restoration of attractiveness in aging females by minimally invasive procedures

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    Wollina U

    2013-09-01

    Full Text Available Uwe Wollina Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany Abstract: Lips and the perioral area are of outstanding importance in youthful appearance, attractiveness, and beauty. In contrast to younger and middle aged females, there is only scant published data on minimally invasive procedures to restore and revitalize lips and perioral soft tissue in elderly females. In this review we report the signs of aging in this particular region and the underlying anatomy. We review studies on lip restoration in younger females and present our techniques for elderly women. With an individually tailored approach, elderly females benefit from minimally invasive techniques. Keywords: facial aging, perioral soft tissue, lips, dermal fillers, anatomy

  14. Age-related changes in thoracic skeletal geometry of elderly females.

    Science.gov (United States)

    Holcombe, Sven A; Wang, Stewart C; Grotberg, James B

    2017-05-29

    Both females and the elderly have been identified as vulnerable populations with increased injury and mortality risk in multiple crash scenarios. Particularly in frontal impacts, older females show higher risk to the chest and thorax than their younger or male counterparts. Thoracic geometry plays a role in this increase, and this study aims to quantify key parts of that geometry in a way that can directly inform human body models that incorporate the concept of person age. Computed tomography scans from 2 female subject groups aged 20-35 and 65-99 were selected from the International Center for Automotive Medicine scan database representing young and old female populations. A model of thoracic skeletal anatomy was built for each subject from independent parametric models of the spine, ribs, and sternum, along with further parametric models of those components' spatial relationships. Parameter values between the 2 groups are directly compared, and average parameter values within each group are used to generate statistically average skeletal geometry for young and old females. In addition to the anatomic measures explicitly used in the parameterization scheme, key measures of rib cage depth and spine curvature are taken from both the underlying subject pool and from the resultant representative geometries. Statistically significant differences were seen between the young and old groups' spine and rib anatomic components, with no significant differences in local sternal geometry found. Vertebral segments in older females had higher angles relative to their inferior neighbors, providing a quantification of the kyphotic curvature known to be associated with age. Ribs in older females had greater end-to-end span, greater aspect ratio, and reduced out-of-plane deviation, producing an elongated and overall flatter curvature that leads to distal rib ends extending further anteriorly in older individuals. Combined differences in spine curvature and rib geometry led to an 18

  15. B16 melanoma tumor growth is delayed in mice in an age-dependent manner

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    Christina Pettan-Brewer

    2012-08-01

    Full Text Available A major risk factor for cancer is increasing age, which suggests that syngeneic tumor implants in old mice would grow more rapidly. However, various reports have suggested that old mice are not as permissive to implanted tumor cells as young mice. In order to determine and characterize the age-related response to B16 melanoma, we implanted 5×105 tumor cells into 8, 16, 24, and 32-month-old male C57BL/6 (B6 and C57BL/6×BALB/c F1 (CB6 F1 mice subcutaneously in the inguinal and axillary spaces, or intradermally in the lateral flank. Results showed decreased tumor volume with increasing age, which varied according to mouse genetic background and the implanted site. The B6 strain showed robust tumor growth at 8 months of age at the inguinal implantation site, with an average tumor volume of 1341.25 mm3. The 16, 24, and 32-month age groups showed a decrease in tumor growth with tumor volumes of 563.69, 481.02, and 264.55 mm3, respectively (p≤0.001. The axillary implantation site was less permissive in 8-month-old B6 mice with an average tumor volume of 761.52 mm3. The 24- and 32-month age groups showed a similar decrease in tumor growth with tumor volumes of 440 and 178.19 mm3, respectively (p≤0.01. The CB6F1 strain was not as tumor permissive at 8 months of age as B6 mice with average tumor volumes of 446.96 and 426.91 mm3 for the inguinal and axillary sites, respectively. There was a decrease in tumor growth at 24 months of age at both inguinal and axillary sites with an average tumor volume of 271.02 and 249.12 mm3, respectively (p≤0.05. The strain dependence was not apparent in 8-month-old mice injected intradermally with B16 melanoma cells, with average tumor volumes of 736.82 and 842.85 mm3 for B6 and CB6 F1, respectively. However, a strain difference was seen in 32-month-old B6 mice with an average decrease in tumor volume of 250.83 mm3 (p≤0.01. In contrast, tumor growth significantly decreased earlier in CB6 F1 mice with average

  16. Oestrogen-deficient female aromatase knockout (ArKO) mice exhibit depressive-like symptomatology.

    Science.gov (United States)

    Dalla, C; Antoniou, K; Papadopoulou-Daifoti, Z; Balthazart, J; Bakker, J

    2004-07-01

    We recently found that female aromatase knockout (ArKO) mice that are deficient in oestradiol due to a targeted mutation in the aromatase gene show deficits in sexual behaviour that cannot be corrected by adult treatment with oestrogens. We determined here whether these impairments are associated with changes in general levels of activity, anxiety or 'depressive-like' symptomatology due to chronic oestrogen deficiency. We also compared the neurochemical profile of ArKO and wild-type (WT) females, as oestrogens have been shown to modulate dopaminergic, serotonergic and noradrenergic brain activities. ArKO females did not differ from WT in spontaneous motor activity, exploration or anxiety. These findings are in line with the absence of major neurochemical alterations in hypothalamus, prefrontal cortex or striatum, which are involved in the expression of these behaviours. By contrast, ArKO females displayed decreased active behaviours, such as struggling and swimming, and increased passive behaviours, such as floating, in repeated sessions of the forced swim test, indicating that these females exhibit 'depressive-like' symptoms. Adult treatment with oestradiol did not reverse the behavioural deficits observed in the forced swim test, suggesting that they may be due to the absence of oestradiol during development. Accordingly, an increased serotonergic activity was observed in the hippocampus of ArKO females compared with WT, which was also not reversed by adult oestradiol treatment. The possible organizational role of oestradiol on the hippocampal serotonergic system and the 'depressive-like' profile of ArKO females provide new insights into the pathophysiology of depression and the increased vulnerability of women to depression.

  17. EFFECTS OF PHYSICAL TRAINING ON THE MYOCARDIUM OF FEMALE LDL KNOCKOUT OVARIECTOMIZED MICE

    OpenAIRE

    Brianezi, Ledimar; Marques, Mara Rubia; Cardoso, Clever Gomes; Miranda, Maria Luiza de Jesus; Fonseca, Fernando Luiz Affonso; Maifrino, Laura Beatriz Mesiano

    2017-01-01

    ABSTRACT Introduction: The emergence of coronary heart disease increases with menopause, physical inactivity and with dyslipidemia. It is known that physical training promotes the improvement of cardiovascular functions. Objective: The purpose of this study was to investigate the effects of aerobic physical training on the left ventricle in female LDL knockout ovariectomized mice. Methods: Thirty animals were divided into 6 groups (n=5), namely, sedentary non-ovariectomized control; sedentary...

  18. Butyl paraben and propyl paraben modulate bisphenol A and estradiol concentrations in female and male mice

    Energy Technology Data Exchange (ETDEWEB)

    Pollock, Tyler; Weaver, Rachel E.; Ghasemi, Ramtin; Catanzaro, Denys de, E-mail: decatanz@mcmaster.ca

    2017-06-15

    People are routinely exposed to the antimicrobial preservatives butyl paraben (BP) and propyl paraben (PP), as well as the monomer of polycarbonate plastics, bisphenol A (BPA). These chemicals are reliably detected in human urine and potentially interact. We investigated whether BP or PP exposure can modulate the concentrations of {sup 14}C-BPA and 17β-estradiol (E{sub 2}). Female and male CF1 mice were each given a subcutaneous injection of oil containing 0 (vehicle), 1, 3, or 9 mg BP or PP, then given a dietary supplement containing 50 μg/kg {sup 14}C-BPA. Radioactivity was measured in tissues through liquid scintillation counting. Significantly elevated {sup 14}C-BPA concentrations were observed following BP treatment in blood serum of both sexes, as well as the lungs, uterus, and ovaries of females and the testes and epididymides of males. Treatment with PP significantly elevated {sup 14}C-BPA concentrations in the uterus only. In another experiment, female and male CF1 mice were each injected with vehicle, 3 mg BP, or 3 mg PP, and E{sub 2} was measured in urine 2–12 h later. Whereas PP did not affect E{sub 2}, BP significantly elevated E{sub 2} 6–10 h after injection in females and 8 h after injection in males. These data indicate that BP and PP can alter the pharmacokinetics of BPA in vivo, and that BP can modulate E{sub 2} concentrations. These results are consistent with evidence that parabens inhibit enzymes that are critical for BPA and E{sub 2} metabolism, and demonstrate the importance of considering concurrent exposure to multiple chemicals when determining regulatory exposure limits. - Highlights: • We studied whether paraben exposure affects the distribution of oral {sup 14}C-BPA. • Elevated {sup 14}C–BPA was observed in mice given butyl or propyl paraben. • We also studied whether paraben exposure affects natural E{sub 2} levels in urine. • Elevated E{sub 2} was observed in mice given butyl, but not propyl, paraben. • Parabens may

  19. Male chimpanzees' grooming rates vary by female age, parity, and fertility status.

    Science.gov (United States)

    Proctor, Darby P; Lambeth, Susan P; Schapiro, Steven J; Brosnan, Sarah F

    2011-10-01

    Copulation preferences in our closest living relative, the chimpanzee, suggest that males prefer older females who have had previous offspring. However, this finding is counter to some behavioral models, which predict that chimpanzee males, as promiscuous breeders with minimal costs to mating, should show little or no preference when choosing mating partners (e.g. should mate indiscriminately). To determine if the preferences indicated by copulations appear in other contexts as well as how they interact, we examined how male chimpanzees' grooming patterns varied amongst females. We found that males' preferences were based on interactions among females' fertility status, age, and parity. First, grooming increased with increasing female parity. We further found an effect of the estrous cycle on grooming; when females were at the lowest point of their cycle, males preferentially groomed parous females at peak reproductive age, but during maximal tumescence, males preferred the oldest multiparous females. Nulliparous females received relatively little grooming regardless of age or fertility. Thus, male chimpanzees apparently chose grooming partners based on both female's experience and fertility, possibly indicating a two-pronged social investment strategy. Male selectivity seems to have evolved to effectively distribute costly social resources in a pattern which may increase their overall reproductive success. © 2011 Wiley-Liss, Inc.

  20. Memory Deficits Are Associated with Impaired Ability to Modulate Neuronal Excitability in Middle-Aged Mice

    Science.gov (United States)

    Kaczorowski, Catherine C.; Disterhoft, John F.

    2009-01-01

    Normal aging disrupts hippocampal neuroplasticity and learning and memory. Aging deficits were exposed in a subset (30%) of middle-aged mice that performed below criterion on a hippocampal-dependent contextual fear conditioning task. Basal neuronal excitability was comparable in middle-aged and young mice, but learning-related modulation of the…

  1. Increased survivorship of testosterone-treated female house mice (Mus musculus) in high-density field conditions

    Science.gov (United States)

    W.J. Zielinski; J.G. Vandenbergh

    1991-01-01

    Differences in hormone levels influence sexual differences in aggression. survival, home-range size and dispcrsal in rodents. The role oftestosterone in establishing some of these differences in wild house mice was examined. Females treated with either 0·5 mg of testosterone enanthate (TE-treated) or oil (control), and an...

  2. DETERMINATION OF AGE AND GENDER DIFFERENCES IN BIOCHEMICAL PROCESSES AFFECTING THE DISPOSITION OF 2-BUTOXYETHANOL AND ITS METABOLITES IN MICE AND RATS TO IMPROVE PBPK MODELING

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Rick A.; Grant, Donna M.; Farris, Elizabeth; Weitz, Karl K.; Soelberg, Jolen J.; Thrall, K D.; Poet, Torka S.

    2005-03-28

    2-Butoxyethanol (BE) is the most widely used glycol ether solvent. BE's major metabolite, butoxyacetic acid (BAA), causes hemolysis with significant species differences in sensitivity. Several PBPK models have been developed over the past two decades to describe the disposition of BE and BAA in male rats and humans to refine health risk assessments. More recent efforts by Lee et al. (1998) to describe the kinetics of BE and BAA in the National Toxicology Program (NTP) chronic inhalation studies required the use of several assumptions to extrapolate model parameters from earlier PBPK models developed for young male rats to include female F344 and both sexes of B6C3F1 mice and the effects of aging. To replace these assumptions, studies were conducted to determine the impact of age, gender and species on the metabolism of BE, and the tissue partitioning, renal acid transport and plasma protein binding of BAA. In the current study, the Lee et al. PBPK model was updated and expanded to include the further metabolism of BAA and the salivary excretion of BE and BAA which may contribute to the forestomach irritation observed in mice in the NTP study. The revised model predicted that peak blood concentrations of BAA achieved following 6-hr inhalation exposures are greatest in young adult female rats at concentrations up to 300 ppm. This is not the case predicted for old (>18 months) animals, where peak blood concentrations of BAA in male and female mice were similar to or greater than female rats. The revised model serves as a quantitative tool for integrating an extensive pharmacokinetic and mechanistic database into a format that can readily be used to compare internal dosimetry across dose, route of exposure and species.

  3. Age-dependent variations of zinc-65 metabolism in LACA mice

    International Nuclear Information System (INIS)

    He Liusheng; Yan Xiaoshan; Wu Dechang

    1991-01-01

    Mice were gavaged with zinc-65 solution, 8.6-19.3 kBq per mouse, and the whole-body retention and organ content of zinc-65 measured at diffe-rent times afterwards. The age-dependence of the fractional absorption of zinc-65 from the gastrointestinal tract (f 1 ) endogenous faecal excretion fraction of zinc-65 (EFEF), tissue distribution and whole-body retention were determined. f 1 values obtained were 0.86 ±0.15, 0.64±0.11, 0.52±0.07 and 0.39±0.02 in suckling, adolescent, young adult and older mice, respectively. The EFEF values determined were 0.083±0.008, 0.099±0.004, 0.122±0.018 and 0.144±0.005 of intraperitoneally injected zinc-65 was in suckling, adolescent, young adult and older mice at administration. Zinc-65 mainly distributed in the liver, muscle, lung, kidney and bone. In some tissues, there was an inverse relationship between relative content of gavaged zinc-65 and animal's age at administration. The whole-body biological half-lives of zinc-65 increased with animal age. (author)

  4. Age-Related Decrease in Stress Responsiveness and Proactive Coping in Male Mice.

    Science.gov (United States)

    Oh, Hee-Jin; Song, Minah; Kim, Young Ki; Bae, Jae Ryong; Cha, Seung-Yun; Bae, Ji Young; Kim, Yeongmin; You, Minsu; Lee, Younpyo; Shim, Jieun; Maeng, Sungho

    2018-01-01

    Coping is a strategic approach to dealing with stressful situations. Those who use proactive coping strategies tend to accept changes and act before changes are expected. In contrast, those who use reactive coping are less flexible and more likely to act in response to changes. However, little research has assessed how coping style changes with age. This study investigated age-related changes in coping strategies and stress responsiveness and the influence of age on the processing of conditioned fear memory in 2-, 12- and 23-month-old male mice. Coping strategy was measured by comparing the escape latency in an active avoidance test and by comparing responses to a shock prod. The results showed that proactivity in coping response gradually decreased with age. Stress responsiveness, measured by stress-induced concentration of corticosterone, was also highest in 2-month-old mice and decreased with age. Consolidation of fear memory was highest in 12-month-old mice and was negatively correlated with the degree of stress responsiveness and proactivity in coping. Fear extinction did not differ among age groups and was not correlated with stress responsiveness or the proactivity of coping. However, the maintenance of extinct fear memory, which was best in 2-month-old mice and worst in 12-month-old mice, was negatively correlated with stress responsiveness but not with coping style. Age-dependent changes in the expression of glucocorticoid receptor (GR) and its regulatory co-chaperones, which are accepted mechanisms for stress hormone stimulation, were measured in the hippocampus. The expression of GR was increased at 12 months compared to other age groups. There were no differences in Hsp70 and BAG1 expression by age. These results can be summarized as follows: (1) stress responsiveness and proactivity in coping decreased with age class; (2) consolidation of fear memory was negatively correlated with both stress responsiveness and proactivity; however, maintenance of

  5. Generation of ER{alpha}-floxed and knockout mice using the Cre/LoxP system

    Energy Technology Data Exchange (ETDEWEB)

    Antonson, P., E-mail: per.antonson@ki.se [Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 83 Huddinge (Sweden); Omoto, Y.; Humire, P. [Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 83 Huddinge (Sweden); Gustafsson, J.-A. [Department of Biosciences and Nutrition, Karolinska Institutet, Novum, SE-141 83 Huddinge (Sweden); Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204 (United States)

    2012-08-10

    Highlights: Black-Right-Pointing-Pointer ER{alpha} floxed and knockout mice were generated. Black-Right-Pointing-Pointer Disruption of the ER{alpha} gene results in sterility in both male and female mice. Black-Right-Pointing-Pointer ER{alpha}{sup -/-} mice have ovaries with hemorrhagic follicles and hypoplastic uterus. Black-Right-Pointing-Pointer Female ER{alpha}{sup -/-} mice develop obesity. -- Abstract: Estrogen receptor alpha (ER{alpha}) is a nuclear receptor that regulates a range of physiological processes in response to estrogens. In order to study its biological role, we generated a floxed ER{alpha} mouse line that can be used to knock out ER{alpha} in selected tissues by using the Cre/LoxP system. In this study, we established a new ER{alpha} knockout mouse line by crossing the floxed ER{alpha} mice with Cre deleter mice. Here we show that genetic disruption of the ER{alpha} gene in all tissues results in sterility in both male and female mice. Histological examination of uterus and ovaries revealed a dramatically atrophic uterus and hemorrhagic cysts in the ovary. These results suggest that infertility in female mice is the result of functional defects of the reproductive tract. Moreover, female knockout mice are hyperglycemic, develop obesity and at the age of 4 months the body weight of these mice was more than 20% higher compared to wild type littermates and this difference increased over time. Our results demonstrate that ER{alpha} is necessary for reproductive tract development and has important functions as a regulator of metabolism in females.

  6. Airway exposure to multi-walled carbon nanotubes disrupts the female reproductive cycle without affecting pregnancy outcomes in mice

    DEFF Research Database (Denmark)

    Johansson, Hanna Katarina Lilith; Hansen, J. S.; Elfving, B.

    2017-01-01

    response and inflammation in experimental animals, which may affect female reproduction. This proof-of-principle study therefore aimed to investigate if lung exposure by intratracheal instillation of the MWCNT NM-400 would affect the estrous cycle and reproductive function in female mice.Results: Estrous...... of irregular cycling after exposure. Our data indicates that MWCNT exposure may interfere with events leading to ovulation....

  7. Deletion of the forebrain mineralocorticoid receptor impairs social discrimination and decision-making in male, but not in female mice.

    Science.gov (United States)

    Ter Horst, Judith P; van der Mark, Maaike; Kentrop, Jiska; Arp, Marit; van der Veen, Rixt; de Kloet, E Ronald; Oitzl, Melly S

    2014-01-01

    Social interaction with unknown individuals requires fast processing of information to decide whether it is friend or foe. This process of discrimination and decision-making is stressful and triggers secretion of corticosterone activating mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The MR is involved in appraisal of novel experiences and risk assessment. Recently, we have demonstrated in a dual-solution memory task that MR plays a role in the early stage of information processing and decision-making. Here we examined social approach and social discrimination in male and female mice lacking MR from hippocampal-amygdala-prefrontal circuitry and controls. The social approach task allows the assessment of time spent with an unfamiliar mouse and the ability to discriminate between familiar and unfamiliar conspecifics. The male and female test mice were both more interested in the social than the non-social experience and deletion of their limbic MR increased the time spent with an unfamiliar mouse. Unlike controls, the male MR(CaMKCre) mice were not able to discriminate between an unfamiliar and the familiar mouse. However, the female MR mutant had retained the discriminative ability between unfamiliar and familiar mice. Administration of the MR antagonist RU28318 to male mice supported the role of the MR in the discrimination between an unfamiliar mouse and a non-social stimulus. No effect was found with a GR antagonist. Our findings suggest that MR is involved in sociability and social discrimination in a sex-specific manner through inhibitory control exerted putatively via limbic-hippocampal efferents. The ability to discriminate between familiar and unfamiliar conspecifics is of uttermost importance for territorial defense and depends on a role of MR in decision-making.

  8. Female scarcity reduces women's marital ages and increases variance in men's marital ages.

    Science.gov (United States)

    Kruger, Daniel J; Fitzgerald, Carey J; Peterson, Tom

    2010-08-05

    When women are scarce in a population relative to men, they have greater bargaining power in romantic relationships and thus may be able to secure male commitment at earlier ages. Male motivation for long-term relationship commitment may also be higher, in conjunction with the motivation to secure a prospective partner before another male retains her. However, men may also need to acquire greater social status and resources to be considered marriageable. This could increase the variance in male marital age, as well as the average male marital age. We calculated the Operational Sex Ratio, and means, medians, and standard deviations in marital ages for women and men for the 50 largest Metropolitan Statistical Areas in the United States with 2000 U.S Census data. As predicted, where women are scarce they marry earlier on average. However, there was no significant relationship with mean male marital ages. The variance in male marital age increased with higher female scarcity, contrasting with a non-significant inverse trend for female marital age variation. These findings advance the understanding of the relationship between the OSR and marital patterns. We believe that these results are best accounted for by sex specific attributes of reproductive value and associated mate selection criteria, demonstrating the power of an evolutionary framework for understanding human relationships and demographic patterns.

  9. Female Scarcity Reduces Women's Marital Ages and Increases Variance in Men's Marital Ages

    Directory of Open Access Journals (Sweden)

    Daniel J. Kruger

    2010-07-01

    Full Text Available When women are scarce in a population relative to men, they have greater bargaining power in romantic relationships and thus may be able to secure male commitment at earlier ages. Male motivation for long-term relationship commitment may also be higher, in conjunction with the motivation to secure a prospective partner before another male retains her. However, men may also need to acquire greater social status and resources to be considered marriageable. This could increase the variance in male marital age, as well as the average male marital age. We calculated the Operational Sex Ratio, and means, medians, and standard deviations in marital ages for women and men for the 50 largest Metropolitan Statistical Areas in the United States with 2000 U.S Census data. As predicted, where women are scarce they marry earlier on average. However, there was no significant relationship with mean male marital ages. The variance in male marital age increased with higher female scarcity, contrasting with a non-significant inverse trend for female marital age variation. These findings advance the understanding of the relationship between the OSR and marital patterns. We believe that these results are best accounted for by sex specific attributes of reproductive value and associated mate selection criteria, demonstrating the power of an evolutionary framework for understanding human relationships and demographic patterns.

  10. Fluoxetine treatment induces dose dependent alterations in depression associated behavior and neural plasticity in female mice

    OpenAIRE

    Hodes, Georgia E.; Hill-Smith, Tiffany E.; Lucki, Irwin

    2010-01-01

    Antidepressant induced increases in neurogenesis and neurotrophin mobilization in rodents and primates are proposed to be necessary for behavioral efficacy. The current study examines the relationship between the effects of fluoxetine treatment on behavior, cell proliferation and the neurotrophin BDNF in females. Female MRL/MpJ mice were treated acutely (5 and 10 mg/kg) or chronically (2.5, 5 and 10 mg/kg b.i.d.) with fluoxetine and tested in the tail suspension test (TST) and or novelty indu...

  11. Insulin signaling displayed a differential tissue-specific response to low-dose dihydrotestosterone in female mice.

    Science.gov (United States)

    Andrisse, Stanley; Billings, Katelyn; Xue, Ping; Wu, Sheng

    2018-04-01

    Hyperandrogenemia and hyperinsulinemia are believed to play prominent roles in polycystic ovarian syndrome (PCOS). We explored the effects of low-dose dihydrotestosterone (DHT), a model of PCOS, on insulin signaling in metabolic and reproductive tissues in a female mouse model. Insulin resistance in the energy storage tissues is associated with type 2 diabetes. Insulin signaling in the ovaries and pituitary either directly or indirectly stimulates androgen production. Energy storage and reproductive tissues were isolated and molecular assays were performed. Livers and white adipose tissue (WAT) from DHT mice displayed lower mRNA and protein expression of insulin signaling intermediates. However, ovaries and pituitaries of DHT mice exhibited higher expression levels of insulin signaling genes/proteins. Insulin-stimulated p-AKT levels were blunted in the livers and WAT of the DHT mice but increased or remained the same in the ovaries and pituitaries compared with controls. Glucose uptake decreased in liver and WAT but was unchanged in pituitary and ovary of DHT mice. Plasma membrane GLUTs were decreased in liver and WAT but increased in ovary and pituitary of DHT mice. Skeletal muscle insulin-signaling genes were not lowered in DHT mice compared with control. DHT mice did not display skeletal muscle insulin resistance. Insulin-stimulated glucose transport increased in skeletal muscles of DHT mice compared with controls. DHT mice were hyperinsulinemic. However, the differential mRNA and protein expression pattern was independent of hyperinsulinemia in cultured hepatocytes and pituitary cells. These findings demonstrate a differential effect of DHT on the insulin-signaling pathway in energy storage vs. reproductive tissues independent of hyperinsulinemia.

  12. Mathematical modeling of left ventricular dimensional changes in mice during aging

    Directory of Open Access Journals (Sweden)

    Yang Tianyi

    2012-12-01

    Full Text Available Abstract Cardiac aging is characterized by diastolic dysfunction of the left ventricle (LV, which is due in part to increased LV wall stiffness. In the diastolic phase, myocytes are relaxed and extracellular matrix (ECM is a critical determinant to the changes of LV wall stiffness. To evaluate the effects of ECM composition on cardiac aging, we developed a mathematical model to predict LV dimension and wall stiffness changes in aging mice by integrating mechanical laws and our experimental results. We measured LV dimension, wall thickness, LV mass, and collagen content for wild type (WT C57/BL6J mice of ages ranging from 7.3 months to those of 34.0 months. The model was established using the thick wall theory and stretch-induced tissue growth to an isotropic and homogeneous elastic composite with mixed constituents. The initial conditions of the simulation were set based on the data from the young mice. Matlab simulations of this mathematical model demonstrated that the model captured the major features of LV remodeling with age and closely approximated experimental results. Specifically, the temporal progression of the LV interior and exterior dimensions demonstrated the same trend and order-of-magnitude change as our experimental results. In conclusion, we present here a validated mathematical model of cardiac aging that applies the thick-wall theory and stretch-induced tissue growth to LV remodeling with age.

  13. No evidence for punishment in communally nursing female house mice (Mus musculus domesticus).

    Science.gov (United States)

    Ferrari, Manuela; König, Barbara

    2017-01-01

    Punishment is claimed as an important mechanism to stabilise costly cooperation in humans, but its importance in social animals has been questioned recently due to both conceptual considerations and a lack of empirical evidence (only few published studies). We empirically tested whether there is evidence for punishment in communally nursing house mice (Mus musculus domesticus, direct descendants of "wild" animals). Communally breeding females pool their litters and raise all offspring together, indiscriminately caring for own and other offspring. Such a situation resembles a public good and provides scope for exploitation if females vary in their relative contributions to the joint nest (offspring number). We allowed two females to communally breed and conducted removal experiments both in the presence and absence of pups. We aimed to test whether reduced investment by one of the females (induced through separation from the partner and their combined offspring for 4 or 12 hours) leads to increased aggression by the other female after the reunion. We found no evidence for punishment, on the contrary, females increased socio-positive behaviours. The costs of losing a partner in a communally breeding species might be too high and hinder the evolution of punishment. Our findings add to a growing list of examples questioning the role of punishment in cooperating non-human animals and emphasise the importance of empirical testing of its assumptions and predictions.

  14. Developmental programming by androgen affects the circadian timing system in female mice.

    Science.gov (United States)

    Mereness, Amanda L; Murphy, Zachary C; Sellix, Michael T

    2015-04-01

    Circadian clocks play essential roles in the timing of events in the mammalian hypothalamo-pituitary-ovarian (HPO) axis. The molecular oscillator driving these rhythms has been localized to tissues of the HPO axis. It has been suggested that synchrony among these oscillators is a feature of normal reproductive function. The impact of fertility disorders on clock function and the role of the clock in the etiology of endocrine pathology remain unknown. Polycystic ovarian syndrome (PCOS) is a particularly devastating fertility disorder, affecting 5%-10% of women at childbearing age with features including a polycystic ovary, anovulation, and elevated serum androgen. Approximately 40% of these women have metabolic syndrome, marked by hyperinsulinemia, dyslipidemia, and insulin resistance. It has been suggested that developmental exposure to excess androgen contributes to the etiology of fertility disorders, including PCOS. To better define the role of the timing system in these disorders, we determined the effects of androgen-dependent developmental programming on clock gene expression in tissues of the metabolic and HPO axes. Female PERIOD2::luciferase (PER2::LUC) mice were exposed to androgen (dihydrotestosterone [DHT]) in utero (Days 16-18 of gestation) or for 9-10 wk (DHT pellet) beginning at weaning (pubertal androgen excess [PAE]). As expected, both groups of androgen-treated mice had disrupted estrous cycles. Analysis of PER2::LUC expression in tissue explants revealed that excess androgen produced circadian misalignment via tissue-dependent effects on phase distribution. In vitro treatment with DHT differentially affected the period of PER2::LUC expression in tissue explants and granulosa cells, indicating that androgen has direct and tissue-specific effects on clock gene expression that may account for the effects of developmental programming on the timing system. © 2015 by the Society for the Study of Reproduction, Inc.

  15. Testosterone and 17β-estradiol have opposite effects on podocyte apoptosis that precedes glomerulosclerosis in female estrogen receptor knockout mice.

    Science.gov (United States)

    Doublier, Sophie; Lupia, Enrico; Catanuto, Paola; Periera-Simon, Simone; Xia, Xiaomei; Korach, Ken; Berho, Mariana; Elliot, Sharon J; Karl, Michael

    2011-02-01

    Podocyte damage and apoptosis are thought to be important if not essential in the development of glomerulosclerosis. Female estrogen receptor knockout mice develop glomerulosclerosis at 9 months of age due to excessive ovarian testosterone production and secretion. Here, we studied the pathogenesis of glomerulosclerosis in this mouse model to determine whether testosterone and/or 17β-estradiol directly affect the function and survival of podocytes. Glomerulosclerosis in these mice was associated with the expression of desmin and the loss of nephrin, markers of podocyte damage and apoptosis. Ovariectomy preserved the function and survival of podocytes by eliminating the source of endogenous testosterone production. In contrast, testosterone supplementation induced podocyte apoptosis in ovariectomized wild-type mice. Importantly, podocytes express functional androgen and estrogen receptors, which, upon stimulation by their respective ligands, have opposing effects. Testosterone induced podocyte apoptosis in vitro by androgen receptor activation, but independent of the TGF-β1 signaling pathway. Pretreatment with 17β-estradiol prevented testosterone-induced podocyte apoptosis, an estrogen receptor-dependent effect mediated by activation of the ERK signaling pathway, and protected podocytes from TGF-β1- or TNF-α-induced apoptosis. Thus, podocytes are target cells for testosterone and 17β-estradiol. These hormones modulate podocyte damage and apoptosis.

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

    OpenAIRE

    Kiran Chaudhari; Jessica M. Wong; Philip H. Vann; Nathalie Sumien

    2014-01-01

    Purpose: The purpose of this study was to determine if antioxidant supplementation, moderate exercise, and the combination of both treatments could ameliorate cognitive performance in adult mice and whether the apolipoprotein E (APOE) genotype as well as sex could influence the functional outcomes of the treatments. Methods: For a period of 16 weeks, separate groups of male and female mice expressing either the human APOE3 or APOE4 isoforms were fed either a control diet (NIH-31) or the co...

  17. Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice.

    Science.gov (United States)

    Kim, In Hee; Xu, Jun; Liu, Xiao; Koyama, Yukinori; Ma, Hsiao-Yen; Diggle, Karin; You, Young-Hyun; Schilling, Jan M; Jeste, Dilip; Sharma, Kumar; Brenner, David A; Kisseleva, Tatiana

    2016-08-01

    We aimed to investigate whether aging increases the susceptibility of hepatic and renal inflammation or fibrosis in response to high-fat diet (HFD) and explore the underlying genetic alterations. Middle (10 months old) and old (20 months old) aged, male C57BL/6N mice were fed either a low-fat diet (4 % fat) or HFD (60 % fat) for 4 months. Young (3 months old) aged mice were included as control group. HFD-induced liver and kidney injuries were analyzed by serum and urine assay, histologic staining, immunohistochemistry, and reverse-transcription real-time quantitative polymerase chain reaction. Total RNA sequencing with next-generation technology was done with RNA extracted from liver tissues. With HFD feeding, aged was associated with higher serum alanine aminotransferase levels, marked infiltration of hepatic macrophages, and increased expression of inflammatory cytokines (MCP1, TNF-α, IL-1β, IL-6, IL-12, IL-17A). Importantly, aged mice showed more advanced hepatic fibrosis and increased expression of fibrogenic markers (Col-I-α1, αSMA, TGF-β1, TGF-β2, TGFβRII, PDGF, PDGFRβII, TIMP1) in response to HFD. Aged mice fed on HFD also showed increased oxidative stress and TLR4 expression. In the total RNA seq and gene ontology analysis of liver, old-aged HFD group showed significant up-regulation of genes linked to innate immune response, immune response, defense response, inflammatory response compared to middle-aged HFD group. Meanwhile, aging and HFD feeding showed significant increase in glomerular size and mesangial area, higher urine albumin/creatinine ratio, and advanced renal inflammation or fibrosis. However, the difference of HFD-induced renal injury between old-aged group and middle-aged group was not significant. The susceptibility of hepatic fibrosis as well as hepatic inflammation in response to HFD was significantly increased with aging. In addition, aging was associated with glomerular alterations and increased renal inflammation or

  18. Loss of miR-10a activates Lpo and collaborates with activated Wnt signaling in inducing intestinal Neoplasia in female mice

    DEFF Research Database (Denmark)

    Stadthagen Gomez, Gustavo; Tehler, Disa Elisabet; Høyland-Kroghsbo, Nina Molin

    2013-01-01

    , in the Apc(min) mouse model of intestinal neoplasia, female miR-10a deficient mice develop significantly more adenomas than miR-10(+/+) and male controls. We further found that Lpo is extensively upregulated in the intestinal epithelium of mice deprived of miR-10a. Using in vitro assays, we demonstrate...... that the primary miR-10a target KLF4 can upregulate transcription of Lpo, whereas siRNA knockdown of KLF4 reduces LPO levels in HCT-116 cells. Furthermore, Klf4 is upregulated in the intestines of miR-10a knockout mice. Lpo has previously been shown to have the capacity to oxidize estrogens into potent...... depurinating mutagens, creating an instable genomic environment that can cause initiation of cancer. Therefore, we postulate that Lpo upregulation in the intestinal epithelium of miR-10a deficient mice together with the predominant abundance of estrogens in female animals mainly accounts for the sex...

  19. Transcriptional profiling reveals progeroid Ercc1-/Δ mice as a model system for glomerular aging

    Science.gov (United States)

    2013-01-01

    Background Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes. Defects in genome maintenance in the Ercc1-/Δ progeroid mouse model result in premature aging and typical age-related pathologies. Here, we compared the glomerular transcriptome of young and aged Ercc1-deficient mice to young and aged WT mice in order to establish a novel model for research of aging-related kidney disease. Results In a principal component analysis, age and genotype emerged as first and second principal components. Hierarchical clustering of all 521 genes differentially regulated between young and old WT and young and old Ercc1-/Δ mice showed cluster formation between young WT and Ercc1-/Δ as well as old WT and Ercc1-/Δ samples. An unexpectedly high number of 77 genes were differentially regulated in both WT and Ercc1-/Δ mice (p aging glomerulus. At the level of the transcriptome, the pattern of gene activities is similar in the progeroid Ercc1-/Δ mouse model constituting a valuable tool for future studies of aging-associated glomerular pathologies. PMID:23947592

  20. Transcriptional profiling reveals progeroid Ercc1(-/Δ) mice as a model system for glomerular aging.

    Science.gov (United States)

    Schermer, Bernhard; Bartels, Valerie; Frommolt, Peter; Habermann, Bianca; Braun, Fabian; Schultze, Joachim L; Roodbergen, Marianne; Hoeijmakers, Jan Hj; Schumacher, Björn; Nürnberg, Peter; Dollé, Martijn Et; Benzing, Thomas; Müller, Roman-Ulrich; Kurschat, Christine E

    2013-08-16

    Aging-related kidney diseases are a major health concern. Currently, models to study renal aging are lacking. Due to a reduced life-span progeroid models hold the promise to facilitate aging studies and allow examination of tissue-specific changes. Defects in genome maintenance in the Ercc1(-/Δ) progeroid mouse model result in premature aging and typical age-related pathologies. Here, we compared the glomerular transcriptome of young and aged Ercc1-deficient mice to young and aged WT mice in order to establish a novel model for research of aging-related kidney disease. In a principal component analysis, age and genotype emerged as first and second principal components. Hierarchical clustering of all 521 genes differentially regulated between young and old WT and young and old Ercc1(-/Δ) mice showed cluster formation between young WT and Ercc1(-/Δ) as well as old WT and Ercc1(-/Δ) samples. An unexpectedly high number of 77 genes were differentially regulated in both WT and Ercc1(-/Δ) mice (p aging glomerulus. At the level of the transcriptome, the pattern of gene activities is similar in the progeroid Ercc1(-/Δ) mouse model constituting a valuable tool for future studies of aging-associated glomerular pathologies.

  1. The nigrostriatal dopamine system of aging GFRα-1 heterozygous mice: neurochemistry, morphology and behavior

    Science.gov (United States)

    Zaman, Vandana; Boger, Heather A.; Granholm, Ann-Charlotte; Rohrer, Baerbel; Moore, Alfred; Buhusi, Mona; Gerhardt, Greg A.; Hoffer, Barry J.; Middaugh, Lawrence D.

    2009-01-01

    Given the established importance of glial cell line-derived neurotrophic factor (GDNF) in maintaining dopaminergic neurotransmitter systems, the nigrostriatal system and associated behaviors of mice with genetic reduction of its high-affinity receptor, GDNF receptor (GFR)α-1 (GFRα-1+/−), were compared with wild-type controls. Motor activity and the stimulatory effects of a dopamine (DA) D1 receptor agonist (SKF 82958) were assessed longitudinally at 8 and 18 months of age. Monoamine concentrations and dopaminergic nerve terminals in the striatum and the number of dopaminergic neurons in the substantia nigra (SN) were assessed. The results support the importance of GFRα-1 in maintaining normal function of the nigrostriatal dopaminergic system, with deficits being observed for GFRα-1+/− mice at both ages. Motor activity was lower and the stimulatory effects of the DA agonist were enhanced for the older GFRα-1+/− mice. DA in the striatum was reduced in the GFRα-1+/− mice at both ages, and tyrosine hydroxylase-positive cell numbers in the SN were reduced most substantially in the older GFRα-1+/− mice. The combined behavioral, pharmacological probe, neurochemical and morphological measures provide evidence of abnormalities in GFRα-1+/− mice that are indicative of an exacerbated aging-related decline in dopaminergic system function. The noted deficiencies, in turn, suggest that GFRα-1 is necessary for GDNF to maintain normal function of the nigrostriatal dopaminergic system. Although the precise mechanism(s) for the aging-related changes in the dopaminergic system remain to be established, the present study clearly establishes that genetic reductions in GFRα-1 can contribute to the degenerative changes observed in this system during the aging process. PMID:18973577

  2. Comparison between C-FOS Expression in Male and Female Mice During Morphine Withdrawal in the Presence and Absence of Acute Administration of Matricaria Recutita

    Directory of Open Access Journals (Sweden)

    Kesmati Mahnaz

    2009-06-01

    Full Text Available Background: There are some evidences that indicate there are sexual differences in drug abuse and response to synthetic and herbal drugs. It has been shown that the expression of C-FOS increases in many areas of brain during morphine withdrawal. Concerning the sedative effect of Matricaria recutita extract, the aim of this study was to compare expression of C-FOS transcription factor during morphine withdrawal with and without acute administration of Matricaria recutita on male and female adult mice.Materials and Methods: This study was done at Shahid Chamran University of Ahvaz in 2007 on NMRI mice. Male and female mice were assigned into 8 groups (morphine + saline; morphine + naloxone; morphine + Matricaria recutita + naloxone; and morphine + saline + naloxone. To develop morphine dependency, increasing doses of morphine (20, 40, 80 mg/kg injected subcutaneously for 4 days. Mice received a final morphine injection (40 mg/kg 3hours prior to naloxone (5 mg/kg on the day of testing (day 4. Matricaria recutita extract whit a dose of 30 mg/kg was administered intraperitoneally 5 minutes before naloxone injection. In cellular study, 90minute after naloxone injection, mice were decapitated and their brains were separated, then mRNA was extracted from brain tissue. Using DIG-labeled DNA probe of C-FOS, beta-actin and dot blot technique, expression of C-FOS was analyzed by Zero Dscan software. Statistical evaluation of data was performed using student t-test and ANOVA with one factor followed by Duncan test in SPSS software. P values less than 0.05 were considered significant. Results: The rate of expression of C-FOS increased in male mice but decreased significantly in female mice after naloxone-precipitated abstinence P<0.01(. Matricaria recutita attenuated the rate of expression of C-FOS in male mice but it showed synergistic effect on it in female mice P<0.05(.Conclusion: It seems that the cellular processes involving morphine dependency and

  3. Camellia sinensis Prevents Perinatal Nicotine-Induced Neurobehavioral Alterations, Tissue Injury, and Oxidative Stress in Male and Female Mice Newborns

    Science.gov (United States)

    Ajarem, Jamaan S.; Al-Basher, Gadh; Allam, Ahmed A.

    2017-01-01

    Nicotine exposure during pregnancy induces oxidative stress and leads to behavioral alterations in early childhood and young adulthood. The current study aimed to investigate the possible protective effects of green tea (Camellia sinensis) against perinatal nicotine-induced behavioral alterations and oxidative stress in mice newborns. Pregnant mice received 50 mg/kg C. sinensis on gestational day 1 (PD1) to postnatal day 15 (D15) and were subcutaneously injected with 0.25 mg/kg nicotine from PD12 to D15. Nicotine-exposed newborns showed significant delay in eye opening and hair appearance and declined body weight at birth and at D21. Nicotine induced neuromotor alterations in both male and female newborns evidenced by the suppressed righting, rotating, and cliff avoidance reflexes. Nicotine-exposed newborns exhibited declined memory, learning, and equilibrium capabilities, as well as marked anxiety behavior. C. sinensis significantly improved the physical development, neuromotor maturation, and behavioral performance in nicotine-exposed male and female newborns. In addition, C. sinensis prevented nicotine-induced tissue injury and lipid peroxidation and enhanced antioxidant defenses in the cerebellum and medulla oblongata of male and female newborns. In conclusion, this study shows that C. sinensis confers protective effects against perinatal nicotine-induced neurobehavioral alterations, tissue injury, and oxidative stress in mice newborns. PMID:28588748

  4. Aging-associated changes in motor axon voltage-gated Na+ channel function in mice

    DEFF Research Database (Denmark)

    Moldovan, Mihai; Rosberg, Mette Romer; Alvarez Herrero, Susana

    2016-01-01

    the functional impairment. The aim of the present study was to investigate the effect of regular aging on motor axon function with particular emphasis on Nav1.8. We compared tibial nerve conduction and excitability measures by threshold tracking in 12 months (mature) and 20 months (aged) wild-type (WT) mice...... expression was found by immunohistochemistry. The depolarizing excitability features were absent in Nav1.8 null mice, and they were counteracted in WT mice by a Nav1.8 blocker. Our data suggest that alteration in voltage-gated Na+ channel isoform expression contributes to changes in motor axon function...

  5. Curcumin attenuates surgery-induced cognitive dysfunction in aged mice.

    Science.gov (United States)

    Wu, Xiang; Chen, Huixin; Huang, Chunhui; Gu, Xinmei; Wang, Jialing; Xu, Dilin; Yu, Xin; Shuai, Chu; Chen, Liping; Li, Shun; Xu, Yiguo; Gao, Tao; Ye, Mingrui; Su, Wei; Liu, Haixiong; Zhang, Jinrong; Wang, Chuang; Chen, Junping; Wang, Qinwen; Cui, Wei

    2017-06-01

    Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

  6. Influence of facial skin ageing characteristics on the perceived age in a Russian female population.

    Science.gov (United States)

    Merinville, E; Grennan, G Z; Gillbro, J M; Mathieu, J; Mavon, A

    2015-10-01

    The desire for a youthful look remains a powerful motivator in the purchase of cosmetics by women globally. To develop an anti-ageing solution that targets the need of end consumers, it is critical to understand which signs of ageing really matter to them and which influence their age perception. To date, such research has not been performed in a Russian population. The aim of this work was to identify the signs of ageing that contribute the most to an 'older' or 'younger' look for Russian women aged 40 years old and above. The age of 203 Russian female volunteers was estimated from their standard photographs by a total of 629 female naïve assessors aged 20-65 years old. Perceived age data were related to 23 facial skin features previously measured using linear correlation coefficients. Differences in average severity of the correlating skin ageing features were evaluated between women perceived older and women perceived younger than their chronological age. Volunteers' responses to a ranking question on their key ageing skin concerns previously collected were analysed to provide an additional view on facial ageing from the consumer perspective. Nine facial skin ageing features were found to correlate the most with perceived age out of the 23 measured. Such results showed the importance of wrinkles in the upper part of the face (crow's feet, glabellar, under eye and forehead wrinkles), but also wrinkles in the lower half of the face associated with facial sagging (upper lip, nasolabial fold). Sagging was confirmed of key importance to female volunteers aged 41-65 years old who were mostly concerned by the sagging of their jawline, ahead of under eye and crow's feet wrinkle. The severity of hyperpigmented spots, red and brown, was also found to contribute to perceived age although to a weaker extent. By providing a clear view on the signs of ageing really matter to Russian women who are aged 40 years old and above, this research offers key information for the

  7. Deletion of the forebrain mineralocorticoid receptor impairs social discrimination and decision-making in male, but not in female mice

    Directory of Open Access Journals (Sweden)

    Judith P Ter Horst

    2014-02-01

    Full Text Available Social interaction with unknown individuals requires fast processing of information to decide whether it is friend or foe. This process of discrimination and decision-making is stressful and triggers secretion of corticosterone activating mineralocorticoid receptors (MR and glucocorticoid receptors (GR. The MR is involved in appraisal of novel experiences and risk assessment. Recently, we have demonstrated in a dual-solution memory task that MR plays a role in the early stage of information processing and decision-making. Here we examined social approach and social discrimination in male and female mice lacking MR from hippocampal-amygdala-prefrontal circuitry and controls. The social approach task allows the assessment of time spent with an unfamiliar mouse and the ability to discriminate between familiar and unfamiliar conspecifics. The male and female test mice were both more interested in the social than the non-social experience and deletion of their limbic MR increased the time spent with an unfamiliar mouse. Unlike controls, the male MRCaMKCre mice were not able to discriminate between an unfamiliar and the familiar mouse. However, the female MR mutant had retained the discriminative ability between unfamiliar and familiar mice. Administration of the MR antagonist RU28318 to male mice supported the role of the MR in the discrimination between an unfamiliar mouse and a non-social stimulus. No effect was found with a GR antagonist. Our findings suggest that MR is involved in sociability and social discrimination in a sex-specific manner through inhibitory control exerted putatively via limbic-hippocampal efferents. The ability to discriminate between familiar and unfamiliar conspecifics is of uttermost importance for territorial defense and depends on a role of MR in decision-making.

  8. Differences in peripheral sensory input to the olfactory bulb between male and female mice

    Science.gov (United States)

    Kass, Marley D.; Czarnecki, Lindsey A.; Moberly, Andrew H.; McGann, John P.

    2017-04-01

    Female mammals generally have a superior sense of smell than males, but the biological basis of this difference is unknown. Here, we demonstrate sexually dimorphic neural coding of odorants by olfactory sensory neurons (OSNs), primary sensory neurons that physically contact odor molecules in the nose and provide the initial sensory input to the brain’s olfactory bulb. We performed in vivo optical neurophysiology to visualize odorant-evoked OSN synaptic output into olfactory bub glomeruli in unmanipulated (gonad-intact) adult mice from both sexes, and found that in females odorant presentation evoked more rapid OSN signaling over a broader range of OSNs than in males. These spatiotemporal differences enhanced the contrast between the neural representations of chemically related odorants in females compared to males during stimulus presentation. Removing circulating sex hormones makes these signals slower and less discriminable in females, while in males they become faster and more discriminable, suggesting opposite roles for gonadal hormones in influencing male and female olfactory function. These results demonstrate that the famous sex difference in olfactory abilities likely originates in the primary sensory neurons, and suggest that hormonal modulation of the peripheral olfactory system could underlie differences in how males and females experience the olfactory world.

  9. Effect of bite-raised condition on the hippocampal cholinergic system of aged SAMP8 mice.

    Science.gov (United States)

    Katayama, Tasuku; Mori, Daisuke; Miyake, Hidekazu; Fujiwara, Shuu; Ono, Yumie; Takahashi, Toru; Onozuka, Minoru; Kubo, Kin-Ya

    2012-06-27

    Occlusal disharmony induces chronic stress, which results in learning deficits in association with the morphologic changes in the hippocampus, e.g., neuronal degeneration and increased hypertrophied glial fibrillary acidic protein-positive cells. To investigate the mechanisms underlying impaired hippocampal function resulting from occlusal disharmony, we examined the effects of the bite-raised condition on the septohippocampal cholinergic system by assessing acetylcholine release in the hippocampus and choline acetyltransferase immunoreactivity in the medial septal nucleus in aged SAMP8 mice that underwent the bite raising procedure. Aged bite-raised mice showed decreased acetylcholine release in the hippocampus and a reduced number of choline acetyltransferase-immunopositive neurons in the medial septal nucleus compared to age-matched control mice. These findings suggest that the bite-raised condition in aged SAMP8 mice enhances the age-related decline in the septohippocampal cholinergic system, leading to impaired learning. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  10. High Sensitivity of Aged Mice to Deoxynivalenol (Vomitoxin)-Induced Anorexia Corresponds to Elevated Proinflammatory Cytokine and Satiety Hormone Responses.

    Science.gov (United States)

    Clark, Erica S; Flannery, Brenna M; Gardner, Elizabeth M; Pestka, James J

    2015-10-19

    Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes.

  11. High Sensitivity of Aged Mice to Deoxynivalenol (Vomitoxin-Induced Anorexia Corresponds to Elevated Proinflammatory Cytokine and Satiety Hormone Responses

    Directory of Open Access Journals (Sweden)

    Erica S. Clark

    2015-10-01

    Full Text Available Deoxynivalenol (DON, a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos and adult (3 mos mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg and dietary (1, 2.5, 10 ppm DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes.

  12. The lemon balm extract ALS-L1023 inhibits obesity and nonalcoholic fatty liver disease in female ovariectomized mice.

    Science.gov (United States)

    Kim, Jeongjun; Lee, Hyunghee; Lim, Jonghoon; Lee, Haerim; Yoon, Seolah; Shin, Soon Shik; Yoon, Michung

    2017-08-01

    Increasing evidence indicates that angiogenesis inhibitors regulate obesity. This study aimed to determine whether the lemon balm extract ALS-L1023 inhibits diet-induced obesity and nonalcoholic fatty liver disease (NAFLD) in female ovariectomized (OVX) mice. OVX mice received a low fat diet (LFD), a high fat diet (HFD) or HFD supplemented with ALS-L1023 (ALS-L1023) for 15 weeks. HFD mice exhibited increases in visceral adipose tissue (VAT) angiogenesis, body weight, VAT mass and VAT inflammation compared with LFD mice. In contrast, all of these effects were reduced in ALS-L1023 mice compared with HFD mice. Serum lipids and liver injury markers were improved in ALS-L1023 mice. Hepatic lipid accumulation, inflammatory cells and collagen levels were lower in ALS-L1023 mice than in HFD mice. ALS-L1023 mice exhibited a tendency to normalize hepatic expression of genes involved in lipid metabolism, inflammation and fibrosis to levels in LFD mice. ALS-L1023 also induced Akt phosphorylation and increased Nrf2 mRNA expression in livers of obese mice. Our results indicate that the angiogenesis inhibitor ALS-L1023 can regulate obesity, hepatic steatosis and fibro-inflammation, in part through improvement of VAT function, in obese OVX mice. These findings suggest that angiogenesis inhibitors may contribute to alleviation of NAFLD in post-menopausal women with obesity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Similar reliability and equivalent performance of female and male mice in the open field and water-maze place navigation task

    OpenAIRE

    Fritz, Ann-Kristina; Amrein, Irmgard; Wolfer, David P.

    2017-01-01

    Although most nervous system diseases affect women and men differentially, most behavioral studies using mouse models do not include subjects of both sexes. Many researchers worry that data of female mice may be unreliable due to the estrous cycle. Here, we retrospectively evaluated sex effects on coefficient of variation (CV) in 5,311 mice which had performed the same place navigation protocol in the water-maze and in 4,554 mice tested in the same open field arena. Confidence intervals for C...

  14. [Effect of Huanglian Jiedu Decoction on Monocyte Development in apoE Gene Knockout Mice].

    Science.gov (United States)

    Chen, Bing; Kong, Ya-xian; Ll, Yu-mei; Xue, Xin; Zhang, Jian-ping; Zeng, Hui; Hu, Jing- qing; Ma, Ya-luan

    2016-01-01

    To observe monocyte (Mo) development in wild type C57BL/6 mice and apoE gene knockout (apoE(-/-)) mice, and to evaluate the immuno-regulatory effect of Huanglian Jiedu Decoction (HJD) on peripheral Mo development in apoE(-/-) mice. Four, 8, 12, and 16 weeks old female C57BL/6 mice were set up as control groups of different ages, while 4, 8, 12, and 16 weeks old female apoE(-/-) mice were set up as hyperlipidemia groups of different ages. Four-week old female C57BL/6 mice were recruited as a blank group. Four-week old female apoE(-/-) mice were randomly divided into the control group, the Western medicine group, and the Chinese medicine group by paired comparison, 5 in each group. Equivalent clinical dose was administered to mice according to body weight. Mice in the Western medicine group were administered with Atrovastatin at the daily dose of 10 mg/kg by gastrogavage, while those in the Chinese medicine group were administered with HJD at the daily dose of 5 g/kg by gastrogavage. Body weight was detected each week. After 4 weeks blood lipids levels (such as TG, TC, LDL-C, and HDL-C), and the proportions of Mo and Ly6c(hi) were detected. Compared with 4-week-old homogenic mice, the proportion of Mo decreased in 16-week-old C57BL/6 mice (P < 0.05). Levels of TC and TG, and the proportion of Ly6c(hi) subtype increased, but the proportion of Mo de- creased in 8-week-old apoE(-/-) mice (P <0. 05). Levels of TC, TG, and LDL-C increased in 12-week-old apoE(-/-) mice (P < 0.05). Levels of TC, TG, LDL-C, and HDL-C increased in 16-week-old apoE(-/-) mice (P < 0.05, P < 0.01). Compared with 8-week-old homogenic mice, the proportion of Mo decreased in 16-week-old C57BL/6 mice (P < 0.05); levels of TC and LDL-C increased in 12-week-old apoE(-/-) mice (P < 0.05); levels of TC and HDL-C increased in 16-week-old apoE(-/-) mice (P < 0.05, P < 0.01). Compared with C57BL/6 mice of the same age, TC and TG increased, HDL-C decreased (P < 0.01) in 4-and 8-week-old apoE(-/-) mice (P

  15. High Intensity Interval Training Improves Physical Performance and Frailty in Aged Mice.

    Science.gov (United States)

    Seldeen, Kenneth Ladd; Lasky, Ginger; Leiker, Merced Marie; Pang, Manhui; Personius, Kirkwood Ely; Troen, Bruce Robert

    2018-03-14

    Sarcopenia and frailty are highly prevalent in older individuals, increasing the risk of disability and loss of independence. High intensity interval training (HIIT) may provide a robust intervention for both sarcopenia and frailty by achieving both strength and endurance benefits with lower time commitments than other exercise regimens. To better understand the impacts of HIIT during aging, we compared 24-month-old C57BL/6J sedentary mice with those that were administered 10-minute uphill treadmill HIIT sessions three times per week over 16 weeks. Baseline and end point assessments included body composition, physical performance, and frailty based on criteria from the Fried physical frailty scale. HIIT-trained mice demonstrated dramatic improvement in grip strength (HIIT 10.9% vs -3.9% in sedentary mice), treadmill endurance (32.6% vs -2.0%), and gait speed (107.0% vs 39.0%). Muscles from HIIT mice also exhibited greater mass, larger fiber size, and an increase in mitochondrial biomass. Furthermore, HIIT exercise led to a dramatic reduction in frailty scores in five of six mice that were frail or prefrail at baseline, with four ultimately becoming nonfrail. The uphill treadmill HIIT exercise sessions were well tolerated by aged mice and led to performance gains, improvement in underlying muscle physiology, and reduction in frailty.

  16. Cannabidiol Prevents the Development of Cold and Mechanical Allodynia in Paclitaxel-Treated Female C57Bl6 Mice

    OpenAIRE

    Ward, Sara Jane; Ramirez, Michael David; Neelakantan, Harshini; Walker, Ellen Ann

    2011-01-01

    The taxane chemotherapeutic paclitaxel frequently produces peripheral neuropathy in humans. Rodent models to investigate mechanisms and treatments are largely restricted to male rats, whereas female mouse studies are lacking. We characterized a range of paclitaxel doses on cold and mechanical allodynia in male and female C57Bl/6 mice. Because the nonpsycho-active phytocannabinoid cannabidiol attenuates other forms of neuropathic pain, we assessed its effect on paclitaxel-induced allodynia. Pa...

  17. Heterozygous ambra1 deficiency in mice: a genetic trait with autism-like behavior restricted to the female gender.

    Science.gov (United States)

    Dere, Ekrem; Dahm, Liane; Lu, Derek; Hammerschmidt, Kurt; Ju, Anes; Tantra, Martesa; Kästner, Anne; Chowdhury, Kamal; Ehrenreich, Hannelore

    2014-01-01

    Autism-spectrum disorders (ASD) are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of approximately 4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g., through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus, and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1 (+/-) females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups, which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1 (+/-) mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1 (+/-) females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.

  18. Heterozygous Ambra1 deficiency in mice: A genetic trait with autism-like behavior restricted to the female gender

    Directory of Open Access Journals (Sweden)

    Ekrem eDere

    2014-05-01

    Full Text Available Autism spectrum disorders (ASD are heterogeneous, highly heritable neurodevelopmental conditions affecting around 0.5% of the population across cultures, with a male/female ratio of ~4:1. Phenotypically, ASD are characterized by social interaction and communication deficits, restricted interests, repetitive behaviors, and reduced cognitive flexibility. Identified causes converge at the level of the synapse, ranging from mutation of synaptic genes to quantitative alterations in synaptic protein expression, e.g. through compromised transcriptional or translational control. We wondered whether reduced turnover and degradation of synapses, due to deregulated autophagy, would lead to similar phenotypical consequences. Ambra1, strongly expressed in cortex, hippocampus and striatum, is a positive regulator of Beclin1, a principal player in autophagosome formation. While homozygosity of the Ambra1 null mutation causes embryonic lethality, heterozygous mice with reduced Ambra1 expression are viable, reproduce normally, and lack any immediately obvious phenotype. Surprisingly, comprehensive behavioral characterization of these mice revealed an autism-like phenotype in Ambra1+/- females only, including compromised communication and social interactions, a tendency of enhanced stereotypies/repetitive behaviors, and impaired cognitive flexibility. Reduced ultrasound communication was found in adults as well as pups which achieved otherwise normal neurodevelopmental milestones. These features were all absent in male Ambra1+/- mice. As a first hint explaining this gender difference, we found a much stronger reduction of Ambra1 protein in the cortex of Ambra1+/- females compared to males. To conclude, Ambra1 deficiency can induce an autism-like phenotype. The restriction to the female gender of autism-generation by a defined genetic trait is unique thus far and warrants further investigation.

  19. Effects of lung exposure to carbon nanotubes on female fertility and pregnancy. A study in mice

    DEFF Research Database (Denmark)

    Hougaard, Karin S.; Jackson, Petra; Kyjovska, Zdenka O.

    2013-01-01

    We studied the effects of preconceptional exposure to multiwalled carbon nanotubes (MWCNTs): mature, female C57BL/6J mice were intratracheally instilled with 67μg NM-400 MWCNT, and the following day co-housed with mature males, in breeding pairs. Time to delivery of the first litter, litter...

  20. Dietary broccoli mildly improves neuroinflammation in aged mice but does not reduce lipopolysaccharide-induced sickness behavior.

    Science.gov (United States)

    Townsend, Brigitte E; Chen, Yung-Ju; Jeffery, Elizabeth H; Johnson, Rodney W

    2014-11-01

    Aging is associated with oxidative stress and heightened inflammatory response to infection. Dietary interventions to reduce these changes are therefore desirable. Broccoli contains glucoraphanin, which is converted to sulforaphane (SFN) by plant myrosinase during cooking preparation or digestion. Sulforaphane increases antioxidant enzymes including NAD(P)H quinone oxidoreductase and heme oxygenase I and inhibits inflammatory cytokines. We hypothesized that dietary broccoli would support an antioxidant response in brain and periphery of aged mice and inhibit lipopolysaccharide (LPS)-induced inflammation and sickness. Young adult and aged mice were fed control or 10% broccoli diet for 28 days before an intraperitoneal LPS injection. Social interactions were assessed 2, 4, 8, and 24 hours after LPS, and mRNA was quantified in liver and brain at 24 hours. Dietary broccoli did not ameliorate LPS-induced decrease in social interactions in young or aged mice. Interleukin-1β (IL-1β) expression was unaffected by broccoli consumption but was induced by LPS in brain and liver of adult and aged mice. In addition, IL-1β was elevated in brain of aged mice without LPS. Broccoli consumption decreased age-elevated cytochrome b-245 β, an oxidative stress marker, and reduced glial activation markers in aged mice. Collectively, these data suggest that 10% broccoli diet provides a modest reduction in age-related oxidative stress and glial reactivity, but is insufficient to inhibit LPS-induced inflammation. Thus, it is likely that SFN would need to be provided in supplement form to control the inflammatory response to LPS. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Reactive oxygen species on bone mineral density and mechanics in Cu,Zn superoxide dismutase (Sod1) knockout mice

    International Nuclear Information System (INIS)

    Smietana, Michael J.; Arruda, Ellen M.; Faulkner, John A.; Brooks, Susan V.; Larkin, Lisa M.

    2010-01-01

    Research highlights: → Reactive oxygen species (ROS) are considered to be a factor in the onset of a number of age-associated conditions, including loss of BMD. → Cu,Zn-superoxide dismutase (Sod1) deficient mice have increased ROS, reduced bone mineral density, decreased bending stiffness, and decreased strength compared to WT controls. → Increased ROS caused by the deficiency of Sod1, may be responsible for the changes in BMD and bone mechanics and therefore represent an appropriate model for studying mechanisms of age-associated bone loss. -- Abstract: Reactive oxygen species (ROS) play a role in a number of degenerative conditions including osteoporosis. Mice deficient in Cu,Zn-superoxide dismutase (Sod1) (Sod1 -/- mice) have elevated oxidative stress and decreased muscle mass and strength compared to wild-type mice (WT) and appear to have an accelerated muscular aging phenotype. Thus, Sod1 -/- mice may be a good model for evaluating the effects of free radical generation on diseases associated with aging. In this experiment, we tested the hypothesis that the structural integrity of bone as measured by bending stiffness (EI; N/mm 2 ) and strength (MPa) is diminished in Sod1 -/- compared to WT mice. Femurs were obtained from male and female WT and Sod1 -/- mice at 8 months of age and three-point bending tests were used to determine bending stiffness and strength. Bones were also analyzed for bone mineral density (BMD; mg/cc) using micro-computed tomography. Femurs were approximately equal in length across all groups, and there were no significant differences in BMD or EI with respect to gender in either genotype. Although male and female mice demonstrated similar properties within each genotype, Sod1 -/- mice exhibited lower BMD and EI of femurs from both males and females compared with gender matched WT mice. Strength of femurs was also lower in Sod1 -/- mice compared to WT as well as between genders. These data indicate that increased oxidative stress

  2. Restoration of the immune functions in aged mice by supplementation with a new herbal composition, HemoHIM.

    Science.gov (United States)

    Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee; Yee, Sung-Tae

    2008-01-01

    The effect of a new herbal composition, HemoHIM, on immune functions was examined in aged mice, in which various immune responses had been impaired. The composition HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs, Angelica Radix, Cnidium Rhizoma and Paeonia Radix. Supplementation to the aged mice with HemoHIM restored the proliferative response and cytokine production of splenocytes with a response to ConA. Also, HemoHIM recovered the NK cell activity which had been impaired in the aged mice. Meanwhile aging is known to reduce the Th1-like function, but not the Th2-like function, resulting in a Th1/Th2 imbalance. HemoHIM restored the Th1/Th2 balance in the aged mice through enhanced IFN-gamma and IgG2a production, and conversely a reduced IL-4 and IgG1 production. It was found that one factor for the Th1/Th2 imbalance in the aged mice was a lower production of IL-12p70. However, HemoHIM restored the IL-12p70 production in the aged mice. These results suggested that HemoHIM was effective for the restoration of impaired immune functions of the aged mice and therefore could be a good recommendation for immune restoration in elderly humans. Copyright (c) 2007 John Wiley & Sons, Ltd.

  3. The estrogen-injected female mouse: new insight into the etiology of PCOS

    Directory of Open Access Journals (Sweden)

    Freeh Steven M

    2009-05-01

    Full Text Available Abstract Background Female mice and rats injected with estrogen perinatally become anovulatory and develop follicular cysts. The current consensus is that this adverse response to estrogen involves the hypothalamus and occurs because of an estrogen-induced alteration in the GnRH delivery system. Whether or not this is true has yet to be firmly established. The present study examined an alternate possibility in which anovulation and cyst development occurs through an estrogen-induced disruption in the immune system, achieved through the intermediation of the thymus gland. Methods, Results and Conclusion A putative role for the thymus in estrogen-induced anovulation and follicular cyst formation (a model of PCOS was examined in female mice by removing the gland prior to estrogen injection. Whereas all intact, female mice injected with 20 ug estrogen at 5–7 days of age had ovaries with follicular cysts, no cysts were observed in animals in which thymectomy at 3 days of age preceded estrogen injection. In fact, after restoring immune function by thymocyte replacement, the majority of thymectomized, estrogen-injected mice had ovaries with corpora lutea. Thus, when estrogen is unable to act on the thymus, ovulation occurs and follicular cysts do not develop. This implicates the thymus in the cysts' genesis and discounts the role of the hypothalamus. Subsequent research established that the disease is transferable by lymphocyte infusion. Transfer took place between 100-day-old estrogen-injected and 15-day-old naïve mice only when recipients were thymectomized at 3 days of age. Thus, a prerequisite for cyst formation is the absence of regulatory T cells. Their absence in donor mice was judged to be the result of an estrogen-induced increase in the thymus' vascular permeability, causing de facto circumvention of the final stages of regulatory T cell development. The human thymus has a similar vulnerability to steroid action during the fetal stage. We

  4. The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice

    International Nuclear Information System (INIS)

    Ziv-Gal, Ayelet; Wang, Wei; Zhou, Changqing; Flaws, Jodi A.

    2015-01-01

    In utero bisphenol A (BPA) exposure affects reproductive function in the first generation (F1) of mice; however, not many studies have examined the reproductive effects of BPA exposure on subsequent generations. In this study, pregnant mice (F0) were orally dosed with vehicle, BPA (0.5, 20, and 50 μg/kg/day) or diethylstilbestrol (DES; 0.05 μg/kg/day) daily from gestation day 11 until birth. F1 females were used to generate the F2 generation, and F2 females were used to generate the F3 generation. Breeding studies at the ages of 3, 6, and 9 months were conducted to evaluate reproductive capacity over time. Further, studies were conducted to evaluate pubertal onset, litter size, and percentage of dead pups; and to calculate pregnancy rate, and mating, fertility, and gestational indices. The results indicate that BPA exposure (0.5 and 50 μg/kg/day) significantly delayed the age at vaginal opening in the F3 generation compared to vehicle control. Both DES (0.05 μg/kg/day) and BPA (50 μg/kg/day) significantly delayed the age at first estrus in the F3 generation compared to vehicle control. BPA exposure reduced gestational index in the F1 and F2 generations compared to control. Further, BPA exposure (0.5 μg/kg/day) compromised the fertility index in the F3 generation compared to control. Finally, in utero BPA exposure reduced the ability of female mice to maintain pregnancies as they aged. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational in nature. - Highlights: • In utero BPA delayed vaginal opening in the F3 generation compared to control. • In utero BPA delayed estrus in the F3 generation compared to control. • In utero BPA reduced the ability of F1 and F2 female mice to maintain pregnancies. • In utero BPA compromised the ability of F3 female mice to become pregnant. • Some effects of in utero BPA may be transgenerational in nature

  5. The effects of in utero bisphenol A exposure on reproductive capacity in several generations of mice

    Energy Technology Data Exchange (ETDEWEB)

    Ziv-Gal, Ayelet, E-mail: zivgal1@illinois.edu; Wang, Wei, E-mail: weiwang2@illinois.edu; Zhou, Changqing, E-mail: czhou27@illinois.edu; Flaws, Jodi A., E-mail: jflaws@illinois.edu

    2015-05-01

    In utero bisphenol A (BPA) exposure affects reproductive function in the first generation (F1) of mice; however, not many studies have examined the reproductive effects of BPA exposure on subsequent generations. In this study, pregnant mice (F0) were orally dosed with vehicle, BPA (0.5, 20, and 50 μg/kg/day) or diethylstilbestrol (DES; 0.05 μg/kg/day) daily from gestation day 11 until birth. F1 females were used to generate the F2 generation, and F2 females were used to generate the F3 generation. Breeding studies at the ages of 3, 6, and 9 months were conducted to evaluate reproductive capacity over time. Further, studies were conducted to evaluate pubertal onset, litter size, and percentage of dead pups; and to calculate pregnancy rate, and mating, fertility, and gestational indices. The results indicate that BPA exposure (0.5 and 50 μg/kg/day) significantly delayed the age at vaginal opening in the F3 generation compared to vehicle control. Both DES (0.05 μg/kg/day) and BPA (50 μg/kg/day) significantly delayed the age at first estrus in the F3 generation compared to vehicle control. BPA exposure reduced gestational index in the F1 and F2 generations compared to control. Further, BPA exposure (0.5 μg/kg/day) compromised the fertility index in the F3 generation compared to control. Finally, in utero BPA exposure reduced the ability of female mice to maintain pregnancies as they aged. Collectively, these data suggest that BPA exposure affects reproductive function in female mice and that some effects may be transgenerational in nature. - Highlights: • In utero BPA delayed vaginal opening in the F3 generation compared to control. • In utero BPA delayed estrus in the F3 generation compared to control. • In utero BPA reduced the ability of F1 and F2 female mice to maintain pregnancies. • In utero BPA compromised the ability of F3 female mice to become pregnant. • Some effects of in utero BPA may be transgenerational in nature.

  6. Prohibitin-induced obesity leads to anovulation and polycystic ovary in mice

    Directory of Open Access Journals (Sweden)

    Sudharsana Rao Ande

    2017-06-01

    Full Text Available Polycystic ovary syndrome (PCOS is a prevalent endocrine disorder and the most common cause of female infertility. However, its etiology and underlying mechanisms remain unclear. Here we report that a transgenic obese mouse (Mito-Ob developed by overexpressing prohibitin in adipocytes develops polycystic ovaries. Initially, the female Mito-Ob mice were equally fertile to their wild-type littermates. The Mito-Ob mice began to gain weight after puberty, became significantly obese between 3-6 months of age, and ∼25% of them had become infertile by 9 months of age. Despite obesity, female Mito-Ob mice maintained glucose homeostasis and insulin sensitivity similar to their wild-type littermates. Mito-Ob mice showed morphologically distinct polycystic ovaries and elevated estradiol, but normal testosterone and insulin levels. Histological analysis of the ovaries showed signs of impaired follicular dynamics, such as preantral follicular arrest and reduced number, or absence, of corpus luteum. The ovaries of the infertile Mito-Ob mice were closely surrounded by periovarian adipose tissue, suggesting a potential role in anovulation. Collectively, these data suggest that elevated estradiol and obesity per se might lead to anovulation and polycystic ovaries independent of hyperinsulinemia and hyperandrogenism. As obesity often coexists with other abnormalities known to be involved in the development of PCOS such as insulin resistance, compensatory hyperinsulinemia and hyperandrogenism, the precise role of these factors in PCOS remains unclear. Mito-Ob mice provide an opportunity to study the effects of obesity on anovulation and ovarian cyst formation independent of the major drivers of obesity-linked PCOS.

  7. Improvement of skin condition by oral administration of collagen hydrolysates in chronologically aged mice.

    Science.gov (United States)

    Wang, Zhenbin; Wang, Qing; Wang, Lin; Xu, Weidong; He, Yuanqing; Li, Yunliang; He, Song; Ma, Haile

    2017-07-01

    Collagen hydrolysates (CHs) have been demonstrated to have positive effects on skin photoaging by topical application or oral ingestion. However, there has been little research on their influence on skin chronological aging. In this study, 9-month-old female ICR mice were given normal AIN-93M diets containing CHs (2.5, 5 and 10% w/w) from Nile tilapia scale. After 6 months, the collagen content and antioxidant enzyme (superoxide dismutase and glutathione peroxidase) activities increased significantly (P skin did not change (P > 0.05). The color, luster and quantity of hair were obviously ameliorated. Moreover, the structure of epidermis and dermis, the density and distribution of collagen fibers and the ratio of type I to type III collagen were improved in a dose-dependent manner as shown by histochemical staining. Oral ingestion of CHs increased the collagen content and antioxidant enzyme activities and improved the appearance and structure of skin. These results suggest the potential of CHs as an anti-skin-aging ingredient in nutraceuticals or functional foods. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  8. Aged Tg2576 mice are impaired on social memory and open field habituation tests.

    Science.gov (United States)

    Deacon, R M J; Koros, E; Bornemann, K D; Rawlins, J N P

    2009-02-11

    In a previous publication [Deacon RMJ, Cholerton LL, Talbot K, Nair-Roberts RG, Sanderson DJ, Romberg C, et al. Age-dependent and -independent behavioral deficits in Tg2576 mice. Behav Brain Res 2008;189:126-38] we found that very few cognitive tests were suitable for demonstrating deficits in Tg2576 mice, an amyloid over-expression model of Alzheimer's disease, even at 23 months of age. However, in a retrospective analysis of a separate project on these mice, tests of social memory and open field habituation revealed large cognitive impairments. Controls showed good open field habituation, but Tg2576 mice were hyperactive and failed to habituate. In the test of social memory for a juvenile mouse, controls showed considerably less social investigation on the second meeting, indicating memory of the juvenile, whereas Tg2576 mice did not show this decrement.As a control for olfactory sensitivity, on which social memory relies, the ability to find a food pellet hidden under wood chip bedding was assessed. Tg2576 mice found the pellet as quickly as controls. As this test requires digging ability, this was independently assessed in tests of burrowing and directly observed digging. In line with previous results and the hippocampal dysfunction characteristic of aged Tg2576 mice, they both burrowed and dug less than controls.

  9. Rape and Sexual Assault Victimization Among College-Age Females, 1995-2013

    Science.gov (United States)

    ... Statistics DECEMBER 2014 Special Report NCJ 2484 71 Rape and Sexual Assault Victimization Among College-Age Females, 1995–2013 Sofi ... 18 to 24 had the highest rate of rape and sexual assault victimizations compared to females in ...

  10. Trends in Female Breast Cancer by Age Group in the Chiang Mai Population

    Science.gov (United States)

    Sripan, Patumrat; Sriplung, Hutcha; Pongnikorn, Donsuk; Virani, Shama; Bilheem, Surichai; Chaisaengkhaum, Udomlak; Maneesai, Puttachart; Waisri, Narate; Hanpragopsuk, Chirapong; Tansiri, Panrada; Khamsan, Varunee; Poungsombat, Malisa; Mawoot, Aumnart; Chitapanarux, Imjai

    2017-01-01

    Objectives: This study was conducted to determine incidence trends of female breast cancer according to age groups and to predict future change in Chiang Mai women through 2028. Method: Data were collected from all hospitals in Chiang Mai in northern Thailand, from 1989 through 2013, and used to investigate effects of age, year of diagnosis (period) and year of birth (cohort) on female breast cancer incidences using an age-period-cohort model. This model features geometric cut trends to predict change by young (<40 years), middle-aged (40-59) and elderly (≥60) age groups. Result: Of 5, 417 female breast cancer patients with a median age of 50 years (interquartile range: 43 to 59 years), 15%, 61% and 24% were young, middle-aged and elderly, respectively. Seventy nine percent of cancer cases in this study were detected at advanced stage. The trend in stage classification showed an increase in percentage of early stage and a decrease in metastatic cancers. Linear trends for cohort and period were not found in young females but were observed in middle-aged and elderly groups. Age-standardized rates (ASR) can be expected to remain stable around 6.8 per 100,000 women-years in young females. In the other age groups, the ASR trends were calculated to increase and reach peaks in 2024 of 120.2 and 138.2 per 100,000 women-years, respectively. Conclusion: Cohort effects or generation-specific effects, such as life style factors and the year of diagnosis (period) might have impacted on increased incidence in women aged over 40 years but not those under 40 years. A budget should be provided for treatment facilities and strategies to detect early stage cancers. The cost effectiveness of screening measures i.e. mammographic screening may need to be reconsidered for women age over 40 years. PMID:28612595

  11. Impaired immune responses in the lungs of aged mice following influenza infection

    Directory of Open Access Journals (Sweden)

    Toapanta Franklin R

    2009-11-01

    Full Text Available Abstract Background Each year, influenza virus infection causes severe morbidity and mortality, particularly in the most susceptible groups including children, the elderly (>65 years-old and people with chronic respiratory diseases. Among the several factors that contribute to the increased susceptibility in elderly populations are the higher prevalence of chronic diseases (e.g. diabetes and the senescence of the immune system. Methods In this study, aged and adult mice were infected with sublethal doses of influenza virus (A/Puerto Rico/8/1934. Differences in weight loss, morbidity, virus titer and the kinetics of lung infiltration with cells of the innate and adaptive immune responses were analyzed. Additionally, the main cytokines and chemokines produced by these cells were also assayed. Results Compared to adult mice, aged mice had higher morbidity, lost weight more rapidly, and recovered more slowly from infection. There was a delay in the accumulation of granulocytic cells and conventional dendritic cells (cDCs, but not macrophages in the lungs of aged mice compared to adult animals. The delayed infiltration kinetics of APCs in aged animals correlated with alteration in their activation (CD40 expression, which also correlated with a delayed detection of cytokines and chemokines in lung homogenates. This was associated with retarded lung infiltration by natural killer (NK, CD4+ and CD8+ T-cells. Furthermore, the percentage of activated (CD69+ influenza-specific and IL-2 producer CD8+ T-cells was higher in adult mice compared to aged ones. Additionally, activation (CD69+ of adult B-cells was earlier and correlated with a quicker development of neutralizing antibodies in adult animals. Conclusion Overall, alterations in APC priming and activation lead to delayed production of cytokines and chemokines in the lungs that ultimately affected the infiltration of immune cells following influenza infection. This resulted in delayed activation of the

  12. Safety and Efficacy of Scanning Ultrasound Treatment of Aged APP23 Mice

    Directory of Open Access Journals (Sweden)

    Gerhard Leinenga

    2018-02-01

    Full Text Available Deposition of amyloid-β (Aβ peptide leads to amyloid plaques that together with tau deposits characterize the brains of patients with Alzheimer's disease (AD. In modeling this pathology, transgenic animals such as the APP23 strain, that expresses a mutant form of the amyloid precursor protein found in familial cases of AD, have been instrumental. In previous studies, we have shown that repeated treatments with ultrasound in a scanning mode (termed scanning ultrasound or SUS were effective in removing Aβ and restoring memory functions, without the need for a therapeutic agent such as an Aβ antibody. Considering that age is the most important risk factor for AD, we extended this study in which the mice were only 12 months old at the time of treatment by assessing a cohort of 2 year-old mice. Interestingly, at this age, APP23 mice are characterized by cerebral amyloid angiopathy (CAA and the presence of occasional microbleeds. We found that SUS in aged mice that have been exposed to four SUS sessions that were spread out over 8 weeks and analyzed 4 weeks later did not show evidence of increased CAA or microbleeds. Furthermore, amyloid was reduced as assessed by methoxy-XO4 fluorescence. In addition, plaque-associated microglia were more numerous in SUS treated mice. Together this adds to the notion that SUS may be a treatment modality for human neurodegenerative diseases.

  13. The suitability of 129SvEv mice for studying depressive-like behaviour: both males and females develop learned helplessness.

    Science.gov (United States)

    Chourbaji, Sabine; Pfeiffer, Natascha; Dormann, Christof; Brandwein, Christiane; Fradley, Rosa; Sheardown, Malcolm; Gass, P

    2010-07-29

    Behavioural studies using transgenic techniques in mice usually require extensive backcrossing to a defined background strain, e.g. to C57BL/6. In this study we investigated whether backcrossing can be replaced by using the 129SvEv strain from which the embryonic stem cells are generally obtained for gene targeting strategies to analyze e.g. depression-like behaviour. For that purpose we subjected male and female 129SvEv mice to two frequently used depression tests and compared them with commonly used C57BL/6 mice. 129SvEv and C57BL/6 mice exhibited differing profiles with regard to locomotion and pain sensitivity. However, in the learned helplessness paradigm, a procedure, which represents a valid method to detect depressive-like behaviour, 129SvEv animals develop a similar level of helplessness as C57BL/6 mice. One great advantage of the 129SvEv animals though, is the fact that in this strain even females develop helplessness, which could not be produced in C57BL/6 mice. In the tail suspension test, both genders of 129SvEv exhibited more despair behaviour than C57BL/6 animals. We therefore suggest that this strain may be utilized in the establishment of new test procedures for affective diseases, since costly and time-consuming backcrossing can be prevented, depressive-like behaviour may be analyzed effectively, and gender-specific topics could be addressed in an adequate way. Copyright 2010 Elsevier B.V. All rights reserved.

  14. Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance.

    Science.gov (United States)

    Skarra, Danalea V; Hernández-Carretero, Angelina; Rivera, Alissa J; Anvar, Arya R; Thackray, Varykina G

    2017-09-01

    Women with polycystic ovary syndrome (PCOS) diagnosed with hyperandrogenism and ovulatory dysfunction have an increased risk of developing metabolic disorders, including type 2 diabetes and cardiovascular disease. We previously developed a model that uses letrozole to elevate endogenous testosterone levels in female mice. This model has hallmarks of PCOS, including hyperandrogenism, anovulation, and polycystic ovaries, as well as increased abdominal adiposity and glucose intolerance. In the current study, we further characterized the metabolic dysfunction that occurs after letrozole treatment to determine whether this model represents a PCOS-like metabolic phenotype. We focused on whether letrozole treatment results in altered pancreatic or liver function as well as insulin resistance. We also investigated whether hyperinsulinemia occurs secondary to weight gain and insulin resistance in this model or if it can occur independently. Our study demonstrated that letrozole-treated mice developed hyperinsulinemia after 1 week of treatment and without evidence of insulin resistance. After 2 weeks of letrozole treatment, mice became significantly heavier than placebo mice, demonstrating that weight gain was not required to develop hyperinsulinemia. After 5 weeks of letrozole treatment, mice exhibited blunted glucose-stimulated insulin secretion, insulin resistance, and impaired insulin-induced phosphorylation of AKT in skeletal muscle. Moreover, letrozole-treated mice exhibited dyslipidemia after 5 weeks of treatment but no evidence of hepatic disease. Our study demonstrated that the letrozole-induced PCOS mouse model exhibits multiple features of the metabolic dysregulation observed in obese, hyperandrogenic women with PCOS. This model will be useful for mechanistic studies investigating how hyperandrogenemia affects metabolism in females. Copyright © 2017 Endocrine Society.

  15. Bone growth and turnover in progesterone receptor knockout mice.

    Energy Technology Data Exchange (ETDEWEB)

    Rickard, David J.; Iwaniec, Urszula T.; Evans, Glenda; Hefferan, Theresa E.; Hunter, Jaime C.; Waters, Katrina M.; Lydon, John P.; O' Malley, Bert W.; Khosla, Sundeep; Spelsberg, Thomas C.; Turner, Russell T.

    2008-05-01

    The role of progesterone receptor (PR) signaling in skeletal metabolism is controversial. To address whether signaling through the PR is necessary for normal bone growth and turnover, we performed histomorphometric and mCT analyses of bone from homozygous female PR knockout (PRKO) mice at 6, 12, and 26 weeks of age. These mice possess a null mutation of the PR locus, which blocks the gene expression of A and B isoforms of PR. Body weight gain, uterine weight gain and tibia longitudinal bone growth was normal in PRKO mice. In contrast, total and cortical bone mass were increased in long bones of post-pubertal (12 and 26-week-old) PRKO mice, whereas cancellous bone mass was normal in the tibia but increased in the humerus. The striking 57% decrease in cancellous bone from the proximal tibia metaphysis which occurred between 6 and 26 weeks in WT mice was abolished in PRKO mice. The improved bone balance in aging PRKO mice was associated with elevated bone formation and a tendency toward reduced osteoclast perimeter. Taken together, these findings suggest that PR signaling in mice attenuates the accumulation of cortical bone mass during adolescence and is required for early age-related loss of cancellous bone.

  16. Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice.

    Science.gov (United States)

    Xie, Kan; Neff, Frauke; Markert, Astrid; Rozman, Jan; Aguilar-Pimentel, Juan Antonio; Amarie, Oana Veronica; Becker, Lore; Brommage, Robert; Garrett, Lillian; Henzel, Kristin S; Hölter, Sabine M; Janik, Dirk; Lehmann, Isabelle; Moreth, Kristin; Pearson, Brandon L; Racz, Ildiko; Rathkolb, Birgit; Ryan, Devon P; Schröder, Susanne; Treise, Irina; Bekeredjian, Raffi; Busch, Dirk H; Graw, Jochen; Ehninger, Gerhard; Klingenspor, Martin; Klopstock, Thomas; Ollert, Markus; Sandholzer, Michael; Schmidt-Weber, Carsten; Weiergräber, Marco; Wolf, Eckhard; Wurst, Wolfgang; Zimmer, Andreas; Gailus-Durner, Valerie; Fuchs, Helmut; Hrabě de Angelis, Martin; Ehninger, Dan

    2017-07-24

    Dietary restriction regimes extend lifespan in various animal models. Here we show that longevity in male C57BL/6J mice subjected to every-other-day feeding is associated with a delayed onset of neoplastic disease that naturally limits lifespan in these animals. We compare more than 200 phenotypes in over 20 tissues in aged animals fed with a lifelong every-other-day feeding or ad libitum access to food diet to determine whether molecular, cellular, physiological and histopathological aging features develop more slowly in every-other-day feeding mice than in controls. We also analyze the effects of every-other-day feeding on young mice on shorter-term every-other-day feeding or ad libitum to account for possible aging-independent restriction effects. Our large-scale analysis reveals overall only limited evidence for a retardation of the aging rate in every-other-day feeding mice. The data indicate that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice.Dietary restriction can extend the life of various model organisms. Here, Xie et al. show that intermittent periods of fasting achieved through every-other-day feeding protect mice against neoplastic disease but do not broadly delay organismal aging in animals.

  17. Ultraviolet Radiation–Induced Cataract in Mice: The Effect of Age and the Potential Biochemical Mechanism

    Science.gov (United States)

    Zhang, Jie; Yan, Hong; Löfgren, Stefan; Tian, Xiaoli; Lou, Marjorie F.

    2012-01-01

    Purpose. To study the effect of age on the morphologic and biochemical alterations induced by in vivo exposure of ultraviolet radiation (UV). Methods. Young and old C57BL/6 mice were exposed to broadband UVB+UVA and euthanized after 2 days. Another batch of UV-exposed young mice was monitored for changes after 1, 2, 4, and 8 days. Age-matched nonexposed mice served as controls. Lens changes were documented in vivo by slit-lamp biomicroscopy and dark field microscopy photographs ex vivo. Lens homogenates were analyzed for glutathione (GSH) level, and the activities of thioredoxin (Trx), thioltransferase (TTase), and glyceraldehyde-3-phosphate dehydrogenase (G3PD). Glutathionylated lens proteins (PSSGs) were detected by immunoblotting using GSH antibody. Western blot analysis was also done for the expression levels of TTase and Trx. Results. Both age groups developed epithelial and superficial anterior subcapsular cataract at 2 days postexposure. The lens GSH level and G3PD activity were decreased, and PSSGs were elevated in both age groups, but more prominent in the older mice. TTase and Trx activity and protein expression were elevated only in the young mice. Interestingly, lens TTase and Trx in the young mice showed a transient increase, peaking at 2 days after UV exposure and returning to baseline at day 8, corroborated by lens transparency. Conclusions. The lenses of old mice were more susceptible to UV radiation–induced cataract. The upregulated TTase and Trx likely provided oxidation damage repair in the young mice. PMID:23010639

  18. Early Decline in Glucose Transport and Metabolism Precedes Shift to Ketogenic System in Female Aging and Alzheimer's Mouse Brain: Implication for Bioenergetic Intervention

    Science.gov (United States)

    Ding, Fan; Yao, Jia; Rettberg, Jamaica R.; Chen, Shuhua; Brinton, Roberta Diaz

    2013-01-01

    We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3–15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6–9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential

  19. Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.

    Science.gov (United States)

    Ding, Fan; Yao, Jia; Rettberg, Jamaica R; Chen, Shuhua; Brinton, Roberta Diaz

    2013-01-01

    We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3-15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6-9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential

  20. Mutation types and aging differently affect revertant fiber expansion in dystrophic mdx and mdx52 mice.

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    Yusuke Echigoya

    Full Text Available Duchenne muscular dystrophy (DMD, one of the most common and lethal genetic disorders, and the mdx mouse myopathies are caused by a lack of dystrophin protein. These dystrophic muscles contain sporadic clusters of dystrophin-expressing revertant fibers (RFs, as detected by immunohistochemistry. RFs are known to arise from muscle precursor cells with spontaneous exon skipping (alternative splicing and clonally expand in size with increasing age through the process of muscle degeneration/regeneration. The expansion of revertant clusters is thought to represent the cumulative history of muscle regeneration and proliferation of such precursor cells. However, the precise mechanisms by which RFs arise and expand are poorly understood. Here, to test the effects of mutation types and aging on RF expansion and muscle regeneration, we examined the number of RFs in mdx mice (containing a nonsense mutation in exon 23 and mdx52 mice (containing deletion mutation of exon 52 with the same C57BL/6 background at 2, 6, 12, and 18months of age. Mdx mice displayed a significantly higher number of RFs compared to mdx52 mice in all age groups, suggesting that revertant fiber expansion largely depends on the type of mutation and/or location in the gene. A significant increase in the expression and clustering levels of RFs was found beginning at 6months of age in mdx mice compared with mdx52 mice. In contrast to the significant expansion of RFs with increasing age, the number of centrally nucleated fibers and embryonic myosin heavy chain-positive fibers (indicative of cumulative and current muscle regeneration, respectively decreased with age in both mouse strains. These results suggest that mutation types and aging differently affect revertant fiber expansion in mdx and mdx52 mice.

  1. Wired for motherhood: induction of maternal care but not maternal aggression in virgin female CD1 mice.

    Science.gov (United States)

    Martín-Sánchez, Ana; Valera-Marín, Guillermo; Hernández-Martínez, Adoración; Lanuza, Enrique; Martínez-García, Fernando; Agustín-Pavón, Carmen

    2015-01-01

    Virgin adult female mice display nearly spontaneous maternal care towards foster pups after a short period of sensitization. This indicates that maternal care is triggered by sensory stimulation provided by the pups and that its onset is largely independent on the physiological events related to gestation, parturition and lactation. Conversely, the factors influencing maternal aggression are poorly understood. In this study, we sought to characterize two models of maternal sensitization in the outbred CD1 strain. To do so, a group of virgin females (godmothers) were exposed to continuous cohabitation with a lactating dam and their pups from the moment of parturition, whereas a second group (pup-sensitized females), were exposed 2 h daily to foster pups. Both groups were tested for maternal behavior on postnatal days 2-4. Godmothers expressed full maternal care from the first test. Also, they expressed higher levels of crouching than dams. Pup-sensitized females differed from dams in all measures of pup-directed behavior in the first test, and expressed full maternal care after two sessions of contact with pups. However, both protocols failed to induce maternal aggression toward a male intruder after full onset of pup-directed maternal behavior, even in the presence of pups. Our study confirms that adult female mice need a short sensitization period before the onset of maternal care. Further, it shows that pup-oriented and non-pup-oriented components of maternal behavior are under different physiological control. We conclude that the godmother model might be useful to study the physiological and neural bases of the maternal behavior repertoire.

  2. Normal X-inactivation mosaicism in corneas of heterozygous FlnaDilp2/+ female mice--a model of human Filamin A (FLNA diseases

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    Douvaras Panagiotis

    2012-02-01

    Full Text Available Abstract Background Some abnormalities of mouse corneal epithelial maintenance can be identified by the atypical mosaic patterns they produce in X-chromosome inactivation mosaics and chimeras. Human FLNA/+ females, heterozygous for X-linked, filamin A gene (FLNA mutations, display a range of disorders and X-inactivation mosaicism is sometimes quantitatively unbalanced. FlnaDilp2/+ mice, heterozygous for an X-linked filamin A (Flna nonsense mutation have variable eye, skeletal and other abnormalities, but X-inactivation mosaicism has not been investigated. The aim of this study was to determine whether X-inactivation mosaicism in the corneal epithelia of FlnaDilp2/+ mice was affected in any way that might predict abnormal corneal epithelial maintenance. Results X-chromosome inactivation mosaicism was studied in the corneal epithelium and a control tissue (liver of FlnaDilp2/+ and wild-type (WT female X-inactivation mosaics, hemizygous for the X-linked, LacZ reporter H253 transgene, using β-galactosidase histochemical staining. The corneal epithelia of FlnaDilp2/+ and WT X-inactivation mosaics showed similar radial, striped patterns, implying epithelial cell movement was not disrupted in FlnaDilp2/+ corneas. Corrected stripe numbers declined with age overall (but not significantly for either genotype individually, consistent with previous reports suggesting an age-related reduction in stem cell function. Corrected stripe numbers were not reduced in FlnaDilp2/+ compared with WT X-inactivation mosaics and mosaicism was not significantly more unbalanced in the corneal epithelia or livers of FlnaDilp2/+ than wild-type Flna+/+ X-inactivation mosaics. Conclusions Mosaic analysis identified no major effect of the mouse FlnaDilp2 mutation on corneal epithelial maintenance or the balance of X-inactivation mosaicism in the corneal epithelium or liver.

  3. Depletion of Pax7+ satellite cells does not affect diaphragm adaptations to running in young or aged mice.

    Science.gov (United States)

    Murach, Kevin A; Confides, Amy L; Ho, Angel; Jackson, Janna R; Ghazala, Lina S; Peterson, Charlotte A; Dupont-Versteegden, Esther E

    2017-10-01

    Satellite cell depletion does not affect diaphragm adaptations to voluntary wheel running in young or aged mice. Satellite cell depletion early in life (4 months of age) has minimal effect on diaphragm phenotype by old age (24 months). Prolonged satellite cell depletion in the diaphragm does not result in excessive extracellular matrix accumulation, in contrast to what has been reported in hind limb muscles. Up-regulation of Pax3 mRNA+ cells after satellite cell depletion in young and aged mice suggests that Pax3+ cells may compensate for a loss of Pax7+ satellite cells in the diaphragm. Future investigations should focus on the role of Pax3+ cells in the diaphragm during adaptation to exercise and ageing. Satellite cell contribution to unstressed diaphragm is higher compared to hind limb muscles, which is probably attributable to constant activation of this muscle to drive ventilation. Whether satellite cell depletion negatively impacts diaphragm quantitative and qualitative characteristics under stressed conditions in young and aged mice is unknown. We therefore challenged the diaphragm with prolonged running activity in the presence and absence of Pax7+ satellite cells in young and aged mice using an inducible Pax7 CreER -R26R DTA model. Mice were vehicle (Veh, satellite cell-replete) or tamoxifen (Tam, satellite cell-depleted) treated at 4 months of age and were then allowed to run voluntarily at 6 months (young) and 22 months (aged). Age-matched, cage-dwelling, Veh- and Tam-treated mice without wheel access served as activity controls. Diaphragm muscles were analysed from young (8 months) and aged (24 months) mice. Satellite cell depletion did not alter diaphragm mean fibre cross-sectional area, fibre type distribution or extracellular matrix content in young or aged mice, regardless of running activity. Resting in vivo diaphragm function was also unaffected by satellite cell depletion. Myonuclear density was maintained in young satellite cell

  4. Prenatal Exposure to Unconventional Oil and Gas Operation Chemical Mixtures Altered Mammary Gland Development in Adult Female Mice.

    Science.gov (United States)

    Sapouckey, Sarah A; Kassotis, Christopher D; Nagel, Susan C; Vandenberg, Laura N

    2018-03-01

    Unconventional oil and gas (UOG) operations, which combine hydraulic fracturing (fracking) and directional drilling, involve the use of hundreds of chemicals, including many with endocrine-disrupting properties. Two previous studies examined mice exposed during early development to a 23-chemical mixture of UOG compounds (UOG-MIX) commonly used or produced in the process. Both male and female offspring exposed prenatally to one or more doses of UOG-MIX displayed alterations to endocrine organ function and serum hormone concentrations. We hypothesized that prenatal UOG-MIX exposure would similarly disrupt development of the mouse mammary gland. Female C57Bl/6 mice were exposed to ~3, ~30, ~ 300, or ~3000 μg/kg/d UOG-MIX from gestational day 11 to birth. Although no effects were observed on the mammary glands of these females before puberty, in early adulthood, females exposed to 300 or 3000 μg/kg/d UOG-MIX developed more dense mammary epithelial ducts; females exposed to 3 μg/kg/d UOG-MIX had an altered ratio of apoptosis to proliferation in the mammary epithelium. Furthermore, adult females from all UOG-MIX-treated groups developed intraductal hyperplasia that resembled terminal end buds (i.e., highly proliferative structures typically seen at puberty). These results suggest that the mammary gland is sensitive to mixtures of chemicals used in UOG production at exposure levels that are environmentally relevant. The effect of these findings on the long-term health of the mammary gland, including its lactational capacity and its risk of cancer, should be evaluated in future studies. Copyright © 2018 Endocrine Society.

  5. IDH2 Deficiency Aggravates Fructose-Induced NAFLD by Modulating Hepatic Fatty Acid Metabolism and Activating Inflammatory Signaling in Female Mice

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    Jeong Hoon Pan

    2018-05-01

    Full Text Available Fructose is a strong risk factor for non-alcoholic fatty liver disease (NAFLD, resulting from the disruption of redox systems by excessive reactive oxygen species production in the liver cells. Of note, recent epidemiological studies indicated that women are more prone to developing metabolic syndrome in response to fructose-sweetened beverages. Hence, we examined whether disruption of the redox system through a deletion of NADPH supplying mitochondrial enzyme, NADP+-dependent isocitrate dehydrogenase (IDH2, exacerbates fructose-induced NAFLD conditions in C57BL/6 female mice. Wild-type (WT and IDH2 knockout (KO mice were treated with either water or 34% fructose water over six weeks. NAFLD phenotypes and key proteins and mRNAs involved in the inflammatory pathway (e.g., NF-κB p65 and IL-1β were assessed. Hepatic lipid accumulation was significantly increased in IDH2 KO mice fed fructose compared to the WT counterpart. Neutrophil infiltration was observed only in IDH2 KO mice fed fructose. Furthermore, phosphorylation of NF-κB p65 and expression of IL-1β was remarkably upregulated in IDH2 KO mice fed fructose, and expression of IκBα was decreased by fructose treatment in both WT and IDH2 KO groups. For the first time, we report our novel findings that IDH2 KO female mice may be more susceptible to fructose-induced NAFLD and the associated inflammatory response, suggesting a mechanistic role of IDH2 in metabolic diseases.

  6. Osteoporosis: knowledge and practices among females of reproductive age group

    International Nuclear Information System (INIS)

    Idrees, Z.; Zakir, U.; Khushdil, A.; Shehzadi, H.

    2017-01-01

    To assess the knowledge of osteoporosis and evaluation of the practice of osteoporosis preventive measures, among females of reproductive age group. Methodology: A cross-sectional questionnaire based study was undertaken from September 2015 to February 2016 on 174 females (age range 15-49 years) from Military Hospital and Combined Military Hospital, Rawalpindi, Pakistan through non- probability convenient sampling. Females with any metabolic, muscular or diagnosed bone disease were excluded from the study. The self -administered questionnaire consisted of questions regarding basic demographics, knowledge and practice of preventive factors related to osteoporosis. Result: Majority (86.8%) females knew about osteoporosis. 80% considered major risk factor to be low calcium intake. Regarding practices, 44.3% of women practiced daily intake of milk in their diet, 69.5 % females practiced physical activity like walking on daily basis and 65.5% have direct exposure of sunlight but only 12.1% of women used calcium supplements. Conclusion: The study revealed that majority of the women knew about osteoporosis and its risk factors but many of them were not practicing appropriate lifestyle and dietary habits to decrease their risk of osteoporosis. Thus, there is a need of standardized approach to promote healthy behaviors to decrease the risk of osteoporosis before menopause. (author)

  7. Taurine increases hippocampal neurogenesis in aging mice

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    Elias Gebara

    2015-05-01

    Full Text Available Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors. Taurine had a direct effect on stem/progenitor cells proliferation, as observed in vitro, and also reduced activated microglia. Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis. Together, these results show that taurine increases several steps of adult neurogenesis and support a beneficial role of taurine on hippocampal neurogenesis in the context of brain aging.

  8. Effects of age and sex on 125I-β-CIT binding to DAT

    International Nuclear Information System (INIS)

    Liu Xingdang; Lin Xiangtong

    2000-01-01

    Objective: To investigate effects of age and sex on 125 I-β-CIT binding to dopamine transporter (DAT). Methods: Detection of the differences in 125 I-β-CIT binding kinetics in vivo between 6 week and 6 month old KM mice, and the differences of in vivo binding between female and male, and between 3 month and 12 month old SD rats.The animals were sacrificed 2 h after injection. Results: Uptake of 125 I-β-CIT in the striatum, frontal cortex, parietal cortex, temporal cortex, occipital cortex, hippocampus, brain stem and whole brain in 6 week old mice was higher than that in 6 month old mice, and similar uptake pattern happened in between 3 month old and in 12 month old SD rats. In 12 months old SD rats, female rats had higher uptake in the striatum than male rats did. Conclusions: Young mice and rats have a higher uptake of 125 I-β-CIT in the striatum than aged ones and female rats have a higher uptake than male ones do. This result indicates that the density of DAT in rat or mouse striatum may be reduced with aging

  9. Resuscitation outcomes of reproductive-age females who experienced out-of-hospital cardiac arrest.

    Science.gov (United States)

    Hagihara, Akihito; Onozuka, Daisuke; Hasegawa, Manabu; Nagata, Takashi; Abe, Takeru; Nabeshima, Yoshihiro

    2017-03-01

    Although some studies have shown that women in their reproductive years have better resuscitation outcomes of out-of-hospital cardiac arrest (OHCA), conflicting results and methodological problems have also been noted. Thus, we evaluated the resuscitation outcomes of OHCA of females by age. This was a prospective observational study using registry data from all OHCA cases between 2005 and 2012 in Japan. The subjects were females aged 18-110 years who suffered an out-of-hospital cardiac arrest. Logistic regression analyses were performed using total and propensity-matched patients. There were 381,123 OHCA cases that met the inclusion criteria. Among propensity-matched patients, females aged 18-49 and 50-60 years of age had similar rates of return of spontaneous circulation before hospital arrival and 1-month survival (all p>0.60). In contrast, females aged 18-49 years of age had significantly lower rates of 1-month survival with minimal neurological impairment than did females aged 50-60 years of age (after adjusting for selected variables: Cerebral Performance Category scale 1 or 2 (CPC (1, 2)), OR=0.45, p=0.020; Overall Performance Category scale 1 or 2 (OPC (1, 2)): OR=0.42, p= 0.014; after adjustment for all variables: CPC (1, 2), OR=0.27, p= 0.008; OPC (1, 2), OR=0.29, p=0.009). Women of reproductive age did not show improved resuscitation outcomes in OHCA. Additionally, women in their reproductive years showed worse neurological outcomes one month after the event, which may be explained by the negative effects of estrogen. These findings need to be verified in further studies.

  10. Effects of tritiated water on mice liver, in relation to age

    Energy Technology Data Exchange (ETDEWEB)

    Bhatia, A L [Rajasthan Univ., Jaipur (India). Radiation Biology Lab.

    1978-06-01

    Tritiated water was administered intraperitoneally at the dose rate of about 20 ..mu..Ci/ml of body water to different six age groups of Swiss albino mice, ranging from 1 to 6 weeks old. They were autopsied at 48 hours post-injection. The liver of 5 weeks old mice is found most vulnerable and that of 4 weeks second but lesser than 5 weeks. Histopathologically, 1, 2, 3 and 6 weeks old mice liver showed lesser degree of damage. The distinct histopathological lesions include oedema, cytoplasmic vacuolation and degranulation, hyperaemia, increase number of Kupffer's cells etc.

  11. Protective effects of lemongrass (Cymbopogon citratus STAPF) essential oil on DNA damage and carcinogenesis in female Balb/C mice.

    Science.gov (United States)

    Bidinotto, Lucas T; Costa, Celso A R A; Salvadori, Daisy M F; Costa, Mirtes; Rodrigues, Maria A M; Barbisan, Luís F

    2011-08-01

    This study investigated the protective effect of oral treatment with lemongrass (Cymbopogon citratus STAPF) essential oil (LGEO) on leukocyte DNA damage induced by N-methyl-N-nitrosurea (MNU). Also, the anticarcinogenic activity of LGEO was investigated in a multi-organ carcinogenesis bioassay induced by 7,12-dimethylbenz(a)antracene, 1,2-dimethylhydrazine and N-butyl-N-(4-hydroxibuthyl)nitrosamine in Balb/C female Balb/c mice (DDB-initiated mice). In the short-term study, the animals were allocated into three groups: vehicle group (negative control), MNU group (positive control) and LGEO 500 mg kg⁻¹ (five times per week for 5 weeks) plus MNU group (test group). Blood samples were collected to analyze leukocyte DNA damage by comet assay 4 h after each MNU application at the end of weeks 3 and 5. The LGEO 500 mg kg⁻¹ treated group showed significantly lower (P lemongrass essential oil provided protective action against MNU-induced DNA damage and a potential anticarcinogenic activity against mammary carcinogenesis in DDB-initiated female Balb/C mice. Copyright © 2010 John Wiley & Sons, Ltd.

  12. Wolf (Canis lupus) generation time and proportion of current breeding females by age

    Science.gov (United States)

    Mech, L. David; Barber-Meyer, Shannon M.; Erb, John

    2016-01-01

    Information is sparse about aspects of female wolf (Canis lupus) breeding in the wild, including age of first reproduction, mean age of primiparity, generation time, and proportion of each age that breeds in any given year. We studied these subjects in 86 wolves (113 captures) in the Superior National Forest (SNF), Minnesota (MN), during 1972–2013 where wolves were legally protected for most of the period, and in 159 harvested wolves from throughout MN wolf range during 2012–2014. Breeding status of SNF wolves were assessed via nipple measurements, and wolves from throughout MN wolf range, by placental scars. In the SNF, proportions of currently breeding females (those breeding in the year sampled) ranged from 19% at age 2 to 80% at age 5, and from throughout wolf range, from 33% at age 2 to 100% at age 7. Excluding pups and yearlings, only 33% to 36% of SNF females and 58% of females from throughout MN wolf range bred in any given year. Generation time for SNF wolves was 4.3 years and for MN wolf range, 4.7 years. These findings will be useful in modeling wolf population dynamics and in wolf genetic and dog-domestication studies.

  13. Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan

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    Nicole M. Templeman

    2017-07-01

    Full Text Available The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1 signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2+/− mice to Ins2+/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2+/− mice. Halving Ins2 lowered circulating insulin by 25%–34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan.

  14. Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan.

    Science.gov (United States)

    Templeman, Nicole M; Flibotte, Stephane; Chik, Jenny H L; Sinha, Sunita; Lim, Gareth E; Foster, Leonard J; Nislow, Corey; Johnson, James D

    2017-07-11

    The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2 +/- mice to Ins2 +/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2 +/- mice. Halving Ins2 lowered circulating insulin by 25%-34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  15. Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice.

    Science.gov (United States)

    Mineur, Yann S; Bentham, Matthew P; Zhou, Wen-Liang; Plantenga, Margreet E; McKee, Sherry A; Picciotto, Marina R

    2015-10-01

    The a2A-noradrenergic agonist guanfacine can decreases stress-induced smoking in female, but not male, human smokers. It is not known whether these effects are due to effects on mood regulation and/or result from nicotinic-cholinergic interactions. The objective of the study was to determine whether there are sex differences in the effect of guanfacine in tests of anxiolytic and antidepressant efficacy in mice at baseline and in a hypercholinergic model of depression induced by the acetylcholinesterase inhibitor physostigmine. The effects of guanfacine were measured in the light/dark box, tail suspension, and the forced swim test in female and male C57BL/6J mice. In parallel, electrophysiological properties were evaluated in the prefrontal cortex, a critical brain region involved in stress responses. c-fos immunoreactivity was measured in other brain regions known to regulate mood. Despite a baseline sex difference in behavior in the forced swim test (female mice were more immobile), guanfacine had similar, dose-dependent, antidepressant-like effects in mice of both sexes (optimal dose, 0.15 mg/kg). An antidepressant-like effect of guanfacine was also observed following pre-treatment with physostigmine. A sex difference in the paired-pulse ratio in the prefrontal cortex (PFC) (male, 1.4; female, 2.1) was observed at baseline that was normalized by guanfacine. Other brain areas involved in cholinergic control of depression-like behaviors, including the basolateral amygdala and lateral septum, showed sex-specific changes in c-fos expression. Guanfacine has a robust antidepressant-like effect and can reverse a depression-like state induced by increased acetylcholine (ACh) signaling. These data suggest that different brain areas are recruited in female and male mice, despite similar behavioral responses to guanfacine.

  16. The male sex pheromone darcin stimulates hippocampal neurogenesis and cell proliferation in the subventricular zone in female mice

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    Emma eHoffman

    2015-04-01

    Full Text Available The integration of newly generated neurons persists throughout life in the mammalian olfactory bulb and hippocampus, regions involved in olfactory and spatial learning. Social cues can be potent stimuli for increasing adult neurogenesis; for example, odors from dominant but not subordinate male mice increase neurogenesis in both brain regions of adult females. However, little is known about the role of neurogenesis in social recognition or the assessment of potential mates. Dominant male mice scent-mark territories using urine that contains a number of pheromones including darcin (MUP20, a male-specific major urinary protein that stimulates rapid learned attraction to the spatial location and individual odor signature of the scent owner. Here we investigate whether exposure to darcin stimulates neurogenesis in the female brain. Hippocampal neurons and cellular proliferation in the lateral ventricles that supply neurons to the olfactory bulbs increased in females exposed for seven days to male urine containing at least 0.5µg/µl darcin. Darcin was effective whether presented alone or in the context of male urine, but other information in male urine appeared to modulate the proliferative response. When exposed to urine from wild male mice, hippocampal proliferation increased only if urine was from the same individual over seven days, suggesting that consistency of individual scent signatures is important. While seven days exposure to male scent initiated the first stages of increased neurogenesis, this caused no immediate increase in female attraction to the scent or in the strength or robustness of spatial learning in short-term conditioned place preference tests. The reliable and consistent stimulation of neurogenesis by a pheromone important in rapid social learning suggests that this may provide an excellent model to explore the relationship between the integration of new neurons and plasticity in spatial and olfactory learning in a socially

  17. Radiosensitivity of spermatogenous epithelium stem cells of mice of different strains and age

    International Nuclear Information System (INIS)

    Konoplyannikova, O.A.; Konoplyannikov, A.G.

    1988-01-01

    In experiments on CBA and BALB/c male mices (3 months of age) and F 1 (CBAxC57BL/6) hybrides (at the age of 3, 12, and 24 months) a difference was noted in the radiosensitivity of spermatogenous epithelium stem cells displayed by the changes in their colony-forming ability to testicular tubules 42 days following local 60 Co-γ-irradiation. The older the hybrid mice the smaller was the number of spermatogenous epithelium stem cells

  18. Resveratrol Enhances Neuroplastic Changes, Including Hippocampal Neurogenesis, and Memory in Balb/C Mice at Six Months of Age.

    Science.gov (United States)

    Torres-Pérez, Mario; Tellez-Ballesteros, Ruth Ivonne; Ortiz-López, Leonardo; Ichwan, Muhammad; Vega-Rivera, Nelly Maritza; Castro-García, Mario; Gómez-Sánchez, Ariadna; Kempermann, Gerd; Ramirez-Rodriguez, Gerardo Bernabe

    2015-01-01

    Resveratrol (RVTL) is a flavonoid found in red wine and has been publicized heavily as an anti-aging compound. Indeed, basic research confirms that although there is much hype in the promotion of RVTL, flavonoids such as RVTL have a wide range of biological effects. We here investigated the effects of RVTL treatment on hippocampal plasticity and memory performance in female Balb/C mice, a strain with low baseline levels of adult neurogenesis. Two weeks of treatment with RVTL (40 mg/kg) induced the production of new neurons in vivo by increasing cell survival and possibly precursor cell proliferation. In addition, RVTL decreased the number of apoptotic cells. The number of doublecortin (DCX)-expressing intermediate cells was increased. RVTL stimulated neuronal differentiation in vitro without effects on proliferation. In the dentate gyrus, RVTL promoted the formation and maturation of spines on granule cell dendrites. RVTL also improved performance in the step down passive avoidance test. The RVTL-treated mice showed increase in the levels of two key signaling proteins, phospho-Akt and phospho-PKC, suggesting the involvement of these signaling pathways. Our results support the vision that flavonoids such as resveratrol deserve further examination as plasticity-inducing compounds in the context of successful cognitive aging.

  19. Resveratrol Enhances Neuroplastic Changes, Including Hippocampal Neurogenesis, and Memory in Balb/C Mice at Six Months of Age.

    Directory of Open Access Journals (Sweden)

    Mario Torres-Pérez

    Full Text Available Resveratrol (RVTL is a flavonoid found in red wine and has been publicized heavily as an anti-aging compound. Indeed, basic research confirms that although there is much hype in the promotion of RVTL, flavonoids such as RVTL have a wide range of biological effects. We here investigated the effects of RVTL treatment on hippocampal plasticity and memory performance in female Balb/C mice, a strain with low baseline levels of adult neurogenesis. Two weeks of treatment with RVTL (40 mg/kg induced the production of new neurons in vivo by increasing cell survival and possibly precursor cell proliferation. In addition, RVTL decreased the number of apoptotic cells. The number of doublecortin (DCX-expressing intermediate cells was increased. RVTL stimulated neuronal differentiation in vitro without effects on proliferation. In the dentate gyrus, RVTL promoted the formation and maturation of spines on granule cell dendrites. RVTL also improved performance in the step down passive avoidance test. The RVTL-treated mice showed increase in the levels of two key signaling proteins, phospho-Akt and phospho-PKC, suggesting the involvement of these signaling pathways. Our results support the vision that flavonoids such as resveratrol deserve further examination as plasticity-inducing compounds in the context of successful cognitive aging.

  20. Administration of red ginseng ameliorates memory decline in aged mice

    OpenAIRE

    Lee, Yeonju; Oh, Seikwan

    2015-01-01

    Background: It has been known that ginseng can be applied as a potential nutraceutical for memory impairment; however, experiments with animals of old age are few. Methods: To determine the memory enhancing effect of red ginseng, C57BL/6 mice (21 mo old) were given experimental diet pellets containing 0.12% red ginseng extract (approximately 200 mg/kg/d) for 3 mo. Young and old mice (4 mo and 21 mo old, respectively) were used as the control group. The effect of red ginseng, which ameliora...

  1. Placental passage of rose bengal 131I, its accumulation in the fetus and its distribution in the organs of the female mice

    International Nuclear Information System (INIS)

    Sudarwati, S.; Sutasurya, L.A.

    1977-01-01

    Female mice of various gestation periods were injected intraperitoneally with 0.25-0.5O ml of rose bengal 131 I with the activity between 225-250 μCi. A group was administered with Lugol's solution one day before treatment. Accumulation of radio-rose bengal in the fetuses started at the eleventh day and great increase occured at the seventeenth day of gestation till birth. Acculmulations in both fetal and female mice's thyroids could be prevented by administering Lugol's solution before treatment, and the second target of the labelled compound after the thyroid gland was liver. (author)

  2. Advanced age-related denervation and fiber-type grouping in skeletal muscle of SOD1 knockout mice.

    Science.gov (United States)

    Kostrominova, Tatiana Y

    2010-11-30

    In this study skeletal muscles from 1.5- and 10-month-old Cu/Zn superoxide dismutase (SOD1) homozygous knockout (JLSod1(-/-)) mice obtained from The Jackson Laboratory (C57Bl6/129SvEv background) were compared with muscles from age- and sex-matched heterozygous (JLSod1(+/-)) littermates. The results of this study were compared with previously published data on two different strains of Sod1(-/-) mice: one from Dr. Epstein's laboratory (ELSod1(-/-); C57Bl6 background) and the other from Cephalon, Inc. (CSod1(-/-); 129/CD-1 background). Grouping of succinate dehydrogenase-positive fibers characterized muscles of Sod1(-/-) mice from all three strains. The 10-month-old Sod1(-/-)C and JL mice displayed pronounced denervation of the gastrocnemius muscle, whereas the ELSod1(-/-) mice displayed a small degree of denervation at this age, but developed accelerated age-related denervation later on. Denervation markers were up-regulated in skeletal muscle of 10-month-old JLSod1(-/-) mice. This study is the first to show that metallothionein mRNA and protein expression was up-regulated in the skeletal muscle of 10-month-old JLSod1(-/-) mice and was mostly localized to the small atrophic muscle fibers. In conclusion, all three strains of Sod1(-/-) mice develop accelerated age-related muscle denervation, but the genetic background has significant influence on the progress of denervation. Copyright © 2010 Elsevier Inc. All rights reserved.

  3. Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice.

    Science.gov (United States)

    Palmisano, Brian T; Le, Thao D; Zhu, Lin; Lee, Yoon Kwang; Stafford, John M

    2016-08-01

    Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver β-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance β-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance β-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

  4. Hops (Humulus lupulus) Content in Beer Modulates Effects of Beer on the Liver After Acute Ingestion in Female Mice.

    Science.gov (United States)

    Landmann, Marianne; Sellmann, Cathrin; Engstler, Anna Janina; Ziegenhardt, Doreen; Jung, Finn; Brombach, Christine; Bergheim, Ina

    2017-01-01

    Using a binge-drinking mouse model, we aimed to determine whether hops (Humulus lupulus) in beer is involved in the less damaging effects of acute beer consumption on the liver in comparison with ethanol. Female C57BL/6 J mice were either fed one iso-alcoholic and iso-caloric bolus dose of ethanol, beer, beer without hops (6 g ethanol/kg body weight) or an iso-caloric bolus of maltodextrin control solution. Markers of steatosis, intestinal barrier function, activation of toll-like receptor 4 signaling cascades, lipid peroxidation and lipogenesis were determined in liver, small intestine and plasma 2 h and 12 h after acute alcohol ingestion. Alcohol-induced hepatic fat accumulation was significantly attenuated in mice fed beer whereas in those fed beer without hops, hepatic fat accumulation was similar to that found in ethanol-fed mice. While markers of intestinal barrier function e.g. portal endotoxin levels and lipogenesis only differed slightly between groups, hepatic concentrations of myeloid differentiation primary response gene 88, inducible nitric oxide synthase (iNOS) and plasminogen-activator inhibitor 1 protein as well as of 4-hydroxynonenal and 3-nitrotyrosine protein adducts were similarly elevated in livers of mice fed ethanol or beer without hops when compared with controls. Induction of these markers was markedly attenuated in mice fed hops-containing beer. Taken together, our data suggest that hops in beer markedly attenuated acute alcohol-induced liver steatosis in female mice through mechanisms involving a suppression of iNOS induction in the liver. © The Author 2016. Medical Council on Alcohol and Oxford University Press. All rights reserved.

  5. Pre-existing weakness is critical for the occurrence of postoperative cognitive dysfunction in mice of the same age.

    Directory of Open Access Journals (Sweden)

    Yujie Tang

    Full Text Available Occurrence of postoperative cognitive dysfunction (POCD is age-dependent and heterogenous. Factors deciding the occurrence of POCD in patients of the same age undergone same surgeries remain unclear. Here we investigated the effects of pre-existing weakness on the occurrence of POCD in mice of the same age. Pre-existing weakness of mice was induced by intraperitoneal injection of lipopolysaccharide (8mg/kg and was evaluated by physical frailty index (by open field test, neuroinflammation level (by Iba1 immunostaining and inflammatory factors TNF-α and IL-1β, and neuronal activity (by p-CREB immunostaining. POCD was induced by partial hepatolobectomy and was evaluated by puzzle box test and Morris water maze test. The brains were collected to detect the levels of neuroinflammation, synaptophysin and NMDA receptor subunits NR2A, NR2B and NR1 (by western blot, and oxidative stress (by Dihydroethidium. Compared to the normal adult mice of the same age, LPS pretreated mice had increased physical frailty index, higher levels of neuroinflammation, and lower neuronal activity. Partial hepatolobectomy induced obvious impairments in executive function, learning and memory in LPS pretreated mice after surgery, but not in normal mice of the same age. Partial hepatolobectomy also induced heightened neuroinflammation, obvious loss of NMDA receptor subunits, strong oxidative stress in LPS pretreated mice on the 1st and 3rd postoperative day. However, the POCD-associated pathological changes didn't occur in normal mice of the same age after surgery. These results suggest that pre-existing weakness is critical for the occurrence of POCD in mice of the same age.

  6. Blueberry supplementation improves memory in middle-aged mice fed a high-fat diet.

    Science.gov (United States)

    Carey, Amanda N; Gomes, Stacey M; Shukitt-Hale, Barbara

    2014-05-07

    Consuming a high-fat diet may result in behavioral deficits similar to those observed in aging animals. It has been demonstrated that blueberry supplementation can allay age-related behavioral deficits. To determine if supplementation of a high-fat diet with blueberries offers protection against putative high-fat diet-related declines, 9-month-old C57Bl/6 mice were maintained on low-fat (10% fat calories) or high-fat (60% fat calories) diets with and without 4% freeze-dried blueberry powder. Novel object recognition memory was impaired by the high-fat diet; after 4 months on the high-fat diet, mice spent 50% of their time on the novel object in the testing trial, performing no greater than chance performance. Blueberry supplementation prevented recognition memory deficits after 4 months on the diets, as mice on this diet spent 67% of their time on the novel object. After 5 months on the diets, mice consuming the high-fat diet passed through the platform location less often than mice on low-fat diets during probe trials on days 2 and 3 of Morris water maze testing, whereas mice consuming the high-fat blueberry diet passed through the platform location as often as mice on the low-fat diets. This study is a first step in determining if incorporating more nutrient-dense foods into a high-fat diet can allay cognitive dysfunction.

  7. Deficiency in Poly(ADP-ribose Polymerase-1 (PARP-1 Accelerates Aging and Spontaneous Carcinogenesis in Mice

    Directory of Open Access Journals (Sweden)

    Tatiana S. Piskunova

    2008-01-01

    Full Text Available Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosylation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosylation and PARP-1 may also play an important role in aging. Here we show that PARP-1−/− mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP-1−/− mice. The incidence of spontaneous tumors in both PARP-1−/− and PARP-1+/+ groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP-1−/− mice than PARP-1+/+ mice (72% and 49%, resp.; < .05. In addition, spontaneous tumors appear earlier in PARP-1−/− mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.

  8. Cigarette Smoke-Induced Cell Death Causes Persistent Olfactory Dysfunction in Aged Mice

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    Rumi Ueha

    2018-06-01

    Full Text Available Introduction: Exposure to cigarette smoke is a cause of olfactory dysfunction. We previously reported that in young mice, cigarette smoke damaged olfactory progenitors and decreased mature olfactory receptor neurons (ORNs, then, mature ORNs gradually recovered after smoking cessation. However, in aged populations, the target cells in ORNs by cigarette smoke, the underlying molecular mechanisms by which cigarette smoke impairs the regenerative ORNs, and the degree of ORN regeneration after smoking cessation remain unclear.Objectives: To explore the effects of cigarette smoke on the ORN cell system using an aged mouse model of smoking, and to investigate the extent to which smoke-induced damage to ORNs recovers following cessation of exposure to cigarette smoke in aged mice.Methods: We intranasally administered a cigarette smoke solution (CSS to 16-month-old male mice over 24 days, then examined ORN existence, cell survival, changes of inflammatory cytokines in the olfactory epithelium (OE, and olfaction using histological analyses, gene analyses and olfactory habituation/dishabituation tests.Results: CSS administration reduced the number of mature ORNs in the OE and induced olfactory dysfunction. These changes coincided with an increase in the number of apoptotic cells and Tumor necrosis factor (TNF expression and a decrease in Il6 expression. Notably, the reduction in mature ORNs did not recover even on day 28 after cessation of treatment with CSS, resulting in persistent olfactory dysfunction.Conclusion: In aged mice, by increasing ORN death, CSS exposure could eventually overwhelm the regenerative capacity of the OE, resulting in continued reduction in the number of mature ORNs and olfactory dysfunction.

  9. Relationship between age at menarche and skeletal maturation stages in Taiwanese female orthodontic patients.

    Science.gov (United States)

    Lai, Eddie Hsiang-Hua; Chang, Jenny Zwei-Chieng; Jane Yao, Chung-Chen; Tsai, Shih-Jaw; Liu, Jen-Pei; Chen, Yi-Jane; Lin, Chun-Pin

    2008-07-01

    The age at menarche reflects a pubertal girl's physiologic maturity. The aims of this study were to evaluate the relationship between the age at menarche and skeletal maturation in female orthodontic patients. Hand-wrist radiographs and lateral cephalometric radiographs from 304 adolescent female subjects (age, 8-18.9 years) were selected from the files of the Department of Orthodontics, National Taiwan University Hospital (NTUH). Hand-wrist bone maturation stages were assessed using the NTUH Skeletal Maturation Index (NTUH-SMI). Cervical vertebral maturation stages (CVMS) were determined using the latest CVMS Index. Menarcheal ages were self-reported by the patients and verified by the patients' mothers. The relationships between the NTUH-SMI or CVM stages and menarcheal status were investigated. More than 90% of the 148 subjects who had already attained menstruation had skeletal maturation beyond the NTUH-SMI stage four or CVMS III. However, the subjects who had never experienced menarche mostly had skeletal maturation before NTUH-SMI stage five or CVMS IV. During the period of orthodontic treatment, 19 females experienced their menarche. The mean age at menarche for the 167 female patients in total was 11.97 years. In average, menarche occurred between NTUH-SMI stages four and five or between CVM stages III and IV. The percentage of girls with menses increased from 1.2% at age 9 to 6.6% at age 10, 39.5% at age 11, 81.4% at age 12, 97% at age 13, and 100% at age 14. Compared with the results obtained 20 years previously, we found a downward shift of 0.47 years per decade for the mean age at menarche in female orthodontic patients. The majority of female orthodontic patients have passed the pubertal growth spurt when they experience their menarche. Menarche usually follows the pubertal growth spurt by about 1 year and occurs after NTUH-SMI stage four or CVMS III.

  10. Age-graded risks for commercial sexual exploitation of male and female youth.

    Science.gov (United States)

    Reid, Joan A; Piquero, Alex R

    2014-06-01

    Emerging evidence indicates male youth are affected by commercial sexual exploitation (CSE). However, most studies investigating risk markers influencing age of onset of CSE have focused on vulnerabilities of girls and women. Using a sample of 1,354 serious youthful offenders (of whom approximately 8% of males and females reported being paid for sex), the current study assessed whether risks associated with age of onset of CSE for girls and young women operated similarly in boys and young men. Findings showed that African American male youth were at heightened risk for CSE, while female youth of all races/ethnicities were at similar risk. For all youth, maternal substance use and earlier age of first sex were associated with early age of onset of CSE. For male youth, experiencing rape and substance use dependency were associated with early age of onset. Psychotic symptoms, likely experienced as social alienation, were associated with both early and late age of onset. For all youth, lower educational attainment was associated with CSE beginning in later adolescence or young adulthood. In addition, substance use dependency was linked to late age of onset for female youth. Implications of the study findings for theory development and application to CSE are noted.

  11. Psychological stress on female mice diminishes the developmental potential of oocytes: a study using the predatory stress model.

    Directory of Open Access Journals (Sweden)

    Yu-Xiang Liu

    Full Text Available Although the predatory stress experimental protocol is considered more psychological than the restraint protocol, it has rarely been used to study the effect of psychological stress on reproduction. Few studies exist on the direct effect of psychological stress to a female on developmental competence of her oocytes, and the direct effect of predatory maternal stress on oocytes has not been reported. In this study, a predatory stress system was first established for mice with cats as predators. Beginning 24 h after injection of equine chorionic gonadotropin, female mice were subjected to predatory stress for 24 h. Evaluation of mouse responses showed that the predatory stress system that we established increased anxiety-like behaviors and plasma cortisol concentrations significantly and continuously while not affecting food and water intake of the mice. In vitro experiments showed that whereas oocyte maturation and Sr(2+ activation or fertilization were unaffected by maternal predatory stress, rate of blastocyst formation and number of cells per blastocyst decreased significantly in stressed mice compared to non-stressed controls. In vivo embryo development indicated that both the number of blastocysts recovered per donor mouse and the average number of young per recipient after embryo transfer of blastocysts with similar cell counts were significantly lower in stressed than in unstressed donor mice. It is concluded that the predatory stress system we established was both effective and durative to induce mouse stress responses. Furthermore, predatory stress applied during the oocyte pre-maturation stage significantly impaired oocyte developmental potential while exerting no measurable impact on nuclear maturation, suggesting that cytoplasmic maturation of mouse oocytes was more vulnerable to maternal stress than nuclear maturation.

  12. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

    Directory of Open Access Journals (Sweden)

    Mikael Bjursell

    Full Text Available Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1, the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

  13. Ageing Fxr deficient mice develop increased energy expenditure, improved glucose control and liver damage resembling NASH.

    Science.gov (United States)

    Bjursell, Mikael; Wedin, Marianne; Admyre, Therése; Hermansson, Majlis; Böttcher, Gerhard; Göransson, Melker; Lindén, Daniel; Bamberg, Krister; Oscarsson, Jan; Bohlooly-Y, Mohammad

    2013-01-01

    Nuclear receptor subfamily 1, group H, member 4 (Nr1h4, FXR) is a bile acid activated nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. Upon activation, the primary function is to suppress cholesterol 7 alpha-hydroxylase (Cyp7a1), the rate-limiting enzyme in the classic or neutral bile acid synthesis pathway. In the present study, a novel Fxr deficient mouse line was created and studied with respect to metabolism and liver function in ageing mice fed chow diet. The Fxr deficient mice were similar to wild type mice in terms of body weight, body composition, energy intake and expenditure as well as behaviours at a young age. However, from 15 weeks of age and onwards, the Fxr deficient mice had almost no body weight increase up to 39 weeks of age mainly because of lower body fat mass. The lower body weight gain was associated with increased energy expenditure that was not compensated by increased food intake. Fasting levels of glucose and insulin were lower and glucose tolerance was improved in old and lean Fxr deficient mice. However, the Fxr deficient mice displayed significantly increased liver weight, steatosis, hepatocyte ballooning degeneration and lobular inflammation together with elevated plasma levels of ALT, bilirubin and bile acids, findings compatible with non-alcoholic steatohepatitis (NASH) and cholestasis. In conclusion, ageing Fxr deficient mice display late onset leanness associated with elevated energy expenditure and improved glucose control but develop severe NASH-like liver pathology.

  14. The developmental neurobehavioral effects of fenugreek seeds on prenatally exposed mice.

    Science.gov (United States)

    Khalki, Loubna; Bennis, Mohamed; Sokar, Zahra; Ba-M'hamed, Saâdia

    2012-01-31

    Fenugreek (Trigonella foenum graecum (L.)), is a medicinal plant whose seeds and leaves are widely used in Moroccan traditional medicine. Consumption of fenugreek seeds during pregnancy has been associated with a range of congenital malformations, including hydrocephalus, anencephaly and spina bifida. In previous work we have shown that exposure of pregnant mice to aqueous extract of fenugreek seeds (AEFS) leads to reduced litter size, intrauterine growth retardation, and malformations. However, there have been no studies to date of its longer-term neurobehavioral effects. We investigated these effects in prenatally exposed mice. Pregnant females were exposed to 0, 500 or 1000 mg/kg/day AEFS, by gavage, for the whole period of gestation. Pups body weight was measured at 1, 7, 14, 21 and 28 day of age. Behavior of progeny was evaluated three weeks after birth using the open field, the rotarod test and the continuous alternation task by the T-maze. At 28 postnatal day age, brain of progeny was removed and cut for histological evaluation. The progeny of exposed mice displayed reduced body weight at birth (1000 mg/kg group: 27%; 500 mg/kg group: 32%) and reduced brain weight (10% in both treated groups). Both males and females mice prenatally exposed to AEFS displayed a significant decrease in the locomotor activity, in the boli deposits during the open field test and in motor coordination. These results seem to show that exposure to AEFS induces a depressive effect in the offspring. Assessment on a continuous alternation T-maze test showed a significant reduction in successful spontaneous alternations in males and females but only in the 1000 mg/kg group. These results suggest that prenatal exposure of mice to high dose of fenugreek seeds causes growth retardation and altered neurobehavioral performance in the post-weaning period in both male and female. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  15. Transgenic expression of cyclooxygenase-2 (COX2) causes premature aging phenotypes in mice.

    Science.gov (United States)

    Kim, Joohwee; Vaish, Vivek; Feng, Mingxiao; Field, Kevin; Chatzistamou, Ioulia; Shim, Minsub

    2016-10-07

    Cyclooxygenase (COX) is a key enzyme in the biosynthesis of prostanoids, lipid signaling molecules that regulate various physiological processes. COX2, one of the isoforms of COX, is highly inducible in response to a wide variety of cellular and environmental stresses. Increased COX2 expression is thought to play a role in the pathogenesis of many age-related diseases. COX2 expression is also reported to be increased in the tissues of aged humans and mice, which suggests the involvement of COX2 in the aging process. However, it is not clear whether the increased COX2 expression is causal to or a result of aging. We have now addressed this question by creating an inducible COX2 transgenic mouse model. Here we show that post-natal expression of COX2 led to a panel of aging-related phenotypes. The expression of p16, p53, and phospho-H2AX was increased in the tissues of COX2 transgenic mice. Additionally, adult mouse lung fibroblasts from COX2 transgenic mice exhibited increased expression of the senescence-associated β-galactosidase. Our study reveals that the increased COX2 expression has an impact on the aging process and suggests that modulation of COX2 and its downstream signaling may be an approach for intervention of age-related disorders.

  16. Influence of female age on blastulation rate of embryo produced by ICSI

    Directory of Open Access Journals (Sweden)

    Jonathas Borges Soares

    2003-03-01

    Full Text Available OBJECTIVES: There is a tendency to adopt prolonged culture inolder patients; however there are no conclusive results about theinfluence of age on blastulation rate. Therefore, we decided to analyzethe influence of female age on prolonged culture results. METHODS:One hundred and seven ICSI procedures performed in our centerfrom January 1999 to December 2000 were retrospectively analyzed.The blastulation rate was verified and correlated with patient age.RESULTS: In average, 2.8 blastocysts/patient were transferred. Theblastulation rate for each age group was: 180 (32% in the group 40 years. The statistical analysis demonstrated a significantdifference (p < 0.05. CONCLUSION: The percentage of embryosthat achieved the blastocyst stage was different in each age groupand this percentage dropped as patient age increased. Female agemay influence on blastulation rate of pre-embryos, observing a dropin this rate as patient age increased.

  17. Haploinsufficiency of myostatin protects against aging-related declines in muscle function and enhances the longevity of mice.

    Science.gov (United States)

    Mendias, Christopher L; Bakhurin, Konstantin I; Gumucio, Jonathan P; Shallal-Ayzin, Mark V; Davis, Carol S; Faulkner, John A

    2015-08-01

    The molecular mechanisms behind aging-related declines in muscle function are not well understood, but the growth factor myostatin (MSTN) appears to play an important role in this process. Additionally, epidemiological studies have identified a positive correlation between skeletal muscle mass and longevity. Given the role of myostatin in regulating muscle size, and the correlation between muscle mass and longevity, we tested the hypotheses that the deficiency of myostatin would protect oldest-old mice (28-30 months old) from an aging-related loss in muscle size and contractility, and would extend the maximum lifespan of mice. We found that MSTN(+/-) and MSTN(-/-) mice were protected from aging-related declines in muscle mass and contractility. While no differences were detected between MSTN(+/+) and MSTN(-/-) mice, MSTN(+/-) mice had an approximately 15% increase in maximal lifespan. These results suggest that targeting myostatin may protect against aging-related changes in skeletal muscle and contribute to enhanced longevity. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  18. Mice lacking the p43 mitochondrial T3 receptor become glucose intolerant and insulin resistant during aging.

    Directory of Open Access Journals (Sweden)

    Christelle Bertrand

    Full Text Available Thyroid hormones (TH play an important regulatory role in energy expenditure regulation and are key regulators of mitochondrial activity. We have previously identified a mitochondrial triiodothyronine (T3 receptor (p43 which acts as a mitochondrial transcription factor of the organelle genome, which leads in vitro and in vivo, to a stimulation of mitochondrial biogenesis. Recently, we generated mice carrying a specific p43 invalidation. At 2 months of age, we reported that p43 depletion in mice induced a major defect in insulin secretion both in vivo and in isolated pancreatic islets, and a loss of glucose-stimulated insulin secretion. The present study was designed to determine whether p43 invalidation influences life expectancy and modulates blood glucose and insulin levels as well as glucose tolerance or insulin sensitivity during aging. We report that from 4 months old onwards, mice lacking p43 are leaner than wild-type mice. p43-/- mice also have a moderate reduction of life expectancy compared to wild type. We found no difference in blood glucose levels, excepted at 24 months old where p43-/- mice showed a strong hyperglycemia in fasting conditions compared to controls animals. However, the loss of glucose-stimulated insulin secretion was maintained whatever the age of mice lacking p43. If up to 12 months old, glucose tolerance remained unchanged, beyond this age p43-/- mice became increasingly glucose intolerant. In addition, if up to 12 months old p43 deficient animals were more sensitive to insulin, after this age we observed a loss of this capacity, culminating in 24 months old mice with a decreased sensitivity to the hormone. In conclusion, we demonstrated that during aging the depletion of the mitochondrial T3 receptor p43 in mice progressively induced an increased glycemia in the fasted state, glucose intolerance and an insulin-resistance several features of type-2 diabetes.

  19. Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system.

    Science.gov (United States)

    Godbout, Jonathan P; Moreau, Maïté; Lestage, Jacques; Chen, Jing; Sparkman, Nathan L; O'Connor, Jason; Castanon, Nathalie; Kelley, Keith W; Dantzer, Robert; Johnson, Rodney W

    2008-09-01

    Exposure to peripheral infections may be permissive to cognitive and behavioral complications in the elderly. We have reported that peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes an exaggerated neuroinflammatory response and prolonged sickness behavior in aged BALB/c mice. Because LPS also causes depressive behavior, the purpose of this study was to determine whether aging is associated with an exacerbated depressive-like response. We confirmed that LPS (0.33 mg/kg intraperitoneal) induced a protracted sickness response in aged mice with reductions in locomotor and feeding activities 24 and 48 h postinjection, when young adults had fully recovered. When submitted to the forced swim test 24 h post-LPS, both young adult and aged mice exhibited an increased duration of immobility. However, when submitted to either the forced swim test or the tail suspension test 72 h post-LPS, an increased duration of immobility was evident only in aged mice. This prolonged depressive-like behavior in aged LPS-treated mice was associated with a more pronounced induction of peripheral and brain indoleamine 2,3-dioxygenase and a markedly higher turnover rate of brain serotonin (as measured by the ratio of 5-hydroxy-indoleacetic acid over 5-hydroxy-tryptamine) compared to young adult mice at 24 post-LPS injection. These results provide the first evidence that age-associated reactivity of the brain cytokine system could play a pathophysiological role in the increased prevalence of depression observed in the elderly.

  20. Hypothalamic-pituitary thyroid axis alterations in female mice with deletion of the neuromedin B receptor gene.

    Science.gov (United States)

    Oliveira, Karen J; Paula, Gabriela S M; Império, Guinever E; Bressane, Nina O; Magalhães, Carolina M A; Miranda-Alves, Leandro; Ortiga-Carvalho, Tania M; Pazos-Moura, Carmen C

    2014-11-01

    Neuromedin B, a peptide highly expressed at the pituitary, has been shown to act as autocrine/paracrine inhibitor of thyrotropin (TSH) release. Here we studied the thyroid axis of adult female mice lacking neuromedin B receptor (NBR-KO), compared to wild type (WT) littermates. They exhibited slight increase in serum TSH (18%), with normal pituitary expression of mRNA coding for α-glycoprotein subunit (Cga), but reduced TSH β-subunit mRNA (Tshb, 41%), lower intra-pituitary TSH content (24%) and increased thyroid hormone transporter MCT-8 (Slc16a2, 44%) and thyroid hormone receptor β mRNA expression (Thrb, 39%). NBR-KO mice exhibited normal thyroxine (T4) and reduced triiodothyronine (T3) (30%), with no alterations in the intra-thyroidal content of T4 and T3 or thyroid morphological changes. Hypothalamic thyrotropin-releasing hormone (TRH) mRNA (Trh) was increased (68%), concomitant with a reduction in type 2 deiodinase mRNA (Dio2, 30%) and no changes in MCT-8 and thyroid hormone receptor mRNA expression. NBR-KO mice exhibited a 56% higher increase in serum TSH in response to an acute single intraperitoneal injection of TRH concomitant with a non-significant increase in pituitary TRH receptor (Trhr) mRNA at basal state. The phenotype of female NBR-KO mice at the hypothalamus-pituitary axis revealed alterations in pituitary and hypothalamic gene expression, associated with reduced serum T3, and higher TSH response to TRH, with apparently normal thyroid morphology and hormonal production. Thus, results confirm that neuromedin B pathways are importantly involved in secretory pathways of TSH and revealed its participation in the in vivo regulation of gene expression of TSH β-subunit and pituitary MCT8 and Thrb and hypothalamic TRH and type 2 deiodinase. Copyright © 2014 Elsevier B.V. All rights reserved.

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

    International Nuclear Information System (INIS)

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

    1986-01-01

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1986-03-01

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

  3. Exposure to chronic variable social stress during adolescence alters affect-related behaviors and adrenocortical activity in adult male and female inbred mice.

    Science.gov (United States)

    Caruso, Michael J; Kamens, Helen M; Cavigelli, Sonia A

    2017-09-01

    Rodent models provide valuable insight into mechanisms that underlie vulnerability to adverse effects of early-life challenges. Few studies have evaluated sex differences in anxiogenic or depressogenic effects of adolescent social stress in a rodent model. Furthermore, adolescent stress studies often use genetically heterogeneous outbred rodents which can lead to variable results. The current study evaluated the effects of adolescent social stress in male and female inbred (BALB/cJ) mice. Adolescent mice were exposed to repeat cycles of alternating social isolation and social novelty for 4 weeks. Adolescent social stress increased anxiety-related behaviors in both sexes and depression-related behavior in females. Locomotion/exploratory behavior was also decreased in both sexes by stress. Previously stressed adult mice produced less basal fecal corticosteroids than controls. Overall, the novel protocol induced sex-specific changes in anxiety- and depression-related behaviors and corticoid production in inbred mice. The chronic variable social stress protocol used here may be beneficial to systematically investigate sex-specific neurobiological mechanisms underlying adolescent stress vulnerability where genetic background can be controlled. © 2017 Wiley Periodicals, Inc.

  4. Short-term Treatment of Daumone Improves Hepatic Inflammation in Aged Mice

    OpenAIRE

    Park, Jong Hee; Ha, Hunjoo

    2015-01-01

    Chronic inflammation has been proposed as one of the main molecular mechanisms of aging and age-related diseases. Although evidence in humans is limited, short-term calorie restriction (CR) has been shown to have anti-inflammatory effects in aged experimental animals. We reported on the long-term treatment of daumone, a synthetic pheromone secreted by Caenorhabditis elegans in an energy deficient environment, extends the life-span and attenuates liver injury in aged mice. The present study ex...

  5. Social isolation reduces serotonergic fiber density in the inferior colliculus of female, but not male, mice.

    Science.gov (United States)

    Keesom, Sarah M; Morningstar, Mitchell D; Sandlain, Rebecca; Wise, Bradley M; Hurley, Laura M

    2018-05-12

    Early-life experiences, including maternal deprivation and social isolation during adolescence, have a profound influence on a range of adult social behaviors. Post-weaning social isolation in rodents influences behavior in part through the alteration of neuromodulatory systems, including the serotonergic system. Of significance to social behavior, the serotonergic system richly innervates brain areas involved in vocal communication, including the auditory system. However, the influence of isolation on serotonergic input to the auditory system remains underexplored. Here, we assess whether 4 weeks of post-weaning individual housing alters serotonergic fiber density in the inferior colliculus (IC), an auditory midbrain nucleus in which serotonin alters auditory-evoked activity. Individually housed male and female mice were compared to conspecifics housed socially in groups of three. Serotonergic projections were subsequently visualized with an antibody to the serotonin transporter, which labels serotonergic fibers with relatively high selectivity. Fiber densities were estimated in the three major subregions of the IC using line-scan intensity analysis. Individually housed female mice showed a significantly reduced fiber density relative to socially housed females, which was accompanied by a lower body weight in individually housed females. In contrast, social isolation did not affect serotonergic fiber density in the IC of males. This finding suggests that sensitivity of the serotonergic system to social isolation is sex-dependent, which could be due to a sex difference in the effect of isolation on psychosocial stress. Since serotonin availability depends on social context, this finding further suggests that social isolation can alter the acute social regulation of auditory processing. Copyright © 2018. Published by Elsevier B.V.

  6. Suppressive effects of Lactobacillus casei cells, a bacterial immunostimulant, on the incidence of spontaneous thymic lymphoma in AKR mice.

    Science.gov (United States)

    Watanabe, T

    1996-06-01

    The mean survival age of female AKR/J mice was significantly prolonged, the enlargement of thymus was markedly suppressed, and the proliferation of ecotropic and recombinant murine leukemia viruses (MuLV) was markedly inhibited when 8-week-old female AKR/J mice were injected intraperitoneally (i.p.) with heat-killed Lactobacillus casei cells twice weekly for 8 weeks. In contrast, such actions of heat-killed L. casei cells were not seen in 20-week-old female AKR/J mice. The leukemogenic activity of the cell-free extract of thymus from adult female AKR/J mice in newborn female AKR/J mice was drastically reduced by i.p. treatment with heat-killed L. casei cells. The difference in adjuvant effectiveness of heat-killed L. casei cells on 8- and 20-week-old animals may be dependent on the difference in the enhancing activity of the cell-mediated immune systems between the groups induced by heat-killed L. casei cells, and, as a result, on the difference in the degree of proliferation of ecotropic and recombinant MuLV in thymus, which consequently causes thymic lymphoma.

  7. Antitumor Effect of Selenium and Modified Pectin Nano Particles and Gamma Radiation on Ehrilch Solid Tumor in Female Mice

    International Nuclear Information System (INIS)

    Mansour, S. Z.; Anis, L.M.; EI- Batal, A.I.

    2010-01-01

    Selenium nano particle (Nano- Se) is a novel Se species with novel biological activities with low toxicity. The aim of the present work was to evaluate the antitumor activity of a novel Nano- Se compound with or without gamma irradiation of female mice. Selenium size- controlled Nano-Se was prepared by a simple method by adding modified pectin to the selenious acid and ascorbic acid. The antitumor activity of Selenium and Modified Pectin Nano Particles (Se-Mp- NPs) were evaluated against Ehrilch ascites carcinoma (In vitro) and Ehrilch solid tumor model (In vivo). The antioxidant states of the novel compound were assessed measuring parameters in blood and tumor tissue of female mice. Malonaldehydoyl (MDA) end product of lipid peroxidation was evaluated in plasma and tumor tissue. Glutathione -S- transferase (GST) and cytochrome P450 (Cyto P450) were determined in tumor tissue homogenate. Tumor necrosis factor alpha (TNF- a) concentration and interleukin 10 (IL- 10) concentrations was evaluated in plasma of female mice. The effect of tumor inoculation and different treatments on liver enzymes (ALT and AST) and kidney Function (urea and creatinine) were detected in the plasma of animals. Apoptosis was shown and estimated in tumor tissue of animals histopathological of tumor in different groups of mice were examined. Ehrilch solid tumor induced a significant increase in MDA content, GSH-Px and GST activities level and in the amount of metabolites of CYP 450. Moreover, a significant decrease was observed in GSH content, SOD activity level in the tumor tissue, INF- a concentration, IL- 10 concentration in the plasma. Also, a significant alteration in kidney and liver functions was occurred as compared to control group. The results showed a significant antitumor activity of selenium and Modified Pectin Nano Particles (Se-Mp- NPs) at the concentration 2.25 μg / ml was 70%

  8. Chronic pyruvate supplementation increases exploratory activity and brain energy reserves in young and middle-aged mice

    DEFF Research Database (Denmark)

    Koivisto, Hennariikka; Leinonen, Henri; Puurula, Mari

    2016-01-01

    to brain and thereby attenuate aging- or AD-related cognitive impairment. Mice received ~800 mg/kg/day Na-pyruvate in their chow for 2-6 months. In middle-aged wild-type mice and in 6.5-month-old APP/PS1 mice, pyruvate facilitated spatial learning and increased exploration of a novel odor. However......, in passive avoidance task for fear memory, the treatment group was clearly impaired. Independent of age, long-term pyruvate increased explorative behavior, which likely explains the paradoxical impairment in passive avoidance. We also assessed pyruvate effects on body weight, muscle force, and endurance...

  9. Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17

    Science.gov (United States)

    Peychal, Stephanie E.-M.; Bilger, Andrea; Pitot, Henry C.; Drinkwater, Norman R.

    2009-01-01

    Sex hormones influence the susceptibility of inbred mice to liver cancer. C57BR/cdJ (BR) females are extremely susceptible to spontaneous and chemically induced liver tumors, in part due to a lack of protection against hepatocarcinogenesis normally offered by ovarian hormones. BR males are also moderately susceptible, and the susceptibility of both sexes of BR mice to liver tumors induced with N,N-diethylnitrosamine relative to the resistant C57BL/6J (B6) strain is caused by two loci designated Hcf1 and Hcf2 (hepatocarcinogenesis in females) located on chromosomes 17 and 1, respectively. The Hcf1 locus on chromosome 17 is the predominant modifier of liver cancer in BR mice. To validate the existence of this locus and investigate its potential interaction with Hcf2, congenic mice for each region were generated. Homozygosity for the B6.BR(D17Mit164-D17Mit2) region resulted in a 4-fold increase in liver tumor multiplicity in females and a 4.5-fold increase in males compared with B6 controls. A series of 16 recombinants covering the entire congenic region was developed to further narrow the area containing Hcf1. Susceptible heterozygous recombinants demonstrated a 3- to 7-fold effect in females and a 1.5- to 2-fold effect in males compared with B6 siblings. The effect in susceptible lines completely recapitulated the susceptibility of heterozygous full-length chromosome 17 congenics and furthermore narrowed the location of the Hcf1 locus to a single region of the chromosome from 30.05 to 35.83 Mb. PMID:19255062

  10. Impact of sex steroid ablation on viral, tumour and vaccine responses in aged mice.

    Directory of Open Access Journals (Sweden)

    Tracy S P Heng

    Full Text Available Recent evidence suggests that the decline in resistance to viral infections with age occurs predominantly as a result of a gradual loss of naïve antigen-specific T cells. As such, restoration of the naïve T cell repertoire to levels seen in young healthy adults may improve defence against infection in the aged. We have previously shown that sex steroid ablation (SSA rejuvenates the ageing thymus and increases thymic export of naïve T cells, but it remains unclear whether T cell responses are improved. Using mouse models of clinically relevant diseases, we now demonstrate that SSA increases the number of naïve T cells able to respond to antigen, thereby enhancing effector responses in aged mice. Specifically, aged mice exhibit a delay in clearing influenza A virus, which correlates with diminished specific cytotoxic activity. This is due to a decreased magnitude of response and not an intrinsic defect in effector T cell function. Upon SSA, aged mice exhibit increased T cell responsiveness that restores efficient viral clearance. We further demonstrate that SSA decreases the incidence of an inducible tumour in aged mice and can potentially increase their responsiveness to a low-dose human papillomavirus vaccine in clearing pre-formed tumours. As thymectomy abrogates the increase in T cell numbers and responsiveness following SSA, we propose that the T cell effects of SSA are dependent on thymic reactivation and subsequent replenishment of the peripheral T cell pool with newly emigrated naïve T cells. These findings have important implications for strategies to improve protection from infection and responsiveness to vaccination in the aged.

  11. Physiological and biochemical effects of 17β estradiol in aging female rat brain.

    Science.gov (United States)

    Kumar, Pardeep; Taha, Asia; Kale, R K; Cowsik, S M; Baquer, Najma Zaheer

    2011-07-01

    Aging in females and males is considered as the end of natural protection against age related diseases like osteoporosis, coronary heart disease, diabetes, Alzheimer's disease and Parkinson's disease. These changes increase during menopausal condition in females when the level of estradiol is decreased. The objective of this study was to observe the changes in activities of monoamine oxidase, glucose transporter-4 levels, membrane fluidity, lipid peroxidation levels and lipofuscin accumulation occurring in brains of female rats of 3 months (young), 12 months (adult) and 24 months (old) age groups, and to see whether these changes are restored to normal levels after exogenous administration of estradiol (0.1 μg/g body weight for 1 month). The results obtained in the present work revealed that normal aging was associated with significant increases in the activity of monoamine oxidase, lipid peroxidation levels and lipofuscin accumulation in the brains of aging female rats, and a decrease in glucose transporter-4 level and membrane fluidity. Our data showed that estradiol treatment significantly decreased monoamine oxidase activity, lipid peroxidation and lipofuscin accumulation in brain regions of aging rats, and a reversal of glucose transporter-4 levels and membrane fluidity was achieved, therefore it can be concluded from the present findings that estradiol's beneficial effects seemed to arise from its antilipofuscin, antioxidant and antilipidperoxidative effects, implying an overall anti-aging action. The results of this study will be useful for pharmacological modification of the aging process and applying new strategies for control of age related disorders. Copyright © 2011 Elsevier Inc. All rights reserved.

  12. Congenital malformations in embryos of female mice exposed to alcohol and nicotinamide

    Directory of Open Access Journals (Sweden)

    Natasha Soares Simões dos Santos

    2009-03-01

    Full Text Available Objective: To compare the incidence of congenital malformations among the offspring of female mice exposed to alcohol or alcohol plus nicotinamide. Methods: Three groups of pregnant C57BL/6J mice were studied; G1 received alcohol (5 g/kg in saline solution (20% - vol/vol; G2 received nicotinamide, 50 mg/ml associated to alcohol; and G3, only saline solution; all by intraperitoneal injection on the seventh day of pregnancy. The animals were killed in a CO2 chamber on day 18 of pregnancy. The intrauterine content was assessed and the number of complete and reabsorbed fetuses was counted. The complete fetuses had their weight and crown-rump length measured and malformations were identified. Rresults: G1 showed the highest number of malformations: micrognathia, low set ears, hypertrophic nose, scoliosis, and atrophy of the lower and upper limbs. Weight was significantly different among the groups (p = 0.0139, and in G1 it was below average as compared to G3 (p = 0.3133. As for length, the lowest values were found in G2 and G3 showed the highest ones. There was a significant difference among the groups (p = 0.0145. Cconclusions: Ethanol, when administered to pregnant mice was teratogenic. However, length of G1 fetuses was, in average, higher than that of other groups. Nicotinamide decreased the number of malformations and may be a possible protector against alcohol effects.

  13. Effect of acute beer ingestion on the liver: studies in female mice.

    Science.gov (United States)

    Kanuri, Giridhar; Wagnerberger, Sabine; Landmann, Marianne; Prigl, Eva; Hellerbrand, Claus; Bischoff, Stephan C; Bergheim, Ina

    2015-04-01

    The aim of the present study was to assess whether the effects of acute consumption of stout or pilsner beer on the liver differ from those of plain ethanol in a mouse model. Seven-week-old female C57BL/6J mice received either ethanol, stout or pilsner beer (ethanol content: 6 g/kg body weight) or isocaloric maltodextrin solution. Plasma alanine transaminase, markers of steatosis, lipogenesis, activation of the toll-like receptor-4 signaling cascade as well as lipid peroxidation and fibrogenesis in the liver were measured 12 h after acute ethanol or beer intake. Acute alcohol ingestion caused a marked ~11-fold increase in hepatic triglyceride accumulation in comparison to controls, whereas in mice exposed to stout and pilsner beer, hepatic triglyceride levels were increased only by ~6.5- and ~4-fold, respectively. mRNA expression of sterol regulatory element-binding protein 1c and fatty acid synthase in the liver did not differ between alcohol and beer groups. In contrast, expression of myeloid differentiation primary response gene 88, inducible nitric oxide synthases, but also the concentrations of 4-hydroxynonenal protein adducts, nuclear factor κB and plasminogen activator inhibitor-1 were induced in livers of ethanol treated mice but not in those exposed to the two beers. Taken together, our results suggest that acute ingestion of beer and herein especially of pilsner beer is less harmful to the liver than the ingestion of plain ethanol.

  14. Age of partners at first intercourse among Danish males and females

    DEFF Research Database (Denmark)

    Wielandt, H; Boldsen, J; Jeune, B

    1989-01-01

    In 1984-1985 a representative sample of 286 Danish women (response rate = 75.3%) and 336 Danish men (response rate = 77.8%), ages 16-20 years, was interviewed about their first sexual intercourse. A cumulative frequency function was constructed and the median age at sexual debut was estimated at 16.......8 years for both male and female. Generally the age difference between the partners at first intercourse was only a few years. However, the young women almost never reported their first sexual partner as younger than themselves. A cross-check was made of the information given by two homogeneous subsamples...... of the 47 young women and 80 young men who had their first sexual intercourse with a partner who was also a debutant. Self-reported age among the males differed significantly from the age of the first sexual partner as stated by the females in these subsamples. Therefore, there is bias in the reporting...

  15. Consequences of advanced aging on renal function in chronic hyperandrogenemic female rat model: implications for aging women with polycystic ovary syndrome.

    Science.gov (United States)

    Patil, Chetan N; Racusen, Lorraine C; Reckelhoff, Jane F

    2017-11-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine and reproductive disorder in premenopausal women, characterized by hyperandrogenemia, metabolic syndrome, and inflammation. Women who had PCOS during their reproductive years remain hyperandrogenemic after menopause. The consequence of chronic hyperandrogenemia with advanced aging has not been studied to our knowledge. We have characterized a model of hyperandrogenemia in female rats and have aged them to 22-25 months to mimic advanced aging in hyperandrogenemic women, and tested the hypothesis that chronic exposure to hyperandrogenemia with aging has a deleterious effect on renal function. Female rats were chronically implanted with dihydrotestosterone pellets (DHT 7.5 mg/90 days) that were changed every 85 days or placebo pellets, and renal function was measured by clearance methods. Aging DHT-treated females had a threefold higher level of DHT with significantly higher body weight, mean arterial pressure, left kidney weight, proteinuria, and kidney injury molecule-1 (KIM-1), than did age-matched controls. In addition, DHT-treated-old females had a 60% reduction in glomerular filtration rate, 40% reduction in renal plasma flow, and significant reduction in urinary nitrate and nitrite excretion (UNOxV), an index of nitric oxide production. Morphological examination of kidneys showed that old DHT-treated females had significant focal segmental glomerulosclerosis, global sclerosis, and interstitial fibrosis compared to controls. Thus chronic hyperandrogenemia that persists into old age in females is associated with renal injury. These data suggest that women with chronic hyperandrogenemia such as in PCOS may be at increased risk for development of chronic kidney disease with advanced age. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  16. Aldh2 knockout mice were more sensitive to DNA damage in leukocytes due to ethyl tertiary butyl ether exposure.

    Science.gov (United States)

    Weng, Zuquan; Suda, Megumi; Ohtani, Katsumi; Mei, Nan; Kawamoto, Toshihiro; Nakajima, Tamie; Wang, Rui-Sheng

    2011-01-01

    To clarify the genotoxicity of ethyl tertiary butyl ether (ETBE), a gasoline additive, male and female C57BL/6 mice of Aldh2+/+ and Aldh2-/- genotypes, aged 8 wk, were exposed to 0, 500, 1,750, or 5,000 ppm ETBE for 6 h/day, 5 d per week for 13 wk. DNA damage in leukocytes was measured by the alkaline comet assay and expressed quantitatively as Tail Intensity (TI). For male mice, TI was significantly higher in all three groups exposed to ETBE than in those without exposure within Aldh2-/- mice, whereas within Aldh2+/+ mice, TI increased only in those exposed to 5,000 ppm of ETBE as compared with mice without exposure. For female mice, a significant increase in TI values was observed in the group exposed to 5,000 ppm of ETBE as compared with those without exposure within Aldh2-/- mice; TI in Aldh2-/- mice exposed to 1,750 and 5,000 ppm was significantly higher than in Aldh2+/+ mice without exposure. TI did not significantly increase in any of the groups exposed to ETBE within female Aldh2+/+ mice. Based on the results we suggest that Aldh2-/- mice are more sensitive to DNA damage caused by ETBE than Aldh2+/+ mice and that males seem more susceptible to this effect than females.

  17. Effects of neonatal oxytocin manipulation on development of social behaviors in mice.

    Science.gov (United States)

    Mogi, Kazutaka; Ooyama, Rumi; Nagasawa, Miho; Kikusui, Takefumi

    2014-06-22

    The oxytocin (OT) neural system is thought to be involved in the underlying mechanisms that guide the development of social behaviors. In the present study, we examined the effects of neonatal oxytocin manipulation in mice. Within 24 hours after birth, pups in the treatment group randomly received an intraperitoneal injection of OT or OT antagonist (OTA), and those in the control group received a saline injection or handling only. Some of these mice underwent a test that counted the number of isolation-induced ultrasound vocalizations they made on postnatal day 6, and they were further tested for sociability at 8-9 weeks of age and for neuroendocrine stress response to novel environments at 19-20 weeks of age. Another group of mice was tested for alloparental responsiveness at 13-15 weeks of age. The OT injection affected sociability and alloparental responsiveness. In an approach/avoidance test, most of the mice made a social approach to an unfamiliar conspecific of the same sex, but females that had received a neonatal injection of 3 μg of OTA did not show this response. The neonatal OTA treatment appeared to inhibit females' sociability in a dose-dependent fashion. In a retrieving test, females that had received a neonatal injection of 3 μg of OT retrieved significantly more pups than did those that had received 3 μg of OTA, although neither of the treatments caused the females to behave significantly differently from control group females. Meanwhile, a neonatal injection of 3 μg of OTA increased the latency to retrieve pups in males. These results suggested that neonatal OT action may positively regulate alloparental responsiveness in adulthood. Considering that the organizational effects of OT have also been shown in voles and rats, the mechanism by which neonatal OT modifies the development of social behaviors appears to be common to all rodents. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Chronic exercise reduces hypothalamic transforming growth factor-β1 in middle-aged obese mice.

    Science.gov (United States)

    Silva, Vagner R R; Katashima, Carlos K; Lenhare, Luciene; Silva, Carla G B; Morari, Joseane; Camargo, Rafael L; Velloso, Licio A; Saad, Mario A; da Silva, Adelino S R; Pauli, Jose Rodrigo; Ropelle, Eduardo Rochete

    2017-08-28

    Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-β (TGF-β1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-β1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF-β1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-β1 expression and IkB-α ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-β1/IkB-α axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging.

  19. Voluntary Exercise Improves Estrous Cyclicity in Prenatally Androgenized Female Mice Despite Programming Decreased Voluntary Exercise: Implications for Polycystic Ovary Syndrome (PCOS).

    Science.gov (United States)

    Homa, Lori D; Burger, Laura L; Cuttitta, Ashley J; Michele, Daniel E; Moenter, Suzanne M

    2015-12-01

    Prenatal androgen (PNA) exposure in mice produces a phenotype resembling lean polycystic ovary syndrome. We studied effects of voluntary exercise on metabolic and reproductive parameters in PNA vs vehicle (VEH)-treated mice. Mice (8 wk of age) were housed individually and estrous cycles monitored. At 10 weeks of age, mice were divided into groups (PNA, PNA-run, VEH, VEH-run, n = 8-9/group); those in the running groups received wheels allowing voluntary running. Unexpectedly, PNA mice ran less distance than VEH mice; ovariectomy eliminated this difference. In ovary-intact mice, there was no difference in glucose tolerance, lower limb muscle fiber types, weight, or body composition among groups after 16 weeks of running, although some mitochondrial proteins were mildly up-regulated by exercise in PNA mice. Before running, estrous cycles in PNA mice were disrupted with most days in diestrus. There was no change in cycles during weeks 1-6 of running (10-15 wk of age). In contrast, from weeks 11 to 16 of running, cycles in PNA mice improved with more days in proestrus and estrus and fewer in diestrus. PNA programs reduced voluntary exercise, perhaps mediated in part by ovarian secretions. Exercise without weight loss improved estrous cycles, which if translated could be important for fertility in and counseling of lean women with polycystic ovary syndrome.

  20. Early social enrichment provided by communal nest increases resilience to depression-like behavior more in female than in male mice.

    Science.gov (United States)

    D'Andrea, Ivana; Gracci, Fiorenza; Alleva, Enrico; Branchi, Igor

    2010-12-20

    Early experiences produce persistent changes in behavior and brain function. Being reared in a communal nest (CN), consisting of a single nest where three mouse mothers keep their pups together and share care-giving behavior from birth to weaning, provides an highly stimulating social environment to the developing pup since both mother-offspring and peer-to-peer interactions are markedly increased. Here we show that being reared in a CN affects adult behavior of CD-1 mice in a gender-dependent fashion, with reduced depression-like responses in females and increased anxiety-like behavior in males. In particular, CN females showed higher sucrose preference at baseline condition, drinking more sweet solution compared to female mice reared in a standard laboratory condition (SN). In the isolation test, both SN and CN females showed a reduction in sucrose preference after exposure to isolation stress. However, after 24h, only CN females significantly recovered. Finally, in the forced swim test, compared to SN, CN females spent longer time floating, a behavioral response that in the CN model has been inversely associated with display of endophenotypes of depression. With regard to the emotional response, CN males displayed an increased anxiety-like behavior in comparison to SN, spending less time in the open arms and displaying reduced head-dippings in the elevated plus-maze test. No difference was found in females. Overall, our findings show that gender and early experiences interact in modulating adult behavior. In particular, we show that early experiences modified developmental trajectories shaping adult endophenotypes of depression more markedly in females than in males. Copyright 2010 Elsevier B.V. All rights reserved.

  1. Mathematical modelling of decline in follicle pool during female reproductive ageing.

    Science.gov (United States)

    Thilagam, Alagu

    2016-03-01

    The factors which govern the subtle links between follicle loss and mammalian female reproductive ageing remain unclear despite extensive studies undertaken to understand the critical physiological and biochemical mechanisms that underly the accelerated decline in follicle numbers in women older than 37 years. It is not certain whether there is a sole control by the ovary or whether other factors which affect ageing also intersect with the ovarian effect. There is convincing experimental evidence for an interplay of several processes that seem to influence the follicle loss-female reproductive ageing links, with specific hormones (follicle-stimulating hormone, anti-Müllerian hormone, dehydroepiandrosterone) noted to play important roles in follicular dynamics and ovarian ageing. In this work, we examine the subtle links between the rate of follicular decline with ageing and the role of hormones via a series of non-autonomous equations. Simulation results based on the time evolution of the number of ovarian follicles and biochemical changes in the ovarian environment influenced by hormone levels is compared with empirical data based on follicle loss-reproductive ageing correlation studies. © Crown copyright 2015.

  2. Protective effect of atorvastatin on d-galactose-induced aging model in mice.

    Science.gov (United States)

    Kaviani, Elham; Rahmani, Mohammadreza; Kaeidi, Ayat; Shamsizadeh, Ali; Allahtavakoli, Mohamad; Mozafari, Nazanin; Fatemi, Iman

    2017-09-15

    Atorvastatin (Ator), competitive inhibitors of 3-hydroxymethyl-3-glutaryl-coenzyme-A reductase, is a cholesterol lowering drug. Ator has been shown to have neuroprotective, antioxidant and anti-inflammatory properties making that a potential candidate for the treatment of central nervous system (CNS) disorders. Here we assessed the effect of Ator on the d-galactose (d-gal)-induced aging in mice. For this purpose, Ator (0.1 and 1mg/kg/p.o.), was administrated daily in d-gal-received (500mg/kg/p.o.) mice model of aging for six weeks. Anxiety-like behaviors and cognitive functions were evaluated by the elevated plus-maze and novel object recognition tasks, respectively. Physical power was assessed by forced swimming capacity test. Animals brains were analyzed for the superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF). We found that Ator decreases the anxiety-like behaviors in d-gal-treated mice. Also, our behavioral tests showed that Ator reverses the d-gal induced learning and memory impairment. Furthermore, we found that Ator increases the physical power of d-gal-treated mice. Our results indicated that the neuroprotective effect of Ator on d-gal induced neurotoxicity is mediated, at least in part, by an increase in the SOD and BDNF levels. The results of present study suggest that Ator could be used as a novel therapeutic strategy for the treatment of age-related conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice.

    Science.gov (United States)

    Newman, John C; Covarrubias, Anthony J; Zhao, Minghao; Yu, Xinxing; Gut, Philipp; Ng, Che-Ping; Huang, Yu; Haldar, Saptarsi; Verdin, Eric

    2017-09-05

    Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies downregulation of insulin, protein synthesis, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, upregulation of PPARα target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice. Published by Elsevier Inc.

  4. Illumination of murine gammaherpesvirus-68 cycle reveals a sexual transmission route from females to males in laboratory mice.

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    Sylvie François

    Full Text Available Transmission is a matter of life or death for pathogen lineages and can therefore be considered as the main motor of their evolution. Gammaherpesviruses are archetypal pathogenic persistent viruses which have evolved to be transmitted in presence of specific immune response. Identifying their mode of transmission and their mechanisms of immune evasion is therefore essential to develop prophylactic and therapeutic strategies against these infections. As the known human gammaherpesviruses, Epstein-Barr virus and Kaposi's Sarcoma-associated Herpesvirus are host-specific and lack a convenient in vivo infection model; related animal gammaherpesviruses, such as murine gammaherpesvirus-68 (MHV-68, are commonly used as general models of gammaherpesvirus infections in vivo. To date, it has however never been possible to monitor viral excretion or virus transmission of MHV-68 in laboratory mice population. In this study, we have used MHV-68 associated with global luciferase imaging to investigate potential excretion sites of this virus in laboratory mice. This allowed us to identify a genital excretion site of MHV-68 following intranasal infection and latency establishment in female mice. This excretion occurred at the external border of the vagina and was dependent on the presence of estrogens. However, MHV-68 vaginal excretion was not associated with vertical transmission to the litter or with horizontal transmission to female mice. In contrast, we observed efficient virus transmission to naïve males after sexual contact. In vivo imaging allowed us to show that MHV-68 firstly replicated in penis epithelium and corpus cavernosum before spreading to draining lymph nodes and spleen. All together, those results revealed the first experimental transmission model for MHV-68 in laboratory mice. In the future, this model could help us to better understand the biology of gammaherpesviruses and could also allow the development of strategies that could prevent

  5. [Effects of chrysalis oil on learning, memory and oxidative stress in D-galactose-induced ageing model of mice].

    Science.gov (United States)

    Chen, Weiping; Yang, Qiongjie; Wei, Xing

    2013-11-01

    To investigate the effects of chrysalis oil on learning, memory and oxidative stress in D-galactose-induced ageing model of mice. Mice were injected intraperitoneally with D-galactose daily and received chrysalis oil intragastrically simultaneously for 30 d. Then mice underwent space navigation test and spatial probe test, superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) activity and malondialdehyde (MDA) contents in mouse brain were measured. Compared to model group, escape latency in mice treated with 6 ml/kg*d chrysalis oil was significantly shorter (Pchrysalis oil were significantly increased (PChrysalis oil treatment (12ml/kg*d) significantly increased SOD and GSH-PX activity and reduced MDA contents in brain of D-galactose-induced aging mice. Chrysalis oil can improve the ability of learning and memory in D-galactose-induced aging mice, and inhibit peroxidation in brain tissue.

  6. Lifetime number of mates interacts with female age to determine reproductive success in female guppies.

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    Jonathan P Evans

    Full Text Available In many species, mating with multiple males confers benefits to females, but these benefits may be offset by the direct and indirect costs associated with elevated mating frequency. Although mating frequency (number of mating events is often positively associated with the degree of multiple mating (actual number of males mated, most studies have experimentally separated these effects when exploring their implications for female fitness. In this paper I describe an alternative approach using the guppy Poecilia reticulata, a livebearing freshwater fish in which females benefit directly and indirectly from mating with multiple males via consensual matings but incur direct and indirect costs of mating as a consequence of male sexual harassment. In the present study, females were experimentally assigned different numbers of mates throughout their lives in order to explore how elevated mating frequency and multiple mating combine to influence lifetime reproductive success (LRS and survival (i.e. direct components of female fitness. Under this mating design, survival and LRS were not significantly affected by mating treatment, but there was a significant interaction between brood size and reproductive cycle (a correlate of female age because females assigned to the high mating treatment produced significantly fewer offspring later in life compared to their low-mating counterparts. This negative effect of mating treatment later in life may be important in these relatively long-lived fishes, and this effect may be further exacerbated by the known cross-generational fitness costs of sexual harassment in guppies.

  7. Metabolism of Dopamine in Nucleus Accumbens Astrocytes Is Preserved in Aged Mice Exposed to MPTP

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    Brittany M. Winner

    2017-12-01

    Full Text Available Parkinson disease (PD is prevalent in elderly individuals and is characterized by selective degeneration of nigrostriatal dopamine (NSDA neurons. Interestingly, not all dopamine (DA neurons are affected equally by PD and aging, particularly mesolimbic (ML DA neurons. Here, effects of aging were examined on presynaptic DA synthesis, reuptake, metabolism and neurotoxicant susceptibility of NSDA and mesolimbic dopamine (MLDA neurons and astrocyte DA metabolism. There were no differences in phenotypic markers of DA synthesis, reuptake or metabolism in NSDA or MLDA neurons in aged mice, but MLDA neurons displayed lower DA stores. Astrocyte metabolism of DA to 3-methoxytyramine (3-MT in the striatum was decreased in aged mice, but was maintained in the nucleus accumbens. Despite diminished DA vesicular storage capacity in MLDA neurons, susceptibility to acute neurotoxicant exposure was similar in young and aged mice. These results reveal an age- and neurotoxicant-induced impairment of DA metabolic activity in astrocytes surrounding susceptible NSDA neurons as opposed to maintenance of DA metabolism in astrocytes surrounding resistant MLDA neurons, and suggest a possible therapeutic target for PD.

  8. Parvalbumin-expressing ependymal cells in rostral lateral ventricle wall adhesions contribute to aging-related ventricle stenosis in mice.

    Science.gov (United States)

    Filice, Federica; Celio, Marco R; Babalian, Alexandre; Blum, Walter; Szabolcsi, Viktoria

    2017-10-15

    Aging-associated ependymal-cell pathologies can manifest as ventricular gliosis, ventricle enlargement, or ventricle stenosis. Ventricle stenosis and fusion of the lateral ventricle (LV) walls is associated with a massive decline of the proliferative capacities of the stem cell niche in the affected subventricular zone (SVZ) in aging mice. We examined the brains of adult C57BL/6 mice and found that ependymal cells located in the adhesions of the medial and lateral walls of the rostral LVs upregulated parvalbumin (PV) and displayed reactive phenotype, similarly to injury-reactive ependymal cells. However, PV+ ependymal cells in the LV-wall adhesions, unlike injury-reactive ones, did not express glial fibrillary acidic protein. S100B+/PV+ ependymal cells found in younger mice diminished in the LV-wall adhesions throughout aging. We found that periventricular PV-immunofluorescence showed positive correlation to the grade of LV stenosis in nonaged mice (wall adhesions and LV stenosis was significantly lower in mid-aged (>10-month-old) PV-knock out (PV-KO) mice. This suggests an involvement of PV+ ependymal cells in aging-associated ventricle stenosis. Additionally, we observed a time-shift in microglial activation in the LV-wall adhesions between age-grouped PV-KO and wild-type mice, suggesting a delay in microglial activation when PV is absent from ependymal cells. Our findings implicate that compromised ependymal cells of the adhering ependymal layers upregulate PV and display phenotype shift to "reactive" ependymal cells in aging-related ventricle stenosis; moreover, they also contribute to the progression of LV-wall fusion associated with a decline of the affected SVZ-stem cell niche in aged mice. © 2017 Wiley Periodicals, Inc.

  9. Impact of short‐term, repeated water fasting on the weight of mice

    OpenAIRE

    Zahra Mishmast; Reza Rahimzadeh Oskuee; Amirali Aryan; Kamran Ghafarzadegan; Kiarash Ghazvini

    2014-01-01

    Introduction: Caloric restriction is a strategy applied for weight loss. Water fasting is a popular way for obesity treatment. However, little is known about the impact of water fasting on weight. Therefore, this study was conducted to investigate the effect of short-term, repeated water fasting on the weight of mice. Methods: In this study, the physiological effect of short-term, repeated water fasting on the weight of female mice was evaluated. At 6 weeks of age, mice were randomly assigned...

  10. Staging of Alzheimer's Pathology in Triple Transgenic Mice: A Light and Electron Microscopic Analysis

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    Kwang-Jin Oh

    2010-01-01

    , and TauP301L gene mutations, remains unclear. At 3 weeks of age, AT180, Alz50, MC1, AT8, and PHF-1 intraneuronal immunoreactivity appeared in the amygdala and hippocampus and at later ages in the cortex of 3xTg-AD mice. AT8 and PHF-1 staining was fixation dependent in young mutant mice. 6E10 staining was seen at all ages. Fluorescent immunomicroscopy revealed CA1 neurons dual stained for 6E10 and Alz50 and single Alz50 immunoreactive neurons in the subiculum at 3 weeks and continuing to 20 months. Although electron microscopy confirmed intraneuronal cytoplasmic Alz50, AT8, and 6E10 reaction product in younger 3xTg-AD mice, straight filaments appeared at 23 months of age in female mice. The present data suggest that other age-related biochemical mechanisms in addition to early intraneuronal accumulation of 6E10 and tau underlie the formation of tau filaments in 3xTg-AD mice.

  11. Pancreatic protective and hypoglycemic effects of Vitex agnus-castus L. fruit hydroalcoholic extract in D-galactose-induced aging mouse model

    OpenAIRE

    Ahangarpour, Akram; Oroojan, Ali Akbar; Khorsandi, Layasadat; Najimi, Seyedeh Asma

    2017-01-01

    D-galactose induces pancreatic disorder along with aging mouse model. Vitex agnus-castus (VAC) has potential pancreatic protective effect. Hence, this study was designed to evaluate the hypoglycemic and pancreas protective effects of VAC hydroalcoholic extract in D-galactose-induced aging female mice. In the present experimental study, 72 adult female Naval Medical Research Institute (NMRI) mice (weighing 30–35 g) were divided into 6 groups of control, VAC hydroalcoholic extract, D-galactose,...

  12. Influence of aging on the activity of mice Sca-1+CD31- cardiac stem cells.

    Science.gov (United States)

    Wu, Qiong; Zhan, Jinxi; Pu, Shiming; Qin, Liu; Li, Yun; Zhou, Zuping

    2017-01-03

    Therapeutic application of cardiac resident stem/progenitor cells (CSC/CPCs) is limited due to decline of their regenerative potential with donor age. A variety of studies have shown that the cardiac aging was the problem of the stem cells, but little is known about the impact of age on the subgroups CSC/CPCs, the relationship between subgroups CSC/CPCs ageing and age-related dysfunction. Here, we studied Sca-1+CD31- subgroups of CSCs from younger(2~3months) and older(22~24months) age mice, biological differentiation was realized using specific mediums for 14 days to induce cardiomyocyte, smooth muscle cells or endothelial cells and immunostain analysis of differentiated cell resulting were done. Proliferation and cell cycle were measured by flow cytometry assay, then used microarray to dissect variability from younger and older mice. Although the number of CSCs was higher in older mice, the advanced age significantly reduced the differentiation ability into cardiac cell lineages and the proliferation ability. Transcriptional changes in Sca-1+CD31- subgroups of CSCs during aging are related to Vitamin B6 metabolism, circadian rhythm, Tyrosine metabolism, Complement and coagulation cascades. Taking together these results indicate that Cardiac resident stem/progenitor cells have significant differences in their proliferative, pluripotency and gene profiles and those differences are age depending.

  13. Recombinant growth differentiation factor 11 influences short-term memory and enhances Sox2 expression in middle-aged mice.

    Science.gov (United States)

    Zhang, Min; Jadavji, Nafisa M; Yoo, Hyung-Suk; Smith, Patrice D

    2018-04-02

    Previous evidence suggests that a significant decline in cognitive ability begins during middle-age and continues to deteriorate with increase in age. Recent work has demonstrated the potential rejuvenation impact of growth differentiation factor-11 (GDF-11) in aged mice. We carried out experiments to evaluate the impact of a single dose of recombinant (rGDF-11) on short-term visual and spatial memory in middle-aged male mice. On the novel object recognition task, we observed middle-aged mice treated rGDF-11 showed improved performance on the novel object recognition task. However, middle-aged mice did not show increased expression of phosphorylated-Smad2/3, a downstream effector of GDF-11. We noted however that the expression of the transcription factor, Sox2 was increased within the dentate gyrus. Our data suggest that a single injection of rGDF-11 contributes to improvements in cognitive function of middle-aged animals, which may be critical in the preservation of short-term memory capacity in old age. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Data file of a deep proteome analysis of the prefrontal cortex in aged mice with progranulin deficiency or neuronal overexpression of progranulin.

    Science.gov (United States)

    Heidler, Juliana; Hardt, Stefanie; Wittig, Ilka; Tegeder, Irmgard

    2016-12-01

    Progranulin deficiency is associated with neurodegeneration in humans and in mice. The mechanisms likely involve progranulin-promoted removal of protein waste via autophagy. We performed a deep proteomic screen of the pre-frontal cortex in aged (13-15 months) female progranulin-deficient mice (GRN -/- ) and mice with inducible neuron-specific overexpression of progranulin (SLICK-GRN-OE) versus the respective control mice. Proteins were extracted and analyzed per liquid chromatography/mass spectrometry (LC/MS) on a Thermo Scientific™ Q Exactive Plus equipped with an ultra-high performance liquid chromatography unit and a Nanospray Flex Ion-Source. Full Scan MS-data were acquired using Xcalibur and raw files were analyzed using the proteomics software Max Quant. The mouse reference proteome set from uniprot (June 2015) was used to identify peptides and proteins. The DiB data file is a reduced MaxQuant output and includes peptide and protein identification, accession numbers, protein and gene names, sequence coverage and label free quantification (LFQ) values of each sample. Differences in protein expression in genotypes are presented in "Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy" (C. Altmann, S. Hardt, C. Fischer, J. Heidler, H.Y. Lim, A. Haussler, B. Albuquerque, B. Zimmer, C. Moser, C. Behrends, F. Koentgen, I. Wittig, M.H. Schmidt, A.M. Clement, T. Deller, I. Tegeder, 2016) [1].

  15. Data file of a deep proteome analysis of the prefrontal cortex in aged mice with progranulin deficiency or neuronal overexpression of progranulin

    Directory of Open Access Journals (Sweden)

    Juliana Heidler

    2016-12-01

    Full Text Available Progranulin deficiency is associated with neurodegeneration in humans and in mice. The mechanisms likely involve progranulin-promoted removal of protein waste via autophagy. We performed a deep proteomic screen of the pre-frontal cortex in aged (13–15 months female progranulin-deficient mice (GRN−/− and mice with inducible neuron-specific overexpression of progranulin (SLICK-GRN-OE versus the respective control mice. Proteins were extracted and analyzed per liquid chromatography/mass spectrometry (LC/MS on a Thermo Scientific™ Q Exactive Plus equipped with an ultra-high performance liquid chromatography unit and a Nanospray Flex Ion-Source. Full Scan MS-data were acquired using Xcalibur and raw files were analyzed using the proteomics software Max Quant. The mouse reference proteome set from uniprot (June 2015 was used to identify peptides and proteins. The DiB data file is a reduced MaxQuant output and includes peptide and protein identification, accession numbers, protein and gene names, sequence coverage and label free quantification (LFQ values of each sample. Differences in protein expression in genotypes are presented in "Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy" (C. Altmann, S. Hardt, C. Fischer, J. Heidler, H.Y. Lim, A. Haussler, B. Albuquerque, B. Zimmer, C. Moser, C. Behrends, F. Koentgen, I. Wittig, M.H. Schmidt, A.M. Clement, T. Deller, I. Tegeder, 2016 [1].

  16. Effects of Dim Light at Night on Food Intake and Body Mass in Developing Mice.

    Science.gov (United States)

    Cissé, Yasmine M; Peng, Juan; Nelson, Randy J

    2017-01-01

    Appropriately timed light is critical for circadian organization; exposure to dim light at night (dLAN) disrupts temporal organization of endogenous biological timing. Exposure to dLAN in adult mice is associated with elevated body mass and changes in metabolism putatively driven by voluntary changes in the time of food intake. We predicted that exposure of young mice to LAN could affect adult metabolic function. At 3 weeks (Experiment 1) or 5 weeks (Experiment 2) of age, mice were either maintained in standard light-dark (DARK) cycles or exposed to nightly dLAN (5 lux). In the first two experiments, food intake and locomotor activity were assessed after 4 weeks and a glucose tolerance test was administered after 6 weeks in experimental lighting conditions. In Experiment 3, tissues were collected around the clock at 6 h intervals to investigate rhythmic hepatic clock gene expression in mice exposed to dLAN from 3 or 5 weeks of age. Male and female mice exposed to dLAN beginning at 3 weeks of age displayed similar growth rates and body mass to DARK-reared offspring, despite increasing day-time food intake. Exposure to dLAN beginning at 5 weeks of age increased body mass and daytime food intake in male, but not female, mice. Consistent with the body mass phenotype, clock gene expression was unaltered in the liver. In contrast to adults, dLAN exposure during the development of the peripheral circadian system has sex- and development-dependent effects on body mass gain.

  17. Effects of Dim Light at Night on Food Intake and Body Mass in Developing Mice

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    Yasmine M. Cissé

    2017-05-01

    Full Text Available Appropriately timed light is critical for circadian organization; exposure to dim light at night (dLAN disrupts temporal organization of endogenous biological timing. Exposure to dLAN in adult mice is associated with elevated body mass and changes in metabolism putatively driven by voluntary changes in the time of food intake. We predicted that exposure of young mice to LAN could affect adult metabolic function. At 3 weeks (Experiment 1 or 5 weeks (Experiment 2 of age, mice were either maintained in standard light-dark (DARK cycles or exposed to nightly dLAN (5 lux. In the first two experiments, food intake and locomotor activity were assessed after 4 weeks and a glucose tolerance test was administered after 6 weeks in experimental lighting conditions. In Experiment 3, tissues were collected around the clock at 6 h intervals to investigate rhythmic hepatic clock gene expression in mice exposed to dLAN from 3 or 5 weeks of age. Male and female mice exposed to dLAN beginning at 3 weeks of age displayed similar growth rates and body mass to DARK-reared offspring, despite increasing day-time food intake. Exposure to dLAN beginning at 5 weeks of age increased body mass and daytime food intake in male, but not female, mice. Consistent with the body mass phenotype, clock gene expression was unaltered in the liver. In contrast to adults, dLAN exposure during the development of the peripheral circadian system has sex- and development-dependent effects on body mass gain.

  18. Chronic intermittent exposure to ayahuasca during aging does not affect memory in mice.

    Science.gov (United States)

    Correa-Netto, N F; Coelho, L S; Galfano, G S; Nishide, F; Tamura, F; Shimizu, M K; Santos, J G; Linardi, A

    2017-06-05

    The Quechua term ayahuasca refers to a beverage obtained from decoctions of the liana Banisteriopsis caapi with leaves of Psychotria viridis. The ritualistic use of ayahuasca is becoming a global phenomenon, with some individuals using this beverage throughout life, including in old age. Cognitive impairment is a common manifestation during aging. There are conflicting reports on the ability of some ayahuasca compounds to exert neuroprotective or neurotoxic effects that could improve or impair learning and memory. Animal models provide a relevant and accessible means of investigating the behavioral effects of ayahuasca without the environmental conditions associated with the ritualistic use of the beverage. In this study, we investigated the influence of chronic ayahuasca exposure throughout aging on the spatial reference and habituation memories of mice. Twenty-eight male c57bl/6 mice (6 months old) received ayahuasca or water (1.5 mL/kg, orally) twice a week for 12 months and were tested in the Morris water maze (MWM), open field and elevated plus maze (EPM) tasks before and after treatment. During aging, there was significant impairment in the evocation (but not acquisition) of spatial reference memory and in habituation to the open field. There was also a decrease in locomotor activity in the open field and EPM tests, whereas the anxiety parameters were unaltered. Ayahuasca treatment did not alter any of these parameters associated with aging. These findings indicate that chronic exposure to ayahuasca during aging did not affect memory in mice.

  19. Paternal Aging Affects Behavior in Pax6 Mutant Mice: A Gene/Environment Interaction in Understanding Neurodevelopmental Disorders.

    Science.gov (United States)

    Yoshizaki, Kaichi; Furuse, Tamio; Kimura, Ryuichi; Tucci, Valter; Kaneda, Hideki; Wakana, Shigeharu; Osumi, Noriko

    2016-01-01

    Neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD) have increased over the last few decades. These neurodevelopmental disorders are characterized by a complex etiology, which involves multiple genes and gene-environmental interactions. Various genes that control specific properties of neural development exert pivotal roles in the occurrence and severity of phenotypes associated with neurodevelopmental disorders. Moreover, paternal aging has been reported as one of the factors that contribute to the risk of ASD and ADHD. Here we report, for the first time, that paternal aging has profound effects on the onset of behavioral abnormalities in mice carrying a mutation of Pax6, a gene with neurodevelopmental regulatory functions. We adopted an in vitro fertilization approach to restrict the influence of additional factors. Comprehensive behavioral analyses were performed in Sey/+ mice (i.e., Pax6 mutant heterozygotes) born from in vitro fertilization of sperm taken from young or aged Sey/+ fathers. No body weight changes were found in the four groups, i.e., Sey/+ and wild type (WT) mice born to young or aged father. However, we found important differences in maternal separation-induced ultrasonic vocalizations of Sey/+ mice born from young father and in the level of hyperactivity of Sey/+ mice born from aged fathers in the open-field test, respectively, compared to WT littermates. Phenotypes of anxiety were observed in both genotypes born from aged fathers compared with those born from young fathers. No significant difference was found in social behavior and sensorimotor gating among the four groups. These results indicate that mice with a single genetic risk factor can develop different phenotypes depending on the paternal age. Our study advocates for serious considerations on the role of paternal aging in breeding strategies for animal studies.

  20. Paternal Aging Affects Behavior in Pax6 Mutant Mice: A Gene/Environment Interaction in Understanding Neurodevelopmental Disorders.

    Directory of Open Access Journals (Sweden)

    Kaichi Yoshizaki

    Full Text Available Neurodevelopmental disorders such as autism spectrum disorder (ASD and attention deficit and hyperactivity disorder (ADHD have increased over the last few decades. These neurodevelopmental disorders are characterized by a complex etiology, which involves multiple genes and gene-environmental interactions. Various genes that control specific properties of neural development exert pivotal roles in the occurrence and severity of phenotypes associated with neurodevelopmental disorders. Moreover, paternal aging has been reported as one of the factors that contribute to the risk of ASD and ADHD. Here we report, for the first time, that paternal aging has profound effects on the onset of behavioral abnormalities in mice carrying a mutation of Pax6, a gene with neurodevelopmental regulatory functions. We adopted an in vitro fertilization approach to restrict the influence of additional factors. Comprehensive behavioral analyses were performed in Sey/+ mice (i.e., Pax6 mutant heterozygotes born from in vitro fertilization of sperm taken from young or aged Sey/+ fathers. No body weight changes were found in the four groups, i.e., Sey/+ and wild type (WT mice born to young or aged father. However, we found important differences in maternal separation-induced ultrasonic vocalizations of Sey/+ mice born from young father and in the level of hyperactivity of Sey/+ mice born from aged fathers in the open-field test, respectively, compared to WT littermates. Phenotypes of anxiety were observed in both genotypes born from aged fathers compared with those born from young fathers. No significant difference was found in social behavior and sensorimotor gating among the four groups. These results indicate that mice with a single genetic risk factor can develop different phenotypes depending on the paternal age. Our study advocates for serious considerations on the role of paternal aging in breeding strategies for animal studies.

  1. Melanoma survival is superior in females across all tumour stages but is influenced by age.

    Science.gov (United States)

    Khosrotehrani, Kiarash; Dasgupta, Paramita; Byrom, Lisa; Youlden, Danny R; Baade, Peter D; Green, Adele C

    2015-10-01

    Among patients with invasive melanoma, females are known to have higher survival than males globally. However, this survival advantage has not been explored in thin melanomas, the most common form of the disease. In addition, it is unclear if this advantage is true across all age groups. We aimed to compare melanoma survival between males and females by clinical stage and within age groups. Melanomas from 1995 to 2008 were extracted from the Queensland Cancer Registry and the Surveillance, Epidemiology, and End Results (SEER) Program, and melanoma-specific deaths were ascertained up to 2011. Flexible parametric survival models compared survival between groups. The Queensland cohort of 28,979 patients experienced 1712 melanoma deaths and the SEER cohort of 57,402 patients included 6929 melanoma deaths. Survival rates were in favour of females across nearly all tumour stages, including thin invasive tumours in both cohorts after adjusting for demographic and clinical factors [odds ratio (OR) death female:male for stage I melanoma = 0.64 in Queensland; and OR = 0.79 in the US, both P age categories. In particular, the survival advantage was inconsistent in females with stage I melanoma aged under 60. Females with melanoma have a survival advantage over males including in stage I melanomas. However, this advantage is dependent on age at diagnosis, suggesting an underlying biological mechanism influenced by age that exists from the very early stages of the disease.

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

    Science.gov (United States)

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

    2014-03-15

    A nascent literature suggests that neonatal infection is a risk factor for the development of brain, behavior and hypothalamic-pituitary-adrenal axis which can affect anxiety- and depression-related behaviors in later life. It has been documented that neonatal infection raises the concentrations of tumor necrosis factor-alpha (TNF-α) in neonate rodents and such infections may result in neonatal brain injury, at least in part, through pro-inflammatory cytokines. In addition, previous studies have shown that TNF-α is involved in cellular differentiation, neurogenesis and programmed cell death during the development of the central nervous system. We investigated for the first time whether neonatal exposure to TNF-α can affect body weight, stress-induced corticosterone (COR), anxiety- and depression-related behaviors in adult mice. In the present study, neonatal mice were treated to recombinant mouse TNF-α (0.2, 0.4, 0.7 and 1 μg/kg) or saline on postnatal days 3 and 5, then adult male and female mice were exposed to different behavioral tests. The results indicated that neonatal TNF-α treatment reduced body weight in neonatal period in both sexes. In addition, this study presents findings indicating that high doses of TNF- increase stress-induced COR levels, anxiety- and depression-related behaviors in adult males, but increase levels of anxiety without significantly influencing depression in adult female mice [corrected]. Our findings suggest that TNF-α exposure during neonatal period can alter brain and behavior development in a dose and sex-dependent manner in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Influence of age of child on differences in life satisfaction of males and females

    OpenAIRE

    Yamamura, Eiji; Andrés, Antonio R.

    2015-01-01

    Using individual-level data for China, Korea, and Japan for 2006, this research examines how life satisfaction for married males and females in East Asian countries is influenced by the age of their children. Our results show (1) the life satisfaction of females who have a child younger than 12 years old is lower than that of females with no children. (2) The greater the marginal effect of child’s age on the life satisfaction, the more developed a nation’s economic condition.

  4. Oxytocin, vasopressin and estrogen receptor gene expression in relation to social recognition in female mice.

    Science.gov (United States)

    Clipperton-Allen, Amy E; Lee, Anna W; Reyes, Anny; Devidze, Nino; Phan, Anna; Pfaff, Donald W; Choleris, Elena

    2012-02-28

    Inter- and intra-species differences in social behavior and recognition-related hormones and receptors suggest that different distribution and/or expression patterns may relate to social recognition. We used qRT-PCR to investigate naturally occurring differences in expression of estrogen receptor-alpha (ERα), ER-beta (ERβ), progesterone receptor (PR), oxytocin (OT) and receptor, and vasopressin (AVP) and receptors in proestrous female mice. Following four 5 min exposures to the same two conspecifics, one was replaced with a novel mouse in the final trial (T5). Gene expression was examined in mice showing high (85-100%) and low (40-60%) social recognition scores (i.e., preferential novel mouse investigation in T5) in eight socially-relevant brain regions. Results supported OT and AVP involvement in social recognition, and suggest that in the medial preoptic area, increased OT and AVP mRNA, together with ERα and ERβ gene activation, relate to improved social recognition. Initial social investigation correlated with ERs, PR and OTR in the dorsolateral septum, suggesting that these receptors may modulate social interest without affecting social recognition. Finally, increased lateral amygdala gene activation in the LR mice may be associated with general learning impairments, while decreased lateral amygdala activity may indicate more efficient cognitive mechanisms in the HR mice. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Aging has small effects on initial ischemic acute kidney injury development despite changing intrarenal immunologic micromilieu in mice.

    Science.gov (United States)

    Jang, Hye Ryoun; Park, Ji Hyeon; Kwon, Ghee Young; Park, Jae Berm; Lee, Jung Eun; Kim, Dae Joong; Kim, Yoon-Goo; Kim, Sung Joo; Oh, Ha Young; Huh, Wooseong

    2016-02-15

    Inflammatory process mediated by innate and adaptive immune systems is a major pathogenic mechanism of renal ischemia-reperfusion injury (IRI). There are concerns that organ recipients may be at increased risk of developing IRI after receiving kidneys from elder donors. To reveal the effects of aging on the development of renal IRI, we compared the immunologic micromilieu of normal and postischemic kidneys from mice of three different ages (9 wk, 6 mo, and 12 mo). There was a higher number of total T cells, especially effector memory CD4/CD8 T cells, and regulatory T cells in the normal kidneys of old mice. On day 2 after IRI, the proportion of necrotic tubules and renal functional changes were comparable between groups although old mice had a higher proportion of damaged tubule compared with young mice. More T cells, but less B cells, trafficked into the postischemic kidneys of old mice. The infiltration of NK T cells was similar across the groups. Macrophages and neutrophils were comparable between groups in both normal kidneys and postischemic kidneys. The intrarenal expressions of TNF-α and VEGF were decreased in normal and postischemic kidneys of aged mice. These mixed effects of aging on lymphocytes and cytokines/chemokines were not different between the two groups of old mice. Our study demonstrates that aging alters the intrarenal micromilieu but has small effects on the development of initial renal injury after IRI. Further study investigating aging-dependent differences in the repair process of renal IRI may be required. Copyright © 2016 the American Physiological Society.

  6. Differential contributions of ApoE4 and female sex to BACE1 activity and expression mediate Aβ deposition and learning and memory in mouse models of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Xu eHou

    2015-10-01

    Full Text Available Alzheimer’s disease (AD, the most common form of dementia, disproportionately affects women in both prevalence and severity. This increased vulnerability to AD in women is strongly associated with age-related ovarian hormone loss and apolipoprotein E 4 allele (ApoE4, the most important genetic risk factor for sporadic AD. Up to date, the mechanism involved in the interaction between ApoE4 and sex/gender in AD is still unclear. This study evaluated the sex-dependent ApoE4 effects on learning and memory, Aβ deposition and potential mechanisms, using mice bearing both sporadic (ApoE4 and familial (APPSwe, PS1M146V, tauP301L; 3xTg AD risk factors and compared with sex- and age-matched 3xTg or nonTg mice. Compared to nonTg mice, transgenic mice of both sexes showed spatial learning and memory deficits in the radial arm water maze and novel arm discrimination tests at 20 months of age. However, at 10 months, only ApoE4/3xTg mice showed significant learning and memory impairment. Moreover, molecular studies of hippocampal tissue revealed significantly higher protein levels of Aβ species, β-site APP cleavage enzyme (BACE1 and Sp1, a transcription factor of BACE1, in female ApoE4/3xTg when compared with female nonTg, female 3xTg and male ApoE4/3xTg mice. Significantly increased BACE1 enzymatic activities were observed in both male and female mice carrying ApoE4; however, only the females showed significant higher BACE1 expressions. Together, these data suggest that ApoE4 allele is associated with increased BACE1 enzymatic activity, while female sex plays an important role in increasing BACE1 expression. The combination of both provides a molecular basis for high Aβ pathology and the resultant hippocampus-dependent learning and memory deficits in female ApoE4 carriers.

  7. Intake of Wild Blueberry Powder Improves Episodic-Like and Working Memory during Normal Aging in Mice.

    Science.gov (United States)

    Beracochea, Daniel; Krazem, Ali; Henkouss, Nadia; Haccard, Guillaume; Roller, Marc; Fromentin, Emilie

    2016-08-01

    The number of Americans older than 65 years old is projected to more than double in the next 40 years. Cognitive changes associated to aging can affect an adult's day-to-day functioning. Among these cognitive changes, reasoning, episodic memory, working memory, and processing speed decline gradually over time. Early memory changes include a decline in both working and episodic memory. The aim of the present study was to determine whether chronic (up to 75 days) daily administration of wild blueberry extract or a wild blueberry full spectrum powder would help prevent memory failure associated with aging in tasks involving various forms of memory. Both blueberry ingredients were used in a study comparing young mice (6 months old) to aged mice (18 months old). At this age, mice exhibit memory decline due to aging, which is exacerbated first by a loss in working and contextual (episodic-like) memory. Contextual memory (episodic-like memory) was evaluated using the contextual serial discrimination test. Working and spatial memory were evaluated using the Morris-Water maze test and the sequential alternation test. Statistical analysis was performed using an ANOVA with the Bonferroni post-hoc test. Supplementation with wild blueberry full spectrum powder and wild blueberry extract resulted in significant improvement of contextual memory, while untreated aged mice experienced a decline in such memory. Only the wild blueberry full spectrum powder significantly contributed to an improvement of spatial and working memory versus untreated aged mice. These improvements of cognitive performance may be related to brain oxidative status, acetylcholinesterase activity, neuroprotection, or attenuation of immunoreactivity. Georg Thieme Verlag KG Stuttgart · New York.

  8. Relationship Between Age at Menarche and Skeletal Maturation Stages in Taiwanese Female Orthodontic Patients

    OpenAIRE

    Lai, Eddie Hsiang-Hua; Chang, Jenny Zwei-Chieng; Yao, Chung-Chen Jane; Tsai, Shih-Jaw; Liu, Jen-Pei; Chen, Yi-Jane; Lin, Chun-Pin

    2008-01-01

    Background/Purpose: The age at menarche reflects a pubertal girl's physiologic maturity. The aims of this study were to evaluate the relationship between the age at menarche and skeletal maturation in female orthodontic patients. Methods: Hand-wrist radiographs and lateral cephalometric radiographs from 304 adolescent female subjects (age, 8–18.9 years) were selected from the files of the Department of Orthodontics, National Taiwan University Hospital (NTUH). Hand-wrist bone maturation sta...

  9. Reduction of age-associated pathology in old mice by overexpression of catalase in mitochondria.

    Science.gov (United States)

    Treuting, Piper M; Linford, Nancy J; Knoblaugh, Sue E; Emond, M J; Morton, John F; Martin, George M; Rabinovitch, Peter S; Ladiges, Warren C

    2008-08-01

    We describe the effects of mitochondrially targeted catalase (MCAT) expression on end-of-life pathology in mice using detailed semiquantitative histopathological evaluation. We previously reported that the median and maximum life spans of MCAT mice were extended relative to those of wild-type littermates. We now report that MCAT expression is associated with reduced malignant nonhematopoietic tumor burden, reduced cardiac lesions, and a trend toward reduced systemic inflammation, with no effect on hematopoietic neoplasia or glomerulonephropathy. Combined disease burden and comorbidity are also reduced, and MCAT expression is not associated with any detrimental clinical effects. The results suggest that oxidative damage is involved in aging of C57BL/6J mice via modulation of a subset of age-associated lesions. Antioxidant interventions targeting mitochondria may therefore be a viable strategy for prevention or postponement of some age-associated diseases. The variability of the MCAT effect across tissues, however, illustrates the importance of developing semiquantitative histopathology for assessment of comorbidity in life-span studies.

  10. Cells derived from young bone marrow alleviate renal aging.

    Science.gov (United States)

    Yang, Hai-Chun; Rossini, Michele; Ma, Li-Jun; Zuo, Yiqin; Ma, Ji; Fogo, Agnes B

    2011-11-01

    Bone marrow-derived stem cells may modulate renal injury, but the effects may depend on the age of the stem cells. Here we investigated whether bone marrow from young mice attenuates renal aging in old mice. We radiated female 12-mo-old 129SvJ mice and reconstituted them with bone marrow cells (BMC) from either 8-wk-old (young-to-old) or 12-mo-old (old-to-old) male mice. Transfer of young BMC resulted in markedly decreased deposition of collagen IV in the mesangium and less β-galactosidase staining, an indicator of cell senescence. These changes paralleled reduced expression of plasminogen activator inhibitor-1 (PAI-1), PDGF-B (PDGF-B), the transdifferentiation marker fibroblast-specific protein-1 (FSP-1), and senescence-associated p16 and p21. Tubulointerstitial and glomerular cells derived from the transplanted BMC did not show β-galactosidase activity, but after 6 mo, there were more FSP-1-expressing bone marrow-derived cells in old-to-old mice compared with young-to-old mice. Young-to-old mice also exhibited higher expression of the anti-aging gene Klotho and less phosphorylation of IGF-1 receptor β. Taken together, these data suggest that young bone marrow-derived cells can alleviate renal aging in old mice. Direct parenchymal reconstitution by stem cells, paracrine effects from adjacent cells, and circulating anti-aging molecules may mediate the aging of the kidney.

  11. Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner.

    Science.gov (United States)

    Sadagurski, Marianna; Cady, Gillian; Miller, Richard A

    2017-08-01

    Aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF-1 signals. Early-life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM-HET3 mice in a sex-specific way: acarbose (ACA), 17-α-estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. In this study, we examined the effect of these anti-aging drugs on neuro-inflammation in hypothalamus and hippocampus. We found that age-associated hypothalamic inflammation is reduced in males but not in females at 12 months of age by ACA and 17αE2 and at 22 months of age in NDGA-treated mice. The three drugs blocked indices of hypothalamic reactive gliosis associated with aging, such as Iba-1-positive microglia and GFAP-positive astrocytes, as well as age-associated overproduction of TNF-α. This effect was not observed in drug-treated female mice or in the hippocampus of the drug-treated animals. On the other hand, caloric restriction (CR; an intervention that extends the lifespan in both sexes) significantly reduced hypothalamic microglia and TNF-α in both sexes at 12 months of age. Together, these results suggest that the extent of drug-induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long-lived nutrient restricted or mutant mice. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  12. Dietary polyphenol supplementation prevents alterations of spatial navigation in middle-aged mice

    Directory of Open Access Journals (Sweden)

    Julien eBensalem

    2016-02-01

    Full Text Available Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB (from the Neurophenols Consortium with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal CaMKII mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of NGF mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline.

  13. Protective Effects of Flax Seed (Linum Usitatissimum) Hydroalcoholic Extract on Fetus Brain in Aged and Young Mice.

    Science.gov (United States)

    Kamali, Mahsa; Bahmanpour, Soghra

    2016-05-01

    One of the major problems of the aged women or older than 35 is getting pregnant in the late fertility life. Fertility rates begin to decline gradually at the age of 30, more so at 35, and markedly at 40. Even with fertility treatments such as in vitro fertilization, women have more difficulty in getting pregnant or may deliver abnormal fetus. The purpose of this study was to assess the effects of flax seed hydroalcoholic extract on the fetal brain of aged mice and its comparison with young mice. In this experimental study, 32 aged and 32 young mice were divided into 4 groups. Controls received no special treatment. The experimental mice groups, 3 weeks before mating, were fed with flax seed hydroalcoholic extract by oral gavages. After giving birth, the brains of the fetus were removed. Data analysis was performed by statistical test ANOVA using SPSS version 18 (P<0.05). The mean fetus brain weight of aged mother groups compared to the control group was increased significantly (P<0.05). This study showed that flax seed hydroalcoholic extract could improve fetal brain weights in the aged groups.

  14. Pax6 interacts with Iba1 and shows age-associated alterations in brain of aging mice.

    Science.gov (United States)

    Maurya, Shashank Kumar; Mishra, Rajnikant

    2017-07-01

    The Pax6, a transcriptional regulator and multifunctional protein, has been found critical for neurogenesis, neuro-degeneration, mental retardation, neuroendocrine tumors, glioblastoma and astrocytomas. The age-associated alteration in the expression of Pax6 in neuron and glia has also been observed in the immunologically privileged brain. Therefore, it is presumed that Pax6 may modulate brain immunity by activation of microglia either directly interacting with genes or proteins of microglia or indirectly though inflammation associated with neurodegeneration. This report describes evaluation of expression, co-localization and interactions of Pax6 with Ionized binding protein1 (Iba1) in brain of aging mice by Immunohistochemistry, Chromatin Immuno-precipitation (ChIP) and Co-immunoprecipitation (Co-IP), respectively. The co-localization of Pax6 with Iba1 was observed in the cerebellum, cerebral cortex, hippocampus, midbrain and olfactory lobe. The Pax6 and Iba1 also interact physically. The age-dependent alteration in their expression and co-localization were also observed in mice. Results indicate Pax6-dependent activities of Iba1 in the remodelling of microglia during immunological surveillance of the brain. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Phenotype screening for genetically deermined age-onset disorders and increased longevity in ENU-mutagenized mice

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, Dabney K [ORNL; Rinchik, Eugene M [ORNL; Moustaid-Moussa, Naima [University of Tennessee, Knoxville (UTK); Miller, Darla R [ORNL; Williams, Robert [University of Tennessee Health Science Center, Memphis; Michaud III, Edward J [ORNL; Jablonski, Monica M. [University of Tennessee Health Science Center, Memphis; Elberger, Andrea [University of Tennessee Health Science Center, Memphis; Hamre, Kristin M. [University of Tennessee Health Science Center, Memphis; Smeyne, Richard [St. Jude Children' s Research Hospital; Chesler, Elissa J [ORNL; Goldowitz, Daniel [University of Tennessee Health Science Center, Memphis

    2005-01-01

    With the goal of discovering genes that contribute to late-onset neurological and ocular disorders and also genes that extend the healthy life span in mammals, we are phenotyping mice carrying new mutations induced by the chemical N-ethyl-N-nitrosourea (ENU). The phenotyping plan includes basic behavioral, neurohistological, and vision testing in sibling cohorts of mice aged to 18 months, and then evaluation for markers of growth trajectory and stress response in these same cohorts aged up to 28 months. Statistical outliers are identified by comparison to test results of similar aged cohorts, and potential mutants are recovered for re-aging to confirm heritability of the phenotype.

  16. Sex differences in depression-like behavior after nerve injury are associated with differential changes in brain-derived neurotrophic factor levels in mice subjected to early life stress.

    Science.gov (United States)

    Nishinaka, Takashi; Kinoshita, Megumi; Nakamoto, Kazuo; Tokuyama, Shogo

    2015-04-10

    We recently demonstrated that exposure to early life stress exacerbates nerve injury-induced thermal and mechanical hypersensitivity in adult male and female mice. Accumulating evidence suggests that chronic pain causes emotional dysfunction, such as anxiety and depression. In the present study, we investigated the impact of early life stress on depression-like behavior after nerve injury in mice. In addition, we examined the expression of brain-derived neurotrophic factor (BDNF), which is known to be involved in the pathogenesis of depression. Early life stress was induced by maternal separation between 2 and 3 weeks of age combined with social isolation after weaning (MSSI). At 9 weeks of age, the sciatic nerve was partially ligated to elicit neuropathic pain. Depression-like behavior was evaluated using the forced swim test at 12 weeks of age. Tissue samples from different regions of the brain were collected at the end of maternal separation (3 weeks of age) or after the forced swim test (12 weeks of age). At 12 weeks of age, immobility time in the forced swim test was increased only in MSSI-stressed female mice with nerve injury. BDNF expression was increased in male, but not female, MSSI-stressed mice at 3 weeks of age. However, MSSI stress did not impact BDNF expression in male or female mice at 12 weeks of age. Our findings suggest that exposure to early life stress exacerbates emotional dysfunction induced by neuropathic pain in a sex-dependent manner. Changes in BDNF expression after early life stress may be associated with neuropathic pain-induced depression-like behavior in adulthood. Furthermore, sex differences in BDNF expression after exposure to early life stress may contribute to sex-specific susceptibility to neuropathic pain-induced emotional dysfunction. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  17. 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

  18. 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

  19. Maternal enrichment affects prenatal hippocampal proliferation and open-field behaviors in female offspring mice.

    Science.gov (United States)

    Maruoka, Takashi; Kodomari, Ikuko; Yamauchi, Rena; Wada, Etsuko; Wada, Keiji

    2009-04-17

    The maternal environment is thought to be important for fetal brain development. However, the effects of maternal environment are not fully understood. Here, we investigated whether enrichment of the maternal environment can influence prenatal brain development and postnatal behaviors in mice. An enriched environment is a housing condition with several objects such as a running wheel, tube and ladder, which are thought to increase sensory, cognitive and motor stimulation in rodents compared with standard housing conditions. First, we measured the number of BrdU-positive cells in the hippocampal dentate gyrus of fetuses from pregnant dams housed in an enriched environment. Our results revealed that maternal enrichment influences cell proliferation in the hippocampus of female, but not male, fetuses. Second, we used the open-field test to investigate postnatal behaviors in the offspring of dams housed in the enriched environment during pregnancy. We found that maternal enrichment significantly affects the locomotor activity and time spent in the center of the open-field in female, but not male, offspring. These results indicate that maternal enrichment influences prenatal brain development and postnatal behaviors in female offspring.

  20. Relationship between hyposalivation and oxidative stress in aging mice.

    Science.gov (United States)

    Yamauchi, Yoshitaka; Matsuno, Tomonori; Omata, Kazuhiko; Satoh, Tazuko

    2017-07-01

    The increase in oxidative stress that accompanies aging has been implicated in the abnormal advance of aging and in the onset of various systemic diseases. However, the details of what effects the increase in oxidative stress that accompanies aging has on saliva secretion are not known. In this study, naturally aging mice were used to examine the stimulated whole saliva flow rate, saliva and serum oxidative stress, antioxidant level, submandibular gland H-E staining, and immunofluorescence staining to investigate the effect of aging on the volume of saliva secretion and the relationship with oxidative stress, as well as the effect of aging on the structure of salivary gland tissue. The stimulated whole saliva flow rate decreased significantly with age. Also, oxidative stress increased significantly with age. Antioxidant levels, however, decreased significantly with age. Structural changes of the submandibular gland accompanying aging included atrophy of parenchyma cells and fatty degeneration and fibrosis of stroma, and the submandibular gland weight ratio decreased. These results suggest that oxidative stress increases with age, not just systemically but also locally in the submandibular gland, and that oxidative stress causes changes in the structure of the salivary gland and is involved in hyposalivation.

  1. ELEVATED TRANS-MAMMARY TRANSMISSION OF Toxocara canis LARVAE IN BALB/c MICE

    Directory of Open Access Journals (Sweden)

    Paula de Lima Telmo

    2015-02-01

    Full Text Available Toxocariasis is a widespread zoonosis and is considered an important worldwide public health problem. The aim of this study was to investigate the frequency of trans-mammary Toxocara canis infection in newborn BALB/c mice nursed by females experimentally infected with 1,200 eggs after delivery. After 50 days of age, the presence of larvae in different organs of the offspring was investigated. Trans-mammary infection was confirmed in 73.9% of the mice that had been nursed by infected females. These data show a high trans-mammary transmission of T. canis and confirm the significance of this transmission route in paratenic hosts.

  2. Severe but Not Moderate Vitamin B12 Deficiency Impairs Lipid Profile, Induces Adiposity, and Leads to Adverse Gestational Outcome in Female C57BL/6 Mice.

    Science.gov (United States)

    Ghosh, Shampa; Sinha, Jitendra Kumar; Putcha, Uday Kumar; Raghunath, Manchala

    2016-01-01

    Vitamin B12 deficiency is widely prevalent in women of childbearing age, especially in developing countries. In the present study, through dietary restriction, we have established mouse models of severe and moderate vitamin B12 deficiencies to elucidate the impact on body composition, biochemical parameters, and reproductive performance. Female weanling C57BL/6 mice were fed for 4 weeks: (a) control AIN-76A diet, (b) vitamin B12-restricted AIN-76A diet with pectin as dietary fiber (severe deficiency group, as pectin inhibits vitamin B12 absorption), or (c) vitamin B12-restricted AIN-76A diet with cellulose as dietary fiber (moderate deficiency group as cellulose does not interfere with vitamin B12 absorption). After confirming deficiency, the mice were mated with male colony mice and maintained on their respective diets throughout pregnancy, lactation, and thereafter till 12 weeks. Severe vitamin B12 deficiency increased body fat% significantly, induced adiposity and altered lipid profile. Pregnant dams of both the deficient groups developed anemia. Severe vitamin B12 deficiency decreased the percentage of conception and litter size, pups were small-for-gestational-age and had significantly lower body weight at birth as well as weaning. Most of the offspring born to severely deficient dams died within 24 h of birth. Stress markers and adipocytokines were elevated in severe deficiency with concomitant decrease in antioxidant defense. The results show that severe but not moderate vitamin B12 restriction had profound impact on the physiology of C57BL/6 mice. Oxidative and corticosteroid stress, inflammation and poor antioxidant defense seem to be the probable underlying mechanisms mediating the deleterious effects.

  3. Severe but not moderate vitamin B12 deficiency impairs lipid profile, induces adiposity and leads to adverse gestational outcome in female C57BL/6 mice

    Directory of Open Access Journals (Sweden)

    Shampa eGhosh

    2016-01-01

    Full Text Available Vitamin B12 deficiency is widely prevalent in women of childbearing age especially in developing countries. In the present study, through dietary restriction, we have established mouse models of severe and moderate vitamin B12 deficiencies to elucidate the impact on body composition, biochemical parameters and reproductive performance. Female weanling C57BL/6 mice were fed for four weeks, (a control AIN-76A diet, (b vitamin B12 restricted AIN-76A diet with pectin as dietary fiber (severe deficiency group, as pectin inhibits vitamin B12 absorption or (c vitamin B12 restricted AIN-76A diet with cellulose as dietary fiber (moderate deficiency group as cellulose does not interfere with vitamin B12 absorption. After confirming deficiency, the mice were mated with male colony mice and maintained on their respective diets throughout pregnancy, lactation and thereafter till 12 weeks. Severe vitamin B12 deficiency increased body fat % significantly, induced adiposity and altered lipid profile. Pregnant dams of both the deficient groups developed anemia. Severe vitamin B12 deficiency decreased the percentage of conception and litter size, pups were small-for-gestational-age and had significantly lower body weight at birth as well as weaning. Most of the offspring born to severely deficient dams died within 24 hours of birth. Stress markers and adipocytokines were elevated in severe deficiency with concomitant decrease in antioxidant defense. The results show that severe but not moderate vitamin B12 restriction had profound impact on the physiology of C57BL/6 mice. Oxidative and corticosteroid stress, inflammation and poor antioxidant defense seem to be the probable underlying mechanisms mediating the deleterious effects.

  4. Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

    Directory of Open Access Journals (Sweden)

    Christopher B Massa

    2017-08-01

    Full Text Available Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs, however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group. An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical

  5. Histologic and biochemical alterations predict pulmonary mechanical dysfunction in aging mice with chronic lung inflammation.

    Science.gov (United States)

    Massa, Christopher B; Groves, Angela M; Jaggernauth, Smita U; Laskin, Debra L; Gow, Andrew J

    2017-08-01

    Both aging and chronic inflammation produce complex structural and biochemical alterations to the lung known to impact work of breathing. Mice deficient in surfactant protein D (Sftpd) develop progressive age-related lung pathology characterized by tissue destruction/remodeling, accumulation of foamy macrophages and alteration in surfactant composition. This study proposes to relate changes in tissue structure seen in normal aging and in chronic inflammation to altered lung mechanics using a computational model. Alterations in lung function in aging and Sftpd -/- mice have been inferred from fitting simple mechanical models to respiratory impedance data (Zrs), however interpretation has been confounded by the simultaneous presence of multiple coexisting pathophysiologic processes. In contrast to the inverse modeling approach, this study uses simulation from experimental measurements to recapitulate how aging and inflammation alter Zrs. Histologic and mechanical measurements were made in C57BL6/J mice and congenic Sftpd-/- mice at 8, 27 and 80 weeks of age (n = 8/group). An anatomic computational model based on published airway morphometry was developed and Zrs was simulated between 0.5 and 20 Hz. End expiratory pressure dependent changes in airway caliber and recruitment were estimated from mechanical measurements. Tissue elements were simulated using the constant phase model of viscoelasticity. Baseline elastance distribution was estimated in 8-week-old wild type mice, and stochastically varied for each condition based on experimentally measured alteration in elastic fiber composition, alveolar geometry and surfactant composition. Weighing reduction in model error against increasing model complexity allowed for identification of essential features underlying mechanical pathology and their contribution to Zrs. Using a maximum likelihood approach, alteration in lung recruitment and diminished elastic fiber density were shown predictive of mechanical alteration at

  6. Chronic intermittent exposure to ayahuasca during aging does not affect memory in mice

    Directory of Open Access Journals (Sweden)

    N.F. Correa-Netto

    Full Text Available The Quechua term ayahuasca refers to a beverage obtained from decoctions of the liana Banisteriopsis caapi with leaves of Psychotria viridis. The ritualistic use of ayahuasca is becoming a global phenomenon, with some individuals using this beverage throughout life, including in old age. Cognitive impairment is a common manifestation during aging. There are conflicting reports on the ability of some ayahuasca compounds to exert neuroprotective or neurotoxic effects that could improve or impair learning and memory. Animal models provide a relevant and accessible means of investigating the behavioral effects of ayahuasca without the environmental conditions associated with the ritualistic use of the beverage. In this study, we investigated the influence of chronic ayahuasca exposure throughout aging on the spatial reference and habituation memories of mice. Twenty-eight male c57bl/6 mice (6 months old received ayahuasca or water (1.5 mL/kg, orally twice a week for 12 months and were tested in the Morris water maze (MWM, open field and elevated plus maze (EPM tasks before and after treatment. During aging, there was significant impairment in the evocation (but not acquisition of spatial reference memory and in habituation to the open field. There was also a decrease in locomotor activity in the open field and EPM tests, whereas the anxiety parameters were unaltered. Ayahuasca treatment did not alter any of these parameters associated with aging. These findings indicate that chronic exposure to ayahuasca during aging did not affect memory in mice.

  7. Probiotic microbes sustain youthful serum testosterone levels and testicular size in aging mice.

    Directory of Open Access Journals (Sweden)

    Theofilos Poutahidis

    Full Text Available The decline of circulating testosterone levels in aging men is associated with adverse health effects. During studies of probiotic bacteria and obesity, we discovered that male mice routinely consuming purified lactic acid bacteria originally isolated from human milk had larger testicles and increased serum testosterone levels compared to their age-matched controls. Further investigation using microscopy-assisted histomorphometry of testicular tissue showed that mice consuming Lactobacillus reuteri in their drinking water had significantly increased seminiferous tubule cross-sectional profiles and increased spermatogenesis and Leydig cell numbers per testis when compared with matched diet counterparts This showed that criteria of gonadal aging were reduced after routinely consuming a purified microbe such as L. reuteri. We tested whether these features typical of sustained reproductive fitness may be due to anti-inflammatory properties of L. reuteri, and found that testicular mass and other indicators typical of old age were similarly restored to youthful levels using systemic administration of antibodies blocking pro-inflammatory cytokine interleukin-17A. This indicated that uncontrolled host inflammatory responses contributed to the testicular atrophy phenotype in aged mice. Reduced circulating testosterone levels have been implicated in many adverse effects; dietary L. reuteri or other probiotic supplementation may provide a viable natural approach to prevention of male hypogonadism, absent the controversy and side-effects of traditional therapies, and yield practical options for management of disorders typically associated with normal aging. These novel findings suggest a potential high impact for microbe therapy in public health by imparting hormonal and gonad features of reproductive fitness typical of much younger healthy individuals.

  8. /sup 35/S induced dominant lethals in immature oocytes in mice

    Energy Technology Data Exchange (ETDEWEB)

    Satyanarayana Reddy, K; Reddy, P P; Reddi, O S [Osmania Univ., Hyderabad (India). Dept. of Genetics

    1977-03-01

    CBA female mice were injected intraperitoneally with a dose of 20..mu..Ci of sulphur-35 on 15.5 day post conception. Another group of pregnant mice injected with normal saline was kept as control. The pregnant females were allowed to litter and the mothers were separated from their offsprings 4 weeks after littering. Eight weeks after treatment i.e. at the age of 22 to 24 weeks, the treated mothers were mated with control C/sub 3/H/He males. The vaginal plugs were checked every morning and those which mated were separated. The pregnant females were killed on the 14th day of gestation. The uterine contents were examined for live and dead embryos and the ovaries for corpora lutea. The pre- and post-implantation losses and total loss were calculated in the treated females and compared with those of controls. Embryonic death was significantly higher among treated animals. The results indicated that /sup 35/S can induced dominant lethal mutations in immature oocytes.

  9. [Epidemiology of arbovirus diseases: use and value of physiologic age determination of female mosquito vectors].

    Science.gov (United States)

    Mondet, B

    1996-01-01

    The physiological age of Yellow Fever Aedes females in Africa was studied during four years, from 1988 to 1992. We used a method, according to Polovodova's method, which looks for the "yellow body" under natural light. Those yellow bodies exist in the old females, the "parous" ones, and not in the young females, the "nulliparous" ones. We present some results to illustrate the interest of studying the physiological age of mosquitoes in the epidemiology of the arboviral diseases. The transmission risk, in relation with abundance and parity rate was illustrated, in particular for Aedes africanus and Aedes luteocephalus, which is useful to compare species, or with a given species, to compare periods. The parity rate of Aedes furcifer females was studied on 6 points along a transect between a forest and a village. The rate and the abundance of the females caught on human bates are inversely proportional. The parity rate is minimum in the canopy forest (about 50%) and maximum inside a house (100%). The rains have different consequences on the species, according to the period of fall. At the beginning of the dry season, they bring about hatching, but not at the end of the dry season. Massive hatching, will occur just at the beginning of the rainy season, some weeks later. Studying the physiological age of Ae. africanus females, the number of nulliparous is not related to the rain. That means a possibility of "natural" hatching for part of the eggs. Among the female of the dry season, young females are found, which is important for the transmission capacity. The method, described herein, to determine the physiological age is perfectly applicable to the Yellow Fever vector Haemagogus janthinomys in Southern America. But for the Dengue vectors Aedes aegypti and probably Aedes albopictus, the Detinova's method seems better. Actually, it seems important to study the physiological age of the vectors Ae. aegypti and Ae. albopictus, as well as the evolution of the physiological

  10. Long-term dietary restriction up-regulates activity and expression of renal arginase II in aging mice.

    Science.gov (United States)

    Majaw, T; Sharma, R

    2017-06-01

    Arginase II is a mitochondrial enzyme that catalyses the hydrolysis of L-arginine into urea and ornithine. It is present in other extra-hepatic tissues that lack urea cycle. Therefore, it is plausible that arginase II has a physiological role other than urea cycle which includes polyamine, proline, glutamate synthesis and regulation of nitric oxide production. The high expression of arginase II in kidney, among extrahepatic tissues, might have an important role associated with kidney functions. The present study is aimed to determine the age-associated alteration in the activity and expression of arginase II in the kidney of mice of different ages. The effect of dietary restriction to modulate the agedependent changes of arginase II was also studied. Results showed that renal arginase II activity declines significantly with the progression of age (p less than 0.01 and p less than 0.001 in 6- and 18-month-old mice, respectively as compared to 2-month old mice) and is due to the reduction in its protein as well as the mRNA level (p less than 0.001 in both 6- and 18-month-old mice as compared to 2-month-old mice). Long-term dietary restriction for three months has significantly up-regulated arginase II activity and expression level in both 2- and 18-month-old mice (p less than 0.01 and p less than 0.001, respectively as compared to AL group). These findings clearly indicate that the reducing level of arginase II during aging might have an impact on the declining renal functions. This age-dependent down-regulation of arginase II in the kidney can be attenuated by dietary restriction which may help in the maintenance of such functions.

  11. The influences of age on T lymphocyte subsets in C57BL/6 mice

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    Jing Xie

    2017-01-01

    Full Text Available The aim of this study is to evaluate the age related changes of T lymphocyte subsets in C57BL/6 mice and immune function. Multi-color immunofluorescence techniques that were used to analyse relative numbers of T lymphocyte subsets include CD4+, CD8+, naive and memory CD4+ and CD8+, CD8+CD28+ T cells in peripheral blood of C57BL/6 mice from different age groups (Group I: 2 months old; Group II: 7 months old; Group III: 21 months old; Splenocytes isolated from different group mice were stimulated with Con A to evaluate the proliferative ability. Compared with group I, group II had a significant reduction in the percentage of CD4+, naive CD4+ and CD8+ T cells and an increase in the percentage of CD8+ T cells, while group III had a significant reduction in the percentage of CD4+, naive CD4+ and CD8+ T cells and increase in the percentage of CD8+, memory CD4+ and CD8+ T cells in peripheral blood. Compared with group II, group III had a significant reduction in the percentage of naive CD8+ T cells and increase in the percentage of memory CD4+ and CD8+, CD8+CD28+ T cells in peripheral blood. The T lymphocyte proliferation in vitro showed that groups II and III had a lower proliferative capacity than group I, between groups II and III, there was not a significant difference. We provide relative values for the T lymphocyte subsets in the different age groups of C57BL/6 mice. The immune system began aging at 7 months old in C57BL/6 mice under a specific pathogen free environment.

  12. A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice

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    Raquel Riquelme

    2010-06-01

    Full Text Available Insulin-like growth factor-I (IGF-I belongs to the family of insulin-related peptides that fulfils a key role during the late development of the nervous system. Human IGF1 mutations cause profound deafness, poor growth and mental retardation. Accordingly, Igf1−/− null mice are dwarfs that have low survival rates, cochlear alterations and severe sensorineural deafness. Presbycusis (age-related hearing loss is a common disorder associated with aging that causes social and cognitive problems. Aging is also associated with a decrease in circulating IGF-I levels and this reduction has been related to cognitive and brain alterations, although there is no information as yet regarding the relationship between presbycusis and IGF-I biodisponibility. Here we present a longitudinal study of wild type Igf1+/+ and null Igf1−/− mice from 2 to 12 months of age comparing the temporal progression of several parameters: hearing, brain morphology, cochlear cytoarchitecture, insulin-related factors and IGF gene expression and IGF-I serum levels. Complementary invasive and non-invasive techniques were used, including auditory brainstem-evoked response (ABR recordings and in vivo MRI brain imaging. Igf1−/− null mice presented profound deafness at all the ages studied, without any obvious worsening of hearing parameters with aging. Igf1+/+ wild type mice suffered significant age-related hearing loss, their auditory thresholds and peak I latencies augmenting as they aged, in parallel with a decrease in the circulating levels of IGF-I. Accordingly, there was an age-related spiral ganglion degeneration in wild type mice that was not evident in the Igf1 null mice. However, the Igf1−/− null mice in turn developed a prematurely aged stria vascularis reminiscent of the diabetic strial phenotype. Our data indicate that IGF-I is required for the correct development and maintenance of hearing, supporting the idea that IGF-I-based therapies could contribute to

  13. Cell lineage analysis of the mammalian female germline.

    Directory of Open Access Journals (Sweden)

    Yitzhak Reizel

    Full Text Available Fundamental aspects of embryonic and post-natal development, including maintenance of the mammalian female germline, are largely unknown. Here we employ a retrospective, phylogenetic-based method for reconstructing cell lineage trees utilizing somatic mutations accumulated in microsatellites, to study female germline dynamics in mice. Reconstructed cell lineage trees can be used to estimate lineage relationships between different cell types, as well as cell depth (number of cell divisions since the zygote. We show that, in the reconstructed mouse cell lineage trees, oocytes form clusters that are separate from hematopoietic and mesenchymal stem cells, both in young and old mice, indicating that these populations belong to distinct lineages. Furthermore, while cumulus cells sampled from different ovarian follicles are distinctly clustered on the reconstructed trees, oocytes from the left and right ovaries are not, suggesting a mixing of their progenitor pools. We also observed an increase in oocyte depth with mouse age, which can be explained either by depth-guided selection of oocytes for ovulation or by post-natal renewal. Overall, our study sheds light on substantial novel aspects of female germline preservation and development.

  14. Bone Mass and Strength are Significantly Improved in Mice Overexpressing Human WNT16 in Osteocytes.

    Science.gov (United States)

    Alam, Imranul; Reilly, Austin M; Alkhouli, Mohammed; Gerard-O'Riley, Rita L; Kasipathi, Charishma; Oakes, Dana K; Wright, Weston B; Acton, Dena; McQueen, Amie K; Patel, Bhavmik; Lim, Kyung-Eun; Robling, Alexander G; Econs, Michael J

    2017-04-01

    Recently, we demonstrated that osteoblast-specific overexpression of human WNT16 increased both cortical and trabecular bone mass and structure in mice. To further identify the cell-specific role of Wnt16 in bone homeostasis, we created transgenic (TG) mice overexpressing human WNT16 in osteocytes using Dmp1 promoter (Dmp1-hWNT16 TG) on C57BL/6 (B6) background. We analyzed bone phenotypes and serum bone biomarkers, performed gene expression analysis and measured dynamic bone histomorphometry in Dmp1-hWNT16 TG and wild-type (WT) mice. Compared to WT mice, Dmp1-hWNT16 TG mice exhibited significantly higher whole-body, spine and femoral aBMD, BMC and trabecular (BV/TV, Tb.N, and Tb.Th) and cortical (bone area and thickness) parameters in both male and female at 12 weeks of age. Femur stiffness and ultimate force were also significantly improved in the Dmp1-hWNT16 TG female mice, compared to sex-matched WT littermates. In addition, female Dmp1-hWNT16 TG mice displayed significantly higher MS/BS, MAR and BFR/BS compared to the WT mice. Gene expression analysis demonstrated significantly higher mRNA level of Alp in both male and female Dmp1-hWNT16 TG mice and significantly higher levels of Osteocalcin, Opg and Rankl in the male Dmp1-hWNT16 TG mice in bone tissue compared to sex-matched WT mice. These results indicate that WNT16 plays a critical role for acquisition of both cortical and trabecular bone mass and strength. Strategies designed to use WNT16 as a target for therapeutic interventions will be valuable to treat osteoporosis and other low bone mass conditions.

  15. Long-term effect of whole-body X-irradiation on cell-mediated immune reaction in mice

    International Nuclear Information System (INIS)

    Norimura, Toshiyuki; Tsuchiya, Takehiko

    1989-01-01

    Age-related change in immunological activity was examined at 10 to 91 weeks following whole-body irradiation by determining the specific anti-tumor cell-mediated immunity in host mice induced and/or enhanced by local irradiation to transplanted tumor. Median survival time of the non-irradiated C3H/He female mice was 98.6 weeks while the median life-span of the mice exposed to two and four Gy of 250 kVp X-rays at the age of 10-12 weeks was shortened by 14.9 and 23.4 weeks, respectively. The rate of tumor reduction within two weeks after local irradiation to tumor and the growth inhibitory activitiy of spleen cells from tumor irradiated mice were reduced in a dose-dependent manner when assessed 10 weeks after whole-body irradiation, but recovered to the near-complete level of the non-irradiated controls within a few months, then gradually decreased with normal aging. These results suggest that the age-dependent decline of this immunological activity apears earlier in the irradiated mice as a result of whole-body X-irradiation at a young age, suggesting accelerated aging of the immune system. (author)

  16. Increased CRF mRNA expression in the sexually dimorphic BNST of male but not female GAD67 mice and TMT predator odor stress effects upon spatial memory retrieval.

    Science.gov (United States)

    Janitzky, K; Peine, A; Kröber, A; Yanagawa, Y; Schwegler, H; Roskoden, T

    2014-10-01

    The bed nucleus of the stria terminalis (BNST) is an important region for 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) predator odor-induced stress responses in mice. It is sexually dimorphic and a region for corticotropin-releasing factor (CRF)-enhanced stress responses. Dense GABAergic and CRF input from the amygdala to the BNST gives point to relevant interactions between CRF and GABA activity in these brain regions. Hence, to investigate sexual dimorphism of stress-induced neuronal changes, we studied effects of acute TMT exposure on CRF mRNA expression in stress-related brain regions in male and female GAD67 mice and their wild-type littermates. In GAD67 mice, heterozygous knock-in of GFP in GABAergic neurons caused a 50% decrease of GAD67 protein level in the brain [91,99]. Results show higher CRF mRNA levels in the BNST of male but not female GAD67 mice after TMT and control odor exposure. While CRF neurons in the BNST are predominantly GABAergic and CRF enhances GABAergic transmission in the BNST [20,51], the deficit in GABAergic transmission in GAD67 mice could induce a compensatory CRF increase. Sexual dimorphism of the BNST with greater density of GABA-ir neurons in females could explain the differences in CRF mRNA levels between male and female GAD67 mice. Effects of odor exposure were studied in a radial arm maze (RAM) task. Results show impaired retrieval of spatial memory after acute TMT exposure in both sexes and genotypes. However, only GAD67 mice show increased working memory errors after control odor exposure. Our work elicits GAD67 mice as a model to further study interactions of GABA and CRF in the BNST for a better understanding of how sex-specific characteristics of the brain may contribute to differences in anxiety- and stress-related psychological disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. Age-related changes in core body temperature and activity in triple-transgenic Alzheimer's disease (3xTgAD) mice.

    Science.gov (United States)

    Knight, Elysse M; Brown, Timothy M; Gümüsgöz, Sarah; Smith, Jennifer C M; Waters, Elizabeth J; Allan, Stuart M; Lawrence, Catherine B

    2013-01-01

    Alzheimer's disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4-10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.

  18. Role of macrophages in age-related oxidative stress and lipofuscin accumulation in mice.

    Science.gov (United States)

    Vida, Carmen; de Toda, Irene Martínez; Cruces, Julia; Garrido, Antonio; Gonzalez-Sanchez, Mónica; De la Fuente, Mónica

    2017-08-01

    The age-related changes in the immune functions (immunosenescence) may be mediated by an increase of oxidative stress and damage affecting leukocytes. Although the "oxidation-inflammation" theory of aging proposes that phagocytes are the main immune cells contributing to "oxi-inflamm-aging", this idea has not been corroborated. The aim of this work was to characterize the age-related changes in several parameters of oxidative stress and immune function, as well as in lipofuscin accumulation ("a hallmark of aging"), in both total peritoneal leukocyte population and isolated peritoneal macrophages. Adult, mature, old and long-lived mice (7, 13, 18 and 30 months of age, respectively) were used. The xanthine oxidase (XO) activity-expression, basal levels of superoxide anion and ROS, catalase activity, oxidized (GSSG) and reduced (GSH) glutathione content and lipofuscin levels, as well as both phagocytosis and digestion capacity were evaluated. The results showed an age-related increase of oxidative stress and lipofuscin accumulation in murine peritoneal leukocytes, but especially in macrophages. Macrophages from old mice showed lower antioxidant defenses (catalase activity and GSH levels), higher oxidizing compounds (XO activity/expression and superoxide, ROS and GSSG levels) and lipofuscin levels, together with an impaired macrophage functions, in comparison to adults. In contrast, long-lived mice showed in their peritoneal leukocytes, and especially in macrophages, a well-preserved redox state and maintenance of their immune functions, all which could account for their high longevity. Interestingly, macrophages showed higher XO activity and lipofuscin accumulation than lymphocytes in all the ages analyzed. Our results support that macrophages play a central role in the chronic oxidative stress associated with aging, and the fact that phagocytes are key cells contributing to immunosenescence and "oxi-inflamm-aging". Moreover, the determination of oxidative stress and

  19. Effect of Cistanche Desertica Polysaccharides on Learning and Memory Functions and Ultrastructure of Cerebral Neurons in Experimental Aging Mice

    Institute of Scientific and Technical Information of China (English)

    孙云; 邓杨梅; 王德俊; 沈春锋; 刘晓梅; 张洪泉

    2001-01-01

    To observe the effects of Cistanche desertica polysaccharides (CDP) on the learning and memory functions and cerebral ultrastructure in experimental aging mice. Methods: CDP was administrated intragastrically 50 or 100 mg/kg per day for 64 successive days to experimental aging model mice induced by D-galactose, then the learning and memory functions of mice were estimated by step-down test and Y-maze test; organelles of brain tissue and cerebral ultrastructure were observed by transmission electron microscope and physical strength was determined by swimming test. Results: CDP could obviously enhance the learning and memory functions (P<0.01) and prolong the swimming time (P<0.05), decrease the number of lipofuscin and slow down the degeneration of mitochondria in neurons(P<0.05), and improve the degeneration of cerebral ultra-structure in aging mice. Conclusion: CDP could improve the impaired physiological function and alleviate cerebral morphological change in experimental aging mice.

  20. Digital Gene Expression Profiling Analysis of Aged Mice under Moxibustion Treatment

    Directory of Open Access Journals (Sweden)

    Nan Liu

    2018-01-01

    Full Text Available Aging is closely connected with death, progressive physiological decline, and increased risk of diseases, such as cancer, arteriosclerosis, heart disease, hypertension, and neurodegenerative diseases. It is reported that moxibustion can treat more than 300 kinds of diseases including aging related problems and can improve immune function and physiological functions. The digital gene expression profiling of aged mice with or without moxibustion treatment was investigated and the mechanisms of moxibustion in aged mice were speculated by gene ontology and pathway analysis in the study. Almost 145 million raw reads were obtained by digital gene expression analysis and about 140 million (96.55% were clean reads. Five differentially expressed genes with an adjusted P value 1 were identified between the control and moxibustion groups. They were Gm6563, Gm8116, Rps26-ps1, Nat8f4, and Igkv3-12. Gene ontology analysis was carried out by the GOseq R package and functional annotations of the differentially expressed genes related to translation, mRNA export from nucleus, mRNA transport, nuclear body, acetyltransferase activity, and so on. Kyoto Encyclopedia of Genes and Genomes database was used for pathway analysis and ribosome was the most significantly enriched pathway term.